Original Research

Veterans’ access to medical care was expanded outside of US Department of Veterans Affairs (VA) facilities with the inception of the 2014 Veterans Access, Choice, and Accountability Act (Choice Act).¹ This legislation aimed to remove barriers some veterans were experiencing, specifically access to health care. In subsequent years, approximately 17% of veterans receiving care from the VA did so under the Choice Act.² The Choice Act positively impacted medical care access for veterans but presented new challenges for VA pharmacies processing community care (CC) prescriptions, including limited access to outside health records, lack of interface between CC prescribers and the VA order entry system, and limited awareness of the VA national formulary.^3,4 These factors made it difficult for VA pharmacies to assess prescriptions for clinical appropriateness, evaluate patient safety parameters, and manage expenditures.

In 2019, the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act, which expanded CC support and better defined which veterans are able to receive care outside the VA, updated the Choice Act.^4,5 However, VA pharmacies faced challenges in managing pharmacy drug costs and ensuring clinical appropriateness of prescription drug therapy. As a result, VA pharmacy departments have adjusted how they allocate workload, time, and funds.⁵

Pharmacists improve clinical outcomes and reduce health care costs by decreasing medication errors, unnecessary prescribing, and adverse drug events.^6-12 Pharmacist-driven formulary management through evaluation of prior authorization drug requests (PADRs) has shown economic value.^13,14 VA pharmacy review of community care PADRs is important because outside health care professionals (HCPs) might not be familiar with the VA formulary. This could lead to high volume of PADRs that do not meet criteria and could result in increased potential for medication misuse, adverse drug events, medication errors, and cost to the health system. It is imperative that CC orders are evaluated as critically as traditional orders.

The value of a centralized CC pharmacy team has not been assessed in the literature. The primary objective of this study was to assess the direct cost savings achieved through a centralized CC PADR process. Secondary objectives were to characterize the CC PADRs submitted to the site, including approval rate, reason for nonapproval, which medications were requested and by whom, and to compare CC prescriptions with other high-complexity (1a) VA facilities.

Community Care Pharmacy

VA health systems are stratified according to complexity, which reflects size, patient population, and services offered. This study was conducted at the Durham Veterans Affairs Health Care System (DVAHCS), North Carolina, a high-complexity, 251-bed, tertiary care referral, teaching, and research system. DVAHCS provides general and specialty medical, surgical, inpatient psychiatric, and ambulatory services, and serves as a major referral center.

DVAHCS created a centralized pharmacy team for processing CC prescriptions and managing customer service. This team’s goal is to increase CC prescription processing efficiency and transparency, ensure accountability of the health care team, and promote veteran-centric customer service. The pharmacy team includes a pharmacist program manager and a dedicated CC pharmacist with administrative support from a health benefits assistant and 4 pharmacy technicians. The CC pharmacy team assesses every new prescription to ensure the veteran is authorized to receive care in the community. Once eligibility is verified, a pharmacy technician or pharmacist evaluates the prescription to ensure it contains all required information, then contacts the prescriber for any missing data. If clinically appropriate, the pharmacist processes the prescription.

In 2020, the CC pharmacy team implemented a new process for reviewing and documenting CC prescriptions that require a PADR. The closed national VA formulary is set up so that all nonformulary medications and some formulary medications, including those that are restricted because of safety and/or cost, require a PADR.¹⁵ After a CC pharmacy technician confirms a veteran’s eligibility, the technician assesses whether the requested medication requires submitting a PADR to the VA internal electronic health record. The PADR is then adjudicated by a formulary management pharmacist, CC program manager, or CC pharmacist who reviews health records to determine whether the CC prescription meets VA medication use policy requirements.

If additional information is needed or an alternate medication is suggested, the pharmacist comments back on the PADR and a CC pharmacy technician contacts the prescriber. The PADR is canceled administratively then resubmitted once all information is obtained. While waiting for a response from the prescriber, the CC pharmacy technician contacts that veteran to give an update on the prescription status, as appropriate. Once there is sufficient information to adjudicate the PADR, the outcome is documented, and if approved, the order is processed.

Methods

The DVAHCS Institutional Review Board approved this retrospective review of CC PADRs submitted from June 1, 2020, through November 30, 2020. CC PADRs were excluded if they were duplicates or were reactivated administratively but had an initial submission date before the study period. Local data were collected for nonapproved CC PADRs including drug requested, dosage and directions, medication specialty, alternative drug recommended, drug acquisition cost, PADR submission date, PADR completion date, PADR nonapproval rationale, and documented time spent per PADR. Additional data was obtained for CC prescriptions at all 42 high-complexity VA facilities from the VA national CC prescription database for the study time interval and included total PADRs, PADR approval status, total CC prescription cost, and total CC fills.

 

Direct cost savings were calculated by assessing the cost of requested therapy that was not approved minus the cost of recommended therapy and cost to review all PADRs, as described by Britt and colleagues.¹³ The cost of the requested and recommended therapy was calculated based on VA drug acquisition cost at time of data collection and multiplied by the expected duration of therapy up to 1 year. For each CC prescription, duration of therapy was based on the duration limit in the prescription or annualized if no duration limit was documented. Cost of PADR review was calculated based on the total time pharmacists and pharmacy technicians documented for each step of the review process for a representative sample of 100 nonapproved PADRs and then multiplied by the salary plus benefits of an entry-level pharmacist and pharmacy technician.¹⁶ The eAppendix  describes specific equations used for determining direct cost savings. Descriptive statistics were used to evaluate study results.

Results

During the 6-month study period, 611 CC PADRs were submitted to the pharmacy and 526 met inclusion criteria (Figure 1). Of those, 243 (46.2%) were approved and 283 (53.8%) were not approved. The cost of requested therapies for nonapproved CC PADRs totaled $584,565.48 and the cost of all recommended therapies was $57,473.59. The mean time per CC PADR was 24 minutes; 16 minutes for pharmacists and 8 minutes for pharmacy technicians. Given an hourly wage (plus benefits) of $67.25 for a pharmacist and $25.53 for a pharmacy technician, the total cost of review per CC PADR was $21.33. After subtracting the costs of all recommended therapies and review of all included CC PADRs, the process generated $515,872.31 in direct cost savings. After factoring in administrative lag time, such as HCP communication, an average of 8 calendar days was needed to complete a nonapproved PADR.

The most common rationale for PADR nonapproval was that the formulary alternative was not exhausted. Ondansetron orally disintegrating tablets was the most commonly nonapproved medication and azelastine was the most commonly approved medication. Dulaglutide was the most expensive nonapproved and tafamidis was the most expensive approved PADR (Table 1). Gastroenterology, endocrinology, and neurology were the top specialties for nonapproved PADRs while neurology, pulmonology, and endocrinology were the top specialties for approved PADRs (Table 2).

Several high-complexity VA facilities had no reported data; we used the median for the analysis to account for these outliers (Figure 2). The median (IQR) adjudicated CC PADRs for all facilities was 97 (20-175), median (IQR) CC PADR approval rate was 80.9% (63.7%-96.8%), median (IQR) total CC prescriptions was 8440 (2464-14,466), and median (IQR) cost per fill was $136.05 ($76.27-$221.28).

Discussion

This study demonstrated direct cost savings of $515,872.31 over 6 months with theadjudication of CC PADRs by a centralized CC pharmacy team. This could result in > $1,000,000 of cost savings per fiscal year.

The CC PADRs observed at DVAHCS had a 46.2% approval rate; almost one-half the approval rate of 84.1% of all PADRs submitted to the study site by VA HCPs captured by Britt and colleagues.¹³ Results from this study showed that coordination of care for nonapproved CC PADRs between the VA pharmacy and non-VA prescriber took an average of 8 calendar days. The noted CC PADR approval rate and administrative burden might be because of lack of familiarity of non-VA providers regarding the VA national formulary. The National VA Pharmacy Benefits Management determines the formulary using cost-effectiveness criteria that considers the medical literature and VA-specific contract pricing and prepares extensive guidance for restricted medications via relevant criteria for use.¹⁵ HCPs outside the VA might not know this information is available online. Because gastroenterology, endocrinology, and neurology specialty medications were among the most frequently nonapproved PADRs, VA formulary education could begin with CC HCPs in these practice areas.

This study showed that the CC PADR process was not solely driven by cost, but also included patient safety. Nonapproval rationale for some requests included submission without an indication, submission by a prescriber that did not have the authority to prescribe a type of medication, or contraindication based on patient-specific factors.

 

Compared with other VA high-complexity facilities, DVAHCS was among the top health care systems for total volume of CC prescriptions (n = 16,096) and among the lowest for cost/fill ($75.74). Similarly, DVAHCS was among the top sites for total adjudicated CC PADRs within the 6-month study period (n = 611) and the lowest approval rate (44.2%). This study shows that despite high volumes of overall CC prescriptions and CC PADRs, it is possible to maintain a low overall CC prescription cost/fill compared with other similarly complex sites across the country. Wide variance in reported results exists across high-complexity VA facilities because some sites had low to no CC fills and/or CC PADRs. This is likely a result of administrative differences when handling CC prescriptions and presents an opportunity to standardize this process nationally.

Limitations

CC PADRs were assessed during the COVID-19 pandemic, which might have resulted in lower-than-normal CC prescription and PADR volumes, therefore underestimating the potential for direct cost savings. Entry-level salary was used to demonstrate cost savings potential from the perspective of a newly hired CC team; however, the cost savings might have been less if the actual salaries of site personnel were higher. National contract pricing data were gathered at the time of data collection and might have been different than at the time of PADR submission. Chronic medication prescriptions were annualized, which could overestimate cost savings if the medication was discontinued or changed to an alternative therapy within that time period.

The study’s exclusion criteria could only be applied locally and did not include data received from the VA CC prescription database. This can be seen by the discrepancy in CC PADR approval rates from the local and national data (46.2% vs 44.2%, respectively) and CC PADR volume. High-complexity VA facility data were captured without assessing the CC prescription process at each site. As a result, definitive conclusions cannot be made regarding the impact of a centralized CC pharmacy team compared with other facilities.

Conclusions

Adjudication of CC PADRs by a centralized CC pharmacy team over a 6-month period provided > $500,000 in direct cost savings to a VA health care system. Considering the CC PADR approval rate seen in this study, the VA could allocate resources to educate CC providers about the VA formulary to increase the PADR approval rate and reduce administrative burden for VA pharmacies and prescribers. Future research should evaluate CC prescription handling practices at other VA facilities to compare the effectiveness among varying approaches and develop recommendations for a nationally standardized process.

Acknowledgments

Concept and design (AJJ, JNB, RBB, LAM, MD, MGH); acquisition of data (AJJ, MGH); analysis and interpretation of data (AJJ, JNB, RBB, LAM, MD, MGH); drafting of the manuscript (AJJ); critical revision of the manuscript for important intellectual content (AJJ, JNB, RBB, LAM, MD, MGH); statistical analysis (AJJ); administrative, technical, or logistic support (LAM, MGH); and supervision (MGH).

Veterans’ access to medical care was expanded outside of US Department of Veterans Affairs (VA) facilities with the inception of the 2014 Veterans Access, Choice, and Accountability Act (Choice Act).¹ This legislation aimed to remove barriers some veterans were experiencing, specifically access to health care. In subsequent years, approximately 17% of veterans receiving care from the VA did so under the Choice Act.² The Choice Act positively impacted medical care access for veterans but presented new challenges for VA pharmacies processing community care (CC) prescriptions, including limited access to outside health records, lack of interface between CC prescribers and the VA order entry system, and limited awareness of the VA national formulary.^3,4 These factors made it difficult for VA pharmacies to assess prescriptions for clinical appropriateness, evaluate patient safety parameters, and manage expenditures.

In 2019, the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act, which expanded CC support and better defined which veterans are able to receive care outside the VA, updated the Choice Act.^4,5 However, VA pharmacies faced challenges in managing pharmacy drug costs and ensuring clinical appropriateness of prescription drug therapy. As a result, VA pharmacy departments have adjusted how they allocate workload, time, and funds.⁵

Pharmacists improve clinical outcomes and reduce health care costs by decreasing medication errors, unnecessary prescribing, and adverse drug events.^6-12 Pharmacist-driven formulary management through evaluation of prior authorization drug requests (PADRs) has shown economic value.^13,14 VA pharmacy review of community care PADRs is important because outside health care professionals (HCPs) might not be familiar with the VA formulary. This could lead to high volume of PADRs that do not meet criteria and could result in increased potential for medication misuse, adverse drug events, medication errors, and cost to the health system. It is imperative that CC orders are evaluated as critically as traditional orders.

The value of a centralized CC pharmacy team has not been assessed in the literature. The primary objective of this study was to assess the direct cost savings achieved through a centralized CC PADR process. Secondary objectives were to characterize the CC PADRs submitted to the site, including approval rate, reason for nonapproval, which medications were requested and by whom, and to compare CC prescriptions with other high-complexity (1a) VA facilities.

Community Care Pharmacy

VA health systems are stratified according to complexity, which reflects size, patient population, and services offered. This study was conducted at the Durham Veterans Affairs Health Care System (DVAHCS), North Carolina, a high-complexity, 251-bed, tertiary care referral, teaching, and research system. DVAHCS provides general and specialty medical, surgical, inpatient psychiatric, and ambulatory services, and serves as a major referral center.

DVAHCS created a centralized pharmacy team for processing CC prescriptions and managing customer service. This team’s goal is to increase CC prescription processing efficiency and transparency, ensure accountability of the health care team, and promote veteran-centric customer service. The pharmacy team includes a pharmacist program manager and a dedicated CC pharmacist with administrative support from a health benefits assistant and 4 pharmacy technicians. The CC pharmacy team assesses every new prescription to ensure the veteran is authorized to receive care in the community. Once eligibility is verified, a pharmacy technician or pharmacist evaluates the prescription to ensure it contains all required information, then contacts the prescriber for any missing data. If clinically appropriate, the pharmacist processes the prescription.

In 2020, the CC pharmacy team implemented a new process for reviewing and documenting CC prescriptions that require a PADR. The closed national VA formulary is set up so that all nonformulary medications and some formulary medications, including those that are restricted because of safety and/or cost, require a PADR.¹⁵ After a CC pharmacy technician confirms a veteran’s eligibility, the technician assesses whether the requested medication requires submitting a PADR to the VA internal electronic health record. The PADR is then adjudicated by a formulary management pharmacist, CC program manager, or CC pharmacist who reviews health records to determine whether the CC prescription meets VA medication use policy requirements.

If additional information is needed or an alternate medication is suggested, the pharmacist comments back on the PADR and a CC pharmacy technician contacts the prescriber. The PADR is canceled administratively then resubmitted once all information is obtained. While waiting for a response from the prescriber, the CC pharmacy technician contacts that veteran to give an update on the prescription status, as appropriate. Once there is sufficient information to adjudicate the PADR, the outcome is documented, and if approved, the order is processed.

Methods

The DVAHCS Institutional Review Board approved this retrospective review of CC PADRs submitted from June 1, 2020, through November 30, 2020. CC PADRs were excluded if they were duplicates or were reactivated administratively but had an initial submission date before the study period. Local data were collected for nonapproved CC PADRs including drug requested, dosage and directions, medication specialty, alternative drug recommended, drug acquisition cost, PADR submission date, PADR completion date, PADR nonapproval rationale, and documented time spent per PADR. Additional data was obtained for CC prescriptions at all 42 high-complexity VA facilities from the VA national CC prescription database for the study time interval and included total PADRs, PADR approval status, total CC prescription cost, and total CC fills.

 

Direct cost savings were calculated by assessing the cost of requested therapy that was not approved minus the cost of recommended therapy and cost to review all PADRs, as described by Britt and colleagues.¹³ The cost of the requested and recommended therapy was calculated based on VA drug acquisition cost at time of data collection and multiplied by the expected duration of therapy up to 1 year. For each CC prescription, duration of therapy was based on the duration limit in the prescription or annualized if no duration limit was documented. Cost of PADR review was calculated based on the total time pharmacists and pharmacy technicians documented for each step of the review process for a representative sample of 100 nonapproved PADRs and then multiplied by the salary plus benefits of an entry-level pharmacist and pharmacy technician.¹⁶ The eAppendix  describes specific equations used for determining direct cost savings. Descriptive statistics were used to evaluate study results.

Results

During the 6-month study period, 611 CC PADRs were submitted to the pharmacy and 526 met inclusion criteria (Figure 1). Of those, 243 (46.2%) were approved and 283 (53.8%) were not approved. The cost of requested therapies for nonapproved CC PADRs totaled $584,565.48 and the cost of all recommended therapies was $57,473.59. The mean time per CC PADR was 24 minutes; 16 minutes for pharmacists and 8 minutes for pharmacy technicians. Given an hourly wage (plus benefits) of $67.25 for a pharmacist and $25.53 for a pharmacy technician, the total cost of review per CC PADR was $21.33. After subtracting the costs of all recommended therapies and review of all included CC PADRs, the process generated $515,872.31 in direct cost savings. After factoring in administrative lag time, such as HCP communication, an average of 8 calendar days was needed to complete a nonapproved PADR.

The most common rationale for PADR nonapproval was that the formulary alternative was not exhausted. Ondansetron orally disintegrating tablets was the most commonly nonapproved medication and azelastine was the most commonly approved medication. Dulaglutide was the most expensive nonapproved and tafamidis was the most expensive approved PADR (Table 1). Gastroenterology, endocrinology, and neurology were the top specialties for nonapproved PADRs while neurology, pulmonology, and endocrinology were the top specialties for approved PADRs (Table 2).

Several high-complexity VA facilities had no reported data; we used the median for the analysis to account for these outliers (Figure 2). The median (IQR) adjudicated CC PADRs for all facilities was 97 (20-175), median (IQR) CC PADR approval rate was 80.9% (63.7%-96.8%), median (IQR) total CC prescriptions was 8440 (2464-14,466), and median (IQR) cost per fill was $136.05 ($76.27-$221.28).

Discussion

This study demonstrated direct cost savings of $515,872.31 over 6 months with theadjudication of CC PADRs by a centralized CC pharmacy team. This could result in > $1,000,000 of cost savings per fiscal year.

The CC PADRs observed at DVAHCS had a 46.2% approval rate; almost one-half the approval rate of 84.1% of all PADRs submitted to the study site by VA HCPs captured by Britt and colleagues.¹³ Results from this study showed that coordination of care for nonapproved CC PADRs between the VA pharmacy and non-VA prescriber took an average of 8 calendar days. The noted CC PADR approval rate and administrative burden might be because of lack of familiarity of non-VA providers regarding the VA national formulary. The National VA Pharmacy Benefits Management determines the formulary using cost-effectiveness criteria that considers the medical literature and VA-specific contract pricing and prepares extensive guidance for restricted medications via relevant criteria for use.¹⁵ HCPs outside the VA might not know this information is available online. Because gastroenterology, endocrinology, and neurology specialty medications were among the most frequently nonapproved PADRs, VA formulary education could begin with CC HCPs in these practice areas.

This study showed that the CC PADR process was not solely driven by cost, but also included patient safety. Nonapproval rationale for some requests included submission without an indication, submission by a prescriber that did not have the authority to prescribe a type of medication, or contraindication based on patient-specific factors.

 

Compared with other VA high-complexity facilities, DVAHCS was among the top health care systems for total volume of CC prescriptions (n = 16,096) and among the lowest for cost/fill ($75.74). Similarly, DVAHCS was among the top sites for total adjudicated CC PADRs within the 6-month study period (n = 611) and the lowest approval rate (44.2%). This study shows that despite high volumes of overall CC prescriptions and CC PADRs, it is possible to maintain a low overall CC prescription cost/fill compared with other similarly complex sites across the country. Wide variance in reported results exists across high-complexity VA facilities because some sites had low to no CC fills and/or CC PADRs. This is likely a result of administrative differences when handling CC prescriptions and presents an opportunity to standardize this process nationally.

Limitations

CC PADRs were assessed during the COVID-19 pandemic, which might have resulted in lower-than-normal CC prescription and PADR volumes, therefore underestimating the potential for direct cost savings. Entry-level salary was used to demonstrate cost savings potential from the perspective of a newly hired CC team; however, the cost savings might have been less if the actual salaries of site personnel were higher. National contract pricing data were gathered at the time of data collection and might have been different than at the time of PADR submission. Chronic medication prescriptions were annualized, which could overestimate cost savings if the medication was discontinued or changed to an alternative therapy within that time period.

The study’s exclusion criteria could only be applied locally and did not include data received from the VA CC prescription database. This can be seen by the discrepancy in CC PADR approval rates from the local and national data (46.2% vs 44.2%, respectively) and CC PADR volume. High-complexity VA facility data were captured without assessing the CC prescription process at each site. As a result, definitive conclusions cannot be made regarding the impact of a centralized CC pharmacy team compared with other facilities.

Conclusions

Adjudication of CC PADRs by a centralized CC pharmacy team over a 6-month period provided > $500,000 in direct cost savings to a VA health care system. Considering the CC PADR approval rate seen in this study, the VA could allocate resources to educate CC providers about the VA formulary to increase the PADR approval rate and reduce administrative burden for VA pharmacies and prescribers. Future research should evaluate CC prescription handling practices at other VA facilities to compare the effectiveness among varying approaches and develop recommendations for a nationally standardized process.

Acknowledgments

Concept and design (AJJ, JNB, RBB, LAM, MD, MGH); acquisition of data (AJJ, MGH); analysis and interpretation of data (AJJ, JNB, RBB, LAM, MD, MGH); drafting of the manuscript (AJJ); critical revision of the manuscript for important intellectual content (AJJ, JNB, RBB, LAM, MD, MGH); statistical analysis (AJJ); administrative, technical, or logistic support (LAM, MGH); and supervision (MGH).

Veterans’ access to medical care was expanded outside of US Department of Veterans Affairs (VA) facilities with the inception of the 2014 Veterans Access, Choice, and Accountability Act (Choice Act).¹ This legislation aimed to remove barriers some veterans were experiencing, specifically access to health care. In subsequent years, approximately 17% of veterans receiving care from the VA did so under the Choice Act.² The Choice Act positively impacted medical care access for veterans but presented new challenges for VA pharmacies processing community care (CC) prescriptions, including limited access to outside health records, lack of interface between CC prescribers and the VA order entry system, and limited awareness of the VA national formulary.^3,4 These factors made it difficult for VA pharmacies to assess prescriptions for clinical appropriateness, evaluate patient safety parameters, and manage expenditures.

In 2019, the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act, which expanded CC support and better defined which veterans are able to receive care outside the VA, updated the Choice Act.^4,5 However, VA pharmacies faced challenges in managing pharmacy drug costs and ensuring clinical appropriateness of prescription drug therapy. As a result, VA pharmacy departments have adjusted how they allocate workload, time, and funds.⁵

Pharmacists improve clinical outcomes and reduce health care costs by decreasing medication errors, unnecessary prescribing, and adverse drug events.^6-12 Pharmacist-driven formulary management through evaluation of prior authorization drug requests (PADRs) has shown economic value.^13,14 VA pharmacy review of community care PADRs is important because outside health care professionals (HCPs) might not be familiar with the VA formulary. This could lead to high volume of PADRs that do not meet criteria and could result in increased potential for medication misuse, adverse drug events, medication errors, and cost to the health system. It is imperative that CC orders are evaluated as critically as traditional orders.

The value of a centralized CC pharmacy team has not been assessed in the literature. The primary objective of this study was to assess the direct cost savings achieved through a centralized CC PADR process. Secondary objectives were to characterize the CC PADRs submitted to the site, including approval rate, reason for nonapproval, which medications were requested and by whom, and to compare CC prescriptions with other high-complexity (1a) VA facilities.

Community Care Pharmacy

VA health systems are stratified according to complexity, which reflects size, patient population, and services offered. This study was conducted at the Durham Veterans Affairs Health Care System (DVAHCS), North Carolina, a high-complexity, 251-bed, tertiary care referral, teaching, and research system. DVAHCS provides general and specialty medical, surgical, inpatient psychiatric, and ambulatory services, and serves as a major referral center.

DVAHCS created a centralized pharmacy team for processing CC prescriptions and managing customer service. This team’s goal is to increase CC prescription processing efficiency and transparency, ensure accountability of the health care team, and promote veteran-centric customer service. The pharmacy team includes a pharmacist program manager and a dedicated CC pharmacist with administrative support from a health benefits assistant and 4 pharmacy technicians. The CC pharmacy team assesses every new prescription to ensure the veteran is authorized to receive care in the community. Once eligibility is verified, a pharmacy technician or pharmacist evaluates the prescription to ensure it contains all required information, then contacts the prescriber for any missing data. If clinically appropriate, the pharmacist processes the prescription.

In 2020, the CC pharmacy team implemented a new process for reviewing and documenting CC prescriptions that require a PADR. The closed national VA formulary is set up so that all nonformulary medications and some formulary medications, including those that are restricted because of safety and/or cost, require a PADR.¹⁵ After a CC pharmacy technician confirms a veteran’s eligibility, the technician assesses whether the requested medication requires submitting a PADR to the VA internal electronic health record. The PADR is then adjudicated by a formulary management pharmacist, CC program manager, or CC pharmacist who reviews health records to determine whether the CC prescription meets VA medication use policy requirements.

If additional information is needed or an alternate medication is suggested, the pharmacist comments back on the PADR and a CC pharmacy technician contacts the prescriber. The PADR is canceled administratively then resubmitted once all information is obtained. While waiting for a response from the prescriber, the CC pharmacy technician contacts that veteran to give an update on the prescription status, as appropriate. Once there is sufficient information to adjudicate the PADR, the outcome is documented, and if approved, the order is processed.

Methods

The DVAHCS Institutional Review Board approved this retrospective review of CC PADRs submitted from June 1, 2020, through November 30, 2020. CC PADRs were excluded if they were duplicates or were reactivated administratively but had an initial submission date before the study period. Local data were collected for nonapproved CC PADRs including drug requested, dosage and directions, medication specialty, alternative drug recommended, drug acquisition cost, PADR submission date, PADR completion date, PADR nonapproval rationale, and documented time spent per PADR. Additional data was obtained for CC prescriptions at all 42 high-complexity VA facilities from the VA national CC prescription database for the study time interval and included total PADRs, PADR approval status, total CC prescription cost, and total CC fills.

 

Direct cost savings were calculated by assessing the cost of requested therapy that was not approved minus the cost of recommended therapy and cost to review all PADRs, as described by Britt and colleagues.¹³ The cost of the requested and recommended therapy was calculated based on VA drug acquisition cost at time of data collection and multiplied by the expected duration of therapy up to 1 year. For each CC prescription, duration of therapy was based on the duration limit in the prescription or annualized if no duration limit was documented. Cost of PADR review was calculated based on the total time pharmacists and pharmacy technicians documented for each step of the review process for a representative sample of 100 nonapproved PADRs and then multiplied by the salary plus benefits of an entry-level pharmacist and pharmacy technician.¹⁶ The eAppendix  describes specific equations used for determining direct cost savings. Descriptive statistics were used to evaluate study results.

Results

During the 6-month study period, 611 CC PADRs were submitted to the pharmacy and 526 met inclusion criteria (Figure 1). Of those, 243 (46.2%) were approved and 283 (53.8%) were not approved. The cost of requested therapies for nonapproved CC PADRs totaled $584,565.48 and the cost of all recommended therapies was $57,473.59. The mean time per CC PADR was 24 minutes; 16 minutes for pharmacists and 8 minutes for pharmacy technicians. Given an hourly wage (plus benefits) of $67.25 for a pharmacist and $25.53 for a pharmacy technician, the total cost of review per CC PADR was $21.33. After subtracting the costs of all recommended therapies and review of all included CC PADRs, the process generated $515,872.31 in direct cost savings. After factoring in administrative lag time, such as HCP communication, an average of 8 calendar days was needed to complete a nonapproved PADR.

The most common rationale for PADR nonapproval was that the formulary alternative was not exhausted. Ondansetron orally disintegrating tablets was the most commonly nonapproved medication and azelastine was the most commonly approved medication. Dulaglutide was the most expensive nonapproved and tafamidis was the most expensive approved PADR (Table 1). Gastroenterology, endocrinology, and neurology were the top specialties for nonapproved PADRs while neurology, pulmonology, and endocrinology were the top specialties for approved PADRs (Table 2).

Several high-complexity VA facilities had no reported data; we used the median for the analysis to account for these outliers (Figure 2). The median (IQR) adjudicated CC PADRs for all facilities was 97 (20-175), median (IQR) CC PADR approval rate was 80.9% (63.7%-96.8%), median (IQR) total CC prescriptions was 8440 (2464-14,466), and median (IQR) cost per fill was $136.05 ($76.27-$221.28).

Discussion

This study demonstrated direct cost savings of $515,872.31 over 6 months with theadjudication of CC PADRs by a centralized CC pharmacy team. This could result in > $1,000,000 of cost savings per fiscal year.

The CC PADRs observed at DVAHCS had a 46.2% approval rate; almost one-half the approval rate of 84.1% of all PADRs submitted to the study site by VA HCPs captured by Britt and colleagues.¹³ Results from this study showed that coordination of care for nonapproved CC PADRs between the VA pharmacy and non-VA prescriber took an average of 8 calendar days. The noted CC PADR approval rate and administrative burden might be because of lack of familiarity of non-VA providers regarding the VA national formulary. The National VA Pharmacy Benefits Management determines the formulary using cost-effectiveness criteria that considers the medical literature and VA-specific contract pricing and prepares extensive guidance for restricted medications via relevant criteria for use.¹⁵ HCPs outside the VA might not know this information is available online. Because gastroenterology, endocrinology, and neurology specialty medications were among the most frequently nonapproved PADRs, VA formulary education could begin with CC HCPs in these practice areas.

This study showed that the CC PADR process was not solely driven by cost, but also included patient safety. Nonapproval rationale for some requests included submission without an indication, submission by a prescriber that did not have the authority to prescribe a type of medication, or contraindication based on patient-specific factors.

 

Compared with other VA high-complexity facilities, DVAHCS was among the top health care systems for total volume of CC prescriptions (n = 16,096) and among the lowest for cost/fill ($75.74). Similarly, DVAHCS was among the top sites for total adjudicated CC PADRs within the 6-month study period (n = 611) and the lowest approval rate (44.2%). This study shows that despite high volumes of overall CC prescriptions and CC PADRs, it is possible to maintain a low overall CC prescription cost/fill compared with other similarly complex sites across the country. Wide variance in reported results exists across high-complexity VA facilities because some sites had low to no CC fills and/or CC PADRs. This is likely a result of administrative differences when handling CC prescriptions and presents an opportunity to standardize this process nationally.

Limitations

CC PADRs were assessed during the COVID-19 pandemic, which might have resulted in lower-than-normal CC prescription and PADR volumes, therefore underestimating the potential for direct cost savings. Entry-level salary was used to demonstrate cost savings potential from the perspective of a newly hired CC team; however, the cost savings might have been less if the actual salaries of site personnel were higher. National contract pricing data were gathered at the time of data collection and might have been different than at the time of PADR submission. Chronic medication prescriptions were annualized, which could overestimate cost savings if the medication was discontinued or changed to an alternative therapy within that time period.

The study’s exclusion criteria could only be applied locally and did not include data received from the VA CC prescription database. This can be seen by the discrepancy in CC PADR approval rates from the local and national data (46.2% vs 44.2%, respectively) and CC PADR volume. High-complexity VA facility data were captured without assessing the CC prescription process at each site. As a result, definitive conclusions cannot be made regarding the impact of a centralized CC pharmacy team compared with other facilities.

Conclusions

Adjudication of CC PADRs by a centralized CC pharmacy team over a 6-month period provided > $500,000 in direct cost savings to a VA health care system. Considering the CC PADR approval rate seen in this study, the VA could allocate resources to educate CC providers about the VA formulary to increase the PADR approval rate and reduce administrative burden for VA pharmacies and prescribers. Future research should evaluate CC prescription handling practices at other VA facilities to compare the effectiveness among varying approaches and develop recommendations for a nationally standardized process.

Acknowledgments

Concept and design (AJJ, JNB, RBB, LAM, MD, MGH); acquisition of data (AJJ, MGH); analysis and interpretation of data (AJJ, JNB, RBB, LAM, MD, MGH); drafting of the manuscript (AJJ); critical revision of the manuscript for important intellectual content (AJJ, JNB, RBB, LAM, MD, MGH); statistical analysis (AJJ); administrative, technical, or logistic support (LAM, MGH); and supervision (MGH).

Although moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer, its adaptation remains limited in the United States.^1,2 MHRT theoretically exploits α/β ratio differences between the prostate (1.5 Gy), bladder (5-10 Gy), and rectum (3 Gy), thereby reducing late treatment-related adverse effects compared with those of conventional fractionation at biologically equivalent doses.^3-8 Multiple randomized noninferiority trials have demonstrated equivalent outcomes between MHRT and conventional fraction with no appreciable increase in patient-reported toxicity.^9-14 Although these studies have led to the acceptance of MHRT as a standard treatment, the majority of these trials involve individuals with low- and intermediate-risk disease.

There are less phase 3 data addressing MHRT for high-risk prostate cancer (HRPC).^10,12,14-17 Only 2 studies examined predominately high-risk populations, accounting for 83 and 292 patients, respectively.^15,16 Additional phase 3 trials with small proportions of high-risk patients (n = 126, 12%; n = 53, 35%) offer limited additional information regarding clinical outcomes and toxicity rates specific to high-risk disease.^10-12 Numerous phase 1 and 2 studies report various field designs and fractionation plans for MHRT in the context of high-risk disease, although the applicability of these data to off-trial populations remains limited.^18-20

Furthermore, African American individuals are underrepresented in the trials establishing the role of MHRT despite higher rates of prostate cancer incidence, more advanced disease stage at diagnosis, and higher rates of prostate cancer–specific survival (PCSS) when compared with White patients.²¹ Racial disparities across patients with prostate cancer and their management are multifactorial across health care literacy, education level, access to care (including transportation issues), and issues of adherence and distrust.^22-25 Correlation of patient race to prostate cancer outcomes varies greatly across health care systems, with the US Department of Veterans Affairs (VA) equal access system providing robust mental health services and transportation services for some patients, while demonstrating similar rates of stage-adjusted PCSS between African American and White patients across a broad range of treatment modalities.^26-28 Given the paucity of data exploring outcomes following MHRT for African American patients with HRPC, the present analysis provides long-term clinical outcomes and toxicity profiles for an off-trial majority African American population with HRPC treated with MHRT within the VA.

Methods

Records were retrospectively reviewed under an institutional review board–approved protocol for all patients with HRPC treated with definitive MHRT at the Durham Veterans Affairs Healthcare System in North Carolina between November 2008 and August 2018. Exclusion criteria included < 12 months of follow-up or elective nodal irradiation. Demographic variables obtained included age at diagnosis, race, clinical T stage, pre-MHRT prostate-specific antigen (PSA), Gleason grade group at diagnosis, favorable vs unfavorable high-risk disease, pre-MHRT international prostate symptom score (IPSS), and pre-MHRT urinary medication usage (yes/no).²⁹

Concurrent androgen deprivation therapy (ADT) was initiated 6 to 8 weeks before MHRT unless medically contraindicated per the discretion of the treating radiation oncologist. Patients generally received 18 to 24 months of ADT, with those with favorable HRPC (ie, T1c disease with either Gleason 4+4 and PSA < 10 mg/mL or Gleason 3+3 and PSA > 20 ng/mL) receiving 6 months after 2015.²⁹ Patients were simulated supine in either standard or custom immobilization with a full bladder and empty rectum. MHRT fractionation plans included 70 Gy at 2.5 Gy per fraction and 60 Gy at 3 Gy per fraction. Radiotherapy targets included the prostate and seminal vesicles without elective nodal coverage per institutional practice. Treatments were delivered following image guidance, either prostate matching with cone beam computed tomography or fiducial matching with kilo voltage imaging. All patients received intensity-modulated radiotherapy. For plans delivering 70 Gy at 2.5 Gy per fraction, constraints included bladder V (volume receiving) 70 < 10 cc, V65 ≤ 15%, V40 ≤ 35%, rectum V70 < 10 cc, V65 ≤ 10%, V40 ≤ 35%, femoral heads maximum point dose ≤ 40 Gy, penile bulb mean dose ≤ 50 Gy, and small bowel V40 ≤ 1%. For plans delivering 60 Gy at 3 Gy per fraction, constraints included rectum V57 ≤ 15%, V46 ≤ 30%, V37 ≤ 50%, bladder V60 ≤ 5%, V46 ≤ 30%, V37 ≤ 50%, and femoral heads V43 ≤ 5%.

Gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, with acute toxicity defined as on-treatment < 3 months following completion of MHRT. Late toxicity was defined as ≥ 3 months following completion of MHRT. Individuals were seen in follow-up at 6 weeks and 3 months with PSA and testosterone after MHRT completion, then every 6 to 12 months for 5 years and annually thereafter. Each follow-up visit included history, physical examination, IPSS, and CTCAE grading for GI and GU toxicity.

The Wilcoxon rank sum test and χ² test were used to compare differences in demographic data, dosimetric parameters, and frequency of toxicity events with respect to patient race. Clinical endpoints including biochemical recurrence-free survival (BRFS; defined by Phoenix criteria as 2.0 above PSA nadir), distant metastases-free survival (DMFS), PCSS, and overall survival (OS) were estimated from time of radiotherapy completion by the Kaplan-Meier method and compared between African American and White race by log-rank testing.³⁰ Late GI and GU toxicity-free survival were estimated by Kaplan-Meier plots and compared between African American and White patients by the log-rank test. Statistical analysis was performed using SAS 9.4.

 

Results

We identified 143 patients with HRPC treated with definitive MHRT between November 2008 and August 2018 (Table 1). Mean age was 65 years (range, 36-80 years); 57% were African American men. Eighty percent of individuals had unfavorable high-risk disease. Median (IQR) PSA was 14.4 (7.8-28.6). Twenty-six percent had grade group 1-3 disease, 47% had grade group 4 disease, and 27% had grade group 5 disease. African American patients had significantly lower pre-MHRT IPSS scores than White patients (mean IPSS, 11 vs 14, respectively; P = .02) despite similar rates of preradiotherapy urinary medication usage (66% and 66%, respectively).

Eighty-six percent received 70 Gy over 28 fractions, with institutional protocol shifting to 60 Gy over 20 fractions (14%) in June 2017. The median (IQR) duration of radiotherapy was 39 (38-42) days, with 97% of individuals undergoing ADT for a median (IQR) duration of 24 (24-36) months. The median follow-up time was 38 months, with 57 (40%) patients followed for at least 60 months.

Grade 3 GI and GU acute toxicity events were observed in 1% and 4% of all individuals, respectively (Table 2). No acute GI or GU grade 4+ events were observed. No significant differences in acute GU or GI toxicity were observed between African American and White patients.

No significant differences between African American and White patients were observed for late grade 2+ GI (P = .19) or GU (P = .55) toxicity. Late grade 2+ GI toxicity was observed in 17 (12%) patients overall (Figure 1A). One grade 3 and 1 grade 4 late GI event were observed following MHRT completion: The latter involved hospitalization for bleeding secondary to radiation proctitis in the context of cirrhosis predating MHRT. Late grade 2+ GU toxicity was observed in 80 (56%) patients, with late grade 2 events steadily increasing over time (Figure 1B). Nine late grade 3 GU toxicity events were observed at a median of 13 months following completion of MHRT, 2 of which occurred more than 24 months after MHRT completion. No late grade 4 or 5 GU events were observed. IPSS values both before MHRT and at time of last follow-up were available for 65 (40%) patients, with a median (IQR) IPSS of 10 (6-16) before MHRT and 12 (8-16) at last follow-up at a median (IQR) interval of 36 months (26-76) from radiation completion.

No significant differences were observed between African American and White patients with respect to BRFS, DMFS, PCSS, or OS (Figure 2). Overall, 21 of 143 (15%) patients experienced biochemical recurrence: 5-year BRFS was 77% (95% CI, 67%-85%) for all patients, 83% (95% CI, 70%-91%) for African American patients, and 71% (95% CI, 53%-82%) for White patients. Five-year DMFS was 87% (95% CI, 77%-92%) for all individuals, 91% (95% CI, 80%-96%) for African American patients, and 81% (95% CI, 62%-91%) for White patients. Five-year PCSS was 89% (95% CI, 80%-94%) for all patients, with 5-year PCSS rates of 90% (95% CI, 79%-95%) for African American patients and 87% (95% CI, 70%-95%) for White patients. Five-year OS was 75% overall (95% CI, 64%-82%), with 5-year OS rates of 73% (95% CI, 58%-83%) for African American patients and 77% (95% CI, 60%-87%) for White patients. 

Discussion

In this study, we reported acute and late GI and GU toxicity rates as well as clinical outcomes for a majority African American population with predominately unfavorable HRPC treated with MHRT in an equal access health care environment. We found that MHRT was well tolerated with high rates of biochemical control, PCSS, and OS. Additionally, outcomes were not significantly different across patient race. To our knowledge, this is the first report of MHRT for HRPC in a majority African American population.

We found that MHRT was an effective treatment for patients with HRPC, in particular those with unfavorable high-risk disease. While prior prospective and randomized studies have investigated the use of MHRT, our series was larger than most and had a predominately unfavorable high-risk population.^12,15-17 Our biochemical and PCSS rates compare favorably with those of HRPC trial populations, particularly given the high proportion of unfavorable high-risk disease.^12,15,16 Despite similar rates of biochemical control, OS was lower in the present cohort than in HRPC trial populations, even with a younger median age at diagnosis. The similarly high rates of non–HRPC-related death across race may reflect differences in baseline comorbidities compared with trial populations as well as reported differences between individuals in the VA and the private sector.³¹ This suggests that MHRT can be an effective treatment for patients with unfavorable HRPC.

We did not find any differences in outcomes between African American and White individuals with HRPC treated with MHRT. Furthermore, our study demonstrates long-term rates of BRFS and PCSS in a majority African American population with predominately unfavorable HRPC that are comparable with those of prior randomized MHRT studies in high-risk, predominately White populations.^12,15,16 Prior reports have found that African American men with HRPC may be at increased risk for inferior clinical outcomes due to a number of socioeconomic, biologic, and cultural mediators.^26,27,32 Such individuals may disproportionally benefit from shorter treatment courses that improve access to radiotherapy, a well-documented disparity for African American men with localized prostate cancer.^33-36 The VA is an ideal system for studying racial disparities within prostate cancer, as accessibility of mental health and transportation services, income, and insurance status are not barriers to preventative or acute care.³⁷ Our results are concordant with those previously seen for African American patients with prostate cancer seen in the VA, which similarly demonstrate equal outcomes with those of other races.^28,36 Incorporation of the earlier mentioned VA services into oncologic care across other health care systems could better characterize determinants of racial disparities in prostate cancer, including the prognostic significance of shortening treatment duration and number of patient visits via MHRT.

 

Despite widespread acceptance in prostate cancer radiotherapy guidelines, routine use of MHRT seems limited across all stages of localized prostate cancer.^1,2 Late toxicity is a frequently noted concern regarding MHRT use. Higher rates of late grade 2+ GI toxicity were observed in the hypofractionation arm of the HYPRO trial.¹⁷ While RTOG 0415 did not include patients with HRPC, significantly higher rates of physician-reported (but not patient-reported) late grade 2+ GI and GU toxicity were observed using the same MHRT fractionation regimen used for the majority of individuals in our cohort.⁹ In our study, the steady increase in late grade 2 GU toxicity is consistent with what is seen following conventionally fractionated radiotherapy and is likely multifactorial.³⁸ The mean IPSS difference of 2/35 from pre-MHRT baseline to the time of last follow-up suggests minimal quality of life decline. The relatively stable IPSSs over time alongside the > 50% prevalence of late grade 2 GU toxicity per CTCAE grading seems consistent with the discrepancy noted in RTOG 0415 between increased physician-reported late toxicity and favorable patient-reported quality of life scores.⁹ Moreover, significant variance exists in toxicity grading across scoring systems, revised editions of CTCAE, and physician-specific toxicity classification, particularly with regard to the use of adrenergic receptor blocker medications. In light of these factors, the high rate of late grade 2 GU toxicity in our study should be interpreted in the context of largely stable post-MHRT IPSSs and favorable rates of late GI grade 2+ and late GU grade 3+ toxicity.

Limitations

This study has several inherent limitations. While the size of the current HRPC cohort is notably larger than similar populations within the majority of phase 3 MHRT trials, these data derive from a single VA hospital. It is unclear whether these outcomes would be representative in a similar high-risk population receiving care outside of the VA equal access system. Follow-up data beyond 5 years was available for less than half of patients, partially due to nonprostate cancer–related mortality at a higher rate than observed in HRPC trial populations.^12,15,16 Furthermore, all GI toxicity events were exclusively physician reported, and GU toxicity reporting was limited in the off-trial setting with not all patients routinely completing IPSS questionnaires following MHRT completion. However, all patients were treated similarly, and radiation quality was verified over the treatment period with mandated accreditation, frequent standardized output checks, and systematic treatment review.³⁹

Conclusions

Patients with HRPC treated with MHRT in an equal access, off-trial setting demonstrated favorable rates of biochemical control with acceptable rates of acute and late GI and GU toxicities. Clinical outcomes, including biochemical control, were not significantly different between African American and White patients, which may reflect equal access to care within the VA irrespective of income and insurance status. Incorporating VA services, such as access to primary care, mental health services, and transportation across other health care systems may aid in characterizing and mitigating racial and gender disparities in oncologic care.  

Acknowledgments

Portions of this work were presented at the November 2020 ASTRO conference. ⁴⁰

Although moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer, its adaptation remains limited in the United States.^1,2 MHRT theoretically exploits α/β ratio differences between the prostate (1.5 Gy), bladder (5-10 Gy), and rectum (3 Gy), thereby reducing late treatment-related adverse effects compared with those of conventional fractionation at biologically equivalent doses.^3-8 Multiple randomized noninferiority trials have demonstrated equivalent outcomes between MHRT and conventional fraction with no appreciable increase in patient-reported toxicity.^9-14 Although these studies have led to the acceptance of MHRT as a standard treatment, the majority of these trials involve individuals with low- and intermediate-risk disease.

There are less phase 3 data addressing MHRT for high-risk prostate cancer (HRPC).^10,12,14-17 Only 2 studies examined predominately high-risk populations, accounting for 83 and 292 patients, respectively.^15,16 Additional phase 3 trials with small proportions of high-risk patients (n = 126, 12%; n = 53, 35%) offer limited additional information regarding clinical outcomes and toxicity rates specific to high-risk disease.^10-12 Numerous phase 1 and 2 studies report various field designs and fractionation plans for MHRT in the context of high-risk disease, although the applicability of these data to off-trial populations remains limited.^18-20

Furthermore, African American individuals are underrepresented in the trials establishing the role of MHRT despite higher rates of prostate cancer incidence, more advanced disease stage at diagnosis, and higher rates of prostate cancer–specific survival (PCSS) when compared with White patients.²¹ Racial disparities across patients with prostate cancer and their management are multifactorial across health care literacy, education level, access to care (including transportation issues), and issues of adherence and distrust.^22-25 Correlation of patient race to prostate cancer outcomes varies greatly across health care systems, with the US Department of Veterans Affairs (VA) equal access system providing robust mental health services and transportation services for some patients, while demonstrating similar rates of stage-adjusted PCSS between African American and White patients across a broad range of treatment modalities.^26-28 Given the paucity of data exploring outcomes following MHRT for African American patients with HRPC, the present analysis provides long-term clinical outcomes and toxicity profiles for an off-trial majority African American population with HRPC treated with MHRT within the VA.

Methods

Records were retrospectively reviewed under an institutional review board–approved protocol for all patients with HRPC treated with definitive MHRT at the Durham Veterans Affairs Healthcare System in North Carolina between November 2008 and August 2018. Exclusion criteria included < 12 months of follow-up or elective nodal irradiation. Demographic variables obtained included age at diagnosis, race, clinical T stage, pre-MHRT prostate-specific antigen (PSA), Gleason grade group at diagnosis, favorable vs unfavorable high-risk disease, pre-MHRT international prostate symptom score (IPSS), and pre-MHRT urinary medication usage (yes/no).²⁹

Concurrent androgen deprivation therapy (ADT) was initiated 6 to 8 weeks before MHRT unless medically contraindicated per the discretion of the treating radiation oncologist. Patients generally received 18 to 24 months of ADT, with those with favorable HRPC (ie, T1c disease with either Gleason 4+4 and PSA < 10 mg/mL or Gleason 3+3 and PSA > 20 ng/mL) receiving 6 months after 2015.²⁹ Patients were simulated supine in either standard or custom immobilization with a full bladder and empty rectum. MHRT fractionation plans included 70 Gy at 2.5 Gy per fraction and 60 Gy at 3 Gy per fraction. Radiotherapy targets included the prostate and seminal vesicles without elective nodal coverage per institutional practice. Treatments were delivered following image guidance, either prostate matching with cone beam computed tomography or fiducial matching with kilo voltage imaging. All patients received intensity-modulated radiotherapy. For plans delivering 70 Gy at 2.5 Gy per fraction, constraints included bladder V (volume receiving) 70 < 10 cc, V65 ≤ 15%, V40 ≤ 35%, rectum V70 < 10 cc, V65 ≤ 10%, V40 ≤ 35%, femoral heads maximum point dose ≤ 40 Gy, penile bulb mean dose ≤ 50 Gy, and small bowel V40 ≤ 1%. For plans delivering 60 Gy at 3 Gy per fraction, constraints included rectum V57 ≤ 15%, V46 ≤ 30%, V37 ≤ 50%, bladder V60 ≤ 5%, V46 ≤ 30%, V37 ≤ 50%, and femoral heads V43 ≤ 5%.

Gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, with acute toxicity defined as on-treatment < 3 months following completion of MHRT. Late toxicity was defined as ≥ 3 months following completion of MHRT. Individuals were seen in follow-up at 6 weeks and 3 months with PSA and testosterone after MHRT completion, then every 6 to 12 months for 5 years and annually thereafter. Each follow-up visit included history, physical examination, IPSS, and CTCAE grading for GI and GU toxicity.

The Wilcoxon rank sum test and χ² test were used to compare differences in demographic data, dosimetric parameters, and frequency of toxicity events with respect to patient race. Clinical endpoints including biochemical recurrence-free survival (BRFS; defined by Phoenix criteria as 2.0 above PSA nadir), distant metastases-free survival (DMFS), PCSS, and overall survival (OS) were estimated from time of radiotherapy completion by the Kaplan-Meier method and compared between African American and White race by log-rank testing.³⁰ Late GI and GU toxicity-free survival were estimated by Kaplan-Meier plots and compared between African American and White patients by the log-rank test. Statistical analysis was performed using SAS 9.4.

 

Results

We identified 143 patients with HRPC treated with definitive MHRT between November 2008 and August 2018 (Table 1). Mean age was 65 years (range, 36-80 years); 57% were African American men. Eighty percent of individuals had unfavorable high-risk disease. Median (IQR) PSA was 14.4 (7.8-28.6). Twenty-six percent had grade group 1-3 disease, 47% had grade group 4 disease, and 27% had grade group 5 disease. African American patients had significantly lower pre-MHRT IPSS scores than White patients (mean IPSS, 11 vs 14, respectively; P = .02) despite similar rates of preradiotherapy urinary medication usage (66% and 66%, respectively).

Eighty-six percent received 70 Gy over 28 fractions, with institutional protocol shifting to 60 Gy over 20 fractions (14%) in June 2017. The median (IQR) duration of radiotherapy was 39 (38-42) days, with 97% of individuals undergoing ADT for a median (IQR) duration of 24 (24-36) months. The median follow-up time was 38 months, with 57 (40%) patients followed for at least 60 months.

Grade 3 GI and GU acute toxicity events were observed in 1% and 4% of all individuals, respectively (Table 2). No acute GI or GU grade 4+ events were observed. No significant differences in acute GU or GI toxicity were observed between African American and White patients.

No significant differences between African American and White patients were observed for late grade 2+ GI (P = .19) or GU (P = .55) toxicity. Late grade 2+ GI toxicity was observed in 17 (12%) patients overall (Figure 1A). One grade 3 and 1 grade 4 late GI event were observed following MHRT completion: The latter involved hospitalization for bleeding secondary to radiation proctitis in the context of cirrhosis predating MHRT. Late grade 2+ GU toxicity was observed in 80 (56%) patients, with late grade 2 events steadily increasing over time (Figure 1B). Nine late grade 3 GU toxicity events were observed at a median of 13 months following completion of MHRT, 2 of which occurred more than 24 months after MHRT completion. No late grade 4 or 5 GU events were observed. IPSS values both before MHRT and at time of last follow-up were available for 65 (40%) patients, with a median (IQR) IPSS of 10 (6-16) before MHRT and 12 (8-16) at last follow-up at a median (IQR) interval of 36 months (26-76) from radiation completion.

No significant differences were observed between African American and White patients with respect to BRFS, DMFS, PCSS, or OS (Figure 2). Overall, 21 of 143 (15%) patients experienced biochemical recurrence: 5-year BRFS was 77% (95% CI, 67%-85%) for all patients, 83% (95% CI, 70%-91%) for African American patients, and 71% (95% CI, 53%-82%) for White patients. Five-year DMFS was 87% (95% CI, 77%-92%) for all individuals, 91% (95% CI, 80%-96%) for African American patients, and 81% (95% CI, 62%-91%) for White patients. Five-year PCSS was 89% (95% CI, 80%-94%) for all patients, with 5-year PCSS rates of 90% (95% CI, 79%-95%) for African American patients and 87% (95% CI, 70%-95%) for White patients. Five-year OS was 75% overall (95% CI, 64%-82%), with 5-year OS rates of 73% (95% CI, 58%-83%) for African American patients and 77% (95% CI, 60%-87%) for White patients. 

Discussion

In this study, we reported acute and late GI and GU toxicity rates as well as clinical outcomes for a majority African American population with predominately unfavorable HRPC treated with MHRT in an equal access health care environment. We found that MHRT was well tolerated with high rates of biochemical control, PCSS, and OS. Additionally, outcomes were not significantly different across patient race. To our knowledge, this is the first report of MHRT for HRPC in a majority African American population.

We found that MHRT was an effective treatment for patients with HRPC, in particular those with unfavorable high-risk disease. While prior prospective and randomized studies have investigated the use of MHRT, our series was larger than most and had a predominately unfavorable high-risk population.^12,15-17 Our biochemical and PCSS rates compare favorably with those of HRPC trial populations, particularly given the high proportion of unfavorable high-risk disease.^12,15,16 Despite similar rates of biochemical control, OS was lower in the present cohort than in HRPC trial populations, even with a younger median age at diagnosis. The similarly high rates of non–HRPC-related death across race may reflect differences in baseline comorbidities compared with trial populations as well as reported differences between individuals in the VA and the private sector.³¹ This suggests that MHRT can be an effective treatment for patients with unfavorable HRPC.

We did not find any differences in outcomes between African American and White individuals with HRPC treated with MHRT. Furthermore, our study demonstrates long-term rates of BRFS and PCSS in a majority African American population with predominately unfavorable HRPC that are comparable with those of prior randomized MHRT studies in high-risk, predominately White populations.^12,15,16 Prior reports have found that African American men with HRPC may be at increased risk for inferior clinical outcomes due to a number of socioeconomic, biologic, and cultural mediators.^26,27,32 Such individuals may disproportionally benefit from shorter treatment courses that improve access to radiotherapy, a well-documented disparity for African American men with localized prostate cancer.^33-36 The VA is an ideal system for studying racial disparities within prostate cancer, as accessibility of mental health and transportation services, income, and insurance status are not barriers to preventative or acute care.³⁷ Our results are concordant with those previously seen for African American patients with prostate cancer seen in the VA, which similarly demonstrate equal outcomes with those of other races.^28,36 Incorporation of the earlier mentioned VA services into oncologic care across other health care systems could better characterize determinants of racial disparities in prostate cancer, including the prognostic significance of shortening treatment duration and number of patient visits via MHRT.

 

Despite widespread acceptance in prostate cancer radiotherapy guidelines, routine use of MHRT seems limited across all stages of localized prostate cancer.^1,2 Late toxicity is a frequently noted concern regarding MHRT use. Higher rates of late grade 2+ GI toxicity were observed in the hypofractionation arm of the HYPRO trial.¹⁷ While RTOG 0415 did not include patients with HRPC, significantly higher rates of physician-reported (but not patient-reported) late grade 2+ GI and GU toxicity were observed using the same MHRT fractionation regimen used for the majority of individuals in our cohort.⁹ In our study, the steady increase in late grade 2 GU toxicity is consistent with what is seen following conventionally fractionated radiotherapy and is likely multifactorial.³⁸ The mean IPSS difference of 2/35 from pre-MHRT baseline to the time of last follow-up suggests minimal quality of life decline. The relatively stable IPSSs over time alongside the > 50% prevalence of late grade 2 GU toxicity per CTCAE grading seems consistent with the discrepancy noted in RTOG 0415 between increased physician-reported late toxicity and favorable patient-reported quality of life scores.⁹ Moreover, significant variance exists in toxicity grading across scoring systems, revised editions of CTCAE, and physician-specific toxicity classification, particularly with regard to the use of adrenergic receptor blocker medications. In light of these factors, the high rate of late grade 2 GU toxicity in our study should be interpreted in the context of largely stable post-MHRT IPSSs and favorable rates of late GI grade 2+ and late GU grade 3+ toxicity.

Limitations

This study has several inherent limitations. While the size of the current HRPC cohort is notably larger than similar populations within the majority of phase 3 MHRT trials, these data derive from a single VA hospital. It is unclear whether these outcomes would be representative in a similar high-risk population receiving care outside of the VA equal access system. Follow-up data beyond 5 years was available for less than half of patients, partially due to nonprostate cancer–related mortality at a higher rate than observed in HRPC trial populations.^12,15,16 Furthermore, all GI toxicity events were exclusively physician reported, and GU toxicity reporting was limited in the off-trial setting with not all patients routinely completing IPSS questionnaires following MHRT completion. However, all patients were treated similarly, and radiation quality was verified over the treatment period with mandated accreditation, frequent standardized output checks, and systematic treatment review.³⁹

Conclusions

Patients with HRPC treated with MHRT in an equal access, off-trial setting demonstrated favorable rates of biochemical control with acceptable rates of acute and late GI and GU toxicities. Clinical outcomes, including biochemical control, were not significantly different between African American and White patients, which may reflect equal access to care within the VA irrespective of income and insurance status. Incorporating VA services, such as access to primary care, mental health services, and transportation across other health care systems may aid in characterizing and mitigating racial and gender disparities in oncologic care.  

Acknowledgments

Portions of this work were presented at the November 2020 ASTRO conference. ⁴⁰

Although moderately hypofractionated radiotherapy (MHRT) is an accepted treatment for localized prostate cancer, its adaptation remains limited in the United States.^1,2 MHRT theoretically exploits α/β ratio differences between the prostate (1.5 Gy), bladder (5-10 Gy), and rectum (3 Gy), thereby reducing late treatment-related adverse effects compared with those of conventional fractionation at biologically equivalent doses.^3-8 Multiple randomized noninferiority trials have demonstrated equivalent outcomes between MHRT and conventional fraction with no appreciable increase in patient-reported toxicity.^9-14 Although these studies have led to the acceptance of MHRT as a standard treatment, the majority of these trials involve individuals with low- and intermediate-risk disease.

There are less phase 3 data addressing MHRT for high-risk prostate cancer (HRPC).^10,12,14-17 Only 2 studies examined predominately high-risk populations, accounting for 83 and 292 patients, respectively.^15,16 Additional phase 3 trials with small proportions of high-risk patients (n = 126, 12%; n = 53, 35%) offer limited additional information regarding clinical outcomes and toxicity rates specific to high-risk disease.^10-12 Numerous phase 1 and 2 studies report various field designs and fractionation plans for MHRT in the context of high-risk disease, although the applicability of these data to off-trial populations remains limited.^18-20

Furthermore, African American individuals are underrepresented in the trials establishing the role of MHRT despite higher rates of prostate cancer incidence, more advanced disease stage at diagnosis, and higher rates of prostate cancer–specific survival (PCSS) when compared with White patients.²¹ Racial disparities across patients with prostate cancer and their management are multifactorial across health care literacy, education level, access to care (including transportation issues), and issues of adherence and distrust.^22-25 Correlation of patient race to prostate cancer outcomes varies greatly across health care systems, with the US Department of Veterans Affairs (VA) equal access system providing robust mental health services and transportation services for some patients, while demonstrating similar rates of stage-adjusted PCSS between African American and White patients across a broad range of treatment modalities.^26-28 Given the paucity of data exploring outcomes following MHRT for African American patients with HRPC, the present analysis provides long-term clinical outcomes and toxicity profiles for an off-trial majority African American population with HRPC treated with MHRT within the VA.

Methods

Records were retrospectively reviewed under an institutional review board–approved protocol for all patients with HRPC treated with definitive MHRT at the Durham Veterans Affairs Healthcare System in North Carolina between November 2008 and August 2018. Exclusion criteria included < 12 months of follow-up or elective nodal irradiation. Demographic variables obtained included age at diagnosis, race, clinical T stage, pre-MHRT prostate-specific antigen (PSA), Gleason grade group at diagnosis, favorable vs unfavorable high-risk disease, pre-MHRT international prostate symptom score (IPSS), and pre-MHRT urinary medication usage (yes/no).²⁹

Concurrent androgen deprivation therapy (ADT) was initiated 6 to 8 weeks before MHRT unless medically contraindicated per the discretion of the treating radiation oncologist. Patients generally received 18 to 24 months of ADT, with those with favorable HRPC (ie, T1c disease with either Gleason 4+4 and PSA < 10 mg/mL or Gleason 3+3 and PSA > 20 ng/mL) receiving 6 months after 2015.²⁹ Patients were simulated supine in either standard or custom immobilization with a full bladder and empty rectum. MHRT fractionation plans included 70 Gy at 2.5 Gy per fraction and 60 Gy at 3 Gy per fraction. Radiotherapy targets included the prostate and seminal vesicles without elective nodal coverage per institutional practice. Treatments were delivered following image guidance, either prostate matching with cone beam computed tomography or fiducial matching with kilo voltage imaging. All patients received intensity-modulated radiotherapy. For plans delivering 70 Gy at 2.5 Gy per fraction, constraints included bladder V (volume receiving) 70 < 10 cc, V65 ≤ 15%, V40 ≤ 35%, rectum V70 < 10 cc, V65 ≤ 10%, V40 ≤ 35%, femoral heads maximum point dose ≤ 40 Gy, penile bulb mean dose ≤ 50 Gy, and small bowel V40 ≤ 1%. For plans delivering 60 Gy at 3 Gy per fraction, constraints included rectum V57 ≤ 15%, V46 ≤ 30%, V37 ≤ 50%, bladder V60 ≤ 5%, V46 ≤ 30%, V37 ≤ 50%, and femoral heads V43 ≤ 5%.

Gastrointestinal (GI) and genitourinary (GU) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, with acute toxicity defined as on-treatment < 3 months following completion of MHRT. Late toxicity was defined as ≥ 3 months following completion of MHRT. Individuals were seen in follow-up at 6 weeks and 3 months with PSA and testosterone after MHRT completion, then every 6 to 12 months for 5 years and annually thereafter. Each follow-up visit included history, physical examination, IPSS, and CTCAE grading for GI and GU toxicity.

The Wilcoxon rank sum test and χ² test were used to compare differences in demographic data, dosimetric parameters, and frequency of toxicity events with respect to patient race. Clinical endpoints including biochemical recurrence-free survival (BRFS; defined by Phoenix criteria as 2.0 above PSA nadir), distant metastases-free survival (DMFS), PCSS, and overall survival (OS) were estimated from time of radiotherapy completion by the Kaplan-Meier method and compared between African American and White race by log-rank testing.³⁰ Late GI and GU toxicity-free survival were estimated by Kaplan-Meier plots and compared between African American and White patients by the log-rank test. Statistical analysis was performed using SAS 9.4.

 

Results

We identified 143 patients with HRPC treated with definitive MHRT between November 2008 and August 2018 (Table 1). Mean age was 65 years (range, 36-80 years); 57% were African American men. Eighty percent of individuals had unfavorable high-risk disease. Median (IQR) PSA was 14.4 (7.8-28.6). Twenty-six percent had grade group 1-3 disease, 47% had grade group 4 disease, and 27% had grade group 5 disease. African American patients had significantly lower pre-MHRT IPSS scores than White patients (mean IPSS, 11 vs 14, respectively; P = .02) despite similar rates of preradiotherapy urinary medication usage (66% and 66%, respectively).

Eighty-six percent received 70 Gy over 28 fractions, with institutional protocol shifting to 60 Gy over 20 fractions (14%) in June 2017. The median (IQR) duration of radiotherapy was 39 (38-42) days, with 97% of individuals undergoing ADT for a median (IQR) duration of 24 (24-36) months. The median follow-up time was 38 months, with 57 (40%) patients followed for at least 60 months.

Grade 3 GI and GU acute toxicity events were observed in 1% and 4% of all individuals, respectively (Table 2). No acute GI or GU grade 4+ events were observed. No significant differences in acute GU or GI toxicity were observed between African American and White patients.

No significant differences between African American and White patients were observed for late grade 2+ GI (P = .19) or GU (P = .55) toxicity. Late grade 2+ GI toxicity was observed in 17 (12%) patients overall (Figure 1A). One grade 3 and 1 grade 4 late GI event were observed following MHRT completion: The latter involved hospitalization for bleeding secondary to radiation proctitis in the context of cirrhosis predating MHRT. Late grade 2+ GU toxicity was observed in 80 (56%) patients, with late grade 2 events steadily increasing over time (Figure 1B). Nine late grade 3 GU toxicity events were observed at a median of 13 months following completion of MHRT, 2 of which occurred more than 24 months after MHRT completion. No late grade 4 or 5 GU events were observed. IPSS values both before MHRT and at time of last follow-up were available for 65 (40%) patients, with a median (IQR) IPSS of 10 (6-16) before MHRT and 12 (8-16) at last follow-up at a median (IQR) interval of 36 months (26-76) from radiation completion.

No significant differences were observed between African American and White patients with respect to BRFS, DMFS, PCSS, or OS (Figure 2). Overall, 21 of 143 (15%) patients experienced biochemical recurrence: 5-year BRFS was 77% (95% CI, 67%-85%) for all patients, 83% (95% CI, 70%-91%) for African American patients, and 71% (95% CI, 53%-82%) for White patients. Five-year DMFS was 87% (95% CI, 77%-92%) for all individuals, 91% (95% CI, 80%-96%) for African American patients, and 81% (95% CI, 62%-91%) for White patients. Five-year PCSS was 89% (95% CI, 80%-94%) for all patients, with 5-year PCSS rates of 90% (95% CI, 79%-95%) for African American patients and 87% (95% CI, 70%-95%) for White patients. Five-year OS was 75% overall (95% CI, 64%-82%), with 5-year OS rates of 73% (95% CI, 58%-83%) for African American patients and 77% (95% CI, 60%-87%) for White patients. 

Discussion

In this study, we reported acute and late GI and GU toxicity rates as well as clinical outcomes for a majority African American population with predominately unfavorable HRPC treated with MHRT in an equal access health care environment. We found that MHRT was well tolerated with high rates of biochemical control, PCSS, and OS. Additionally, outcomes were not significantly different across patient race. To our knowledge, this is the first report of MHRT for HRPC in a majority African American population.

We found that MHRT was an effective treatment for patients with HRPC, in particular those with unfavorable high-risk disease. While prior prospective and randomized studies have investigated the use of MHRT, our series was larger than most and had a predominately unfavorable high-risk population.^12,15-17 Our biochemical and PCSS rates compare favorably with those of HRPC trial populations, particularly given the high proportion of unfavorable high-risk disease.^12,15,16 Despite similar rates of biochemical control, OS was lower in the present cohort than in HRPC trial populations, even with a younger median age at diagnosis. The similarly high rates of non–HRPC-related death across race may reflect differences in baseline comorbidities compared with trial populations as well as reported differences between individuals in the VA and the private sector.³¹ This suggests that MHRT can be an effective treatment for patients with unfavorable HRPC.

We did not find any differences in outcomes between African American and White individuals with HRPC treated with MHRT. Furthermore, our study demonstrates long-term rates of BRFS and PCSS in a majority African American population with predominately unfavorable HRPC that are comparable with those of prior randomized MHRT studies in high-risk, predominately White populations.^12,15,16 Prior reports have found that African American men with HRPC may be at increased risk for inferior clinical outcomes due to a number of socioeconomic, biologic, and cultural mediators.^26,27,32 Such individuals may disproportionally benefit from shorter treatment courses that improve access to radiotherapy, a well-documented disparity for African American men with localized prostate cancer.^33-36 The VA is an ideal system for studying racial disparities within prostate cancer, as accessibility of mental health and transportation services, income, and insurance status are not barriers to preventative or acute care.³⁷ Our results are concordant with those previously seen for African American patients with prostate cancer seen in the VA, which similarly demonstrate equal outcomes with those of other races.^28,36 Incorporation of the earlier mentioned VA services into oncologic care across other health care systems could better characterize determinants of racial disparities in prostate cancer, including the prognostic significance of shortening treatment duration and number of patient visits via MHRT.

 

Despite widespread acceptance in prostate cancer radiotherapy guidelines, routine use of MHRT seems limited across all stages of localized prostate cancer.^1,2 Late toxicity is a frequently noted concern regarding MHRT use. Higher rates of late grade 2+ GI toxicity were observed in the hypofractionation arm of the HYPRO trial.¹⁷ While RTOG 0415 did not include patients with HRPC, significantly higher rates of physician-reported (but not patient-reported) late grade 2+ GI and GU toxicity were observed using the same MHRT fractionation regimen used for the majority of individuals in our cohort.⁹ In our study, the steady increase in late grade 2 GU toxicity is consistent with what is seen following conventionally fractionated radiotherapy and is likely multifactorial.³⁸ The mean IPSS difference of 2/35 from pre-MHRT baseline to the time of last follow-up suggests minimal quality of life decline. The relatively stable IPSSs over time alongside the > 50% prevalence of late grade 2 GU toxicity per CTCAE grading seems consistent with the discrepancy noted in RTOG 0415 between increased physician-reported late toxicity and favorable patient-reported quality of life scores.⁹ Moreover, significant variance exists in toxicity grading across scoring systems, revised editions of CTCAE, and physician-specific toxicity classification, particularly with regard to the use of adrenergic receptor blocker medications. In light of these factors, the high rate of late grade 2 GU toxicity in our study should be interpreted in the context of largely stable post-MHRT IPSSs and favorable rates of late GI grade 2+ and late GU grade 3+ toxicity.

Limitations

This study has several inherent limitations. While the size of the current HRPC cohort is notably larger than similar populations within the majority of phase 3 MHRT trials, these data derive from a single VA hospital. It is unclear whether these outcomes would be representative in a similar high-risk population receiving care outside of the VA equal access system. Follow-up data beyond 5 years was available for less than half of patients, partially due to nonprostate cancer–related mortality at a higher rate than observed in HRPC trial populations.^12,15,16 Furthermore, all GI toxicity events were exclusively physician reported, and GU toxicity reporting was limited in the off-trial setting with not all patients routinely completing IPSS questionnaires following MHRT completion. However, all patients were treated similarly, and radiation quality was verified over the treatment period with mandated accreditation, frequent standardized output checks, and systematic treatment review.³⁹

Conclusions

Patients with HRPC treated with MHRT in an equal access, off-trial setting demonstrated favorable rates of biochemical control with acceptable rates of acute and late GI and GU toxicities. Clinical outcomes, including biochemical control, were not significantly different between African American and White patients, which may reflect equal access to care within the VA irrespective of income and insurance status. Incorporating VA services, such as access to primary care, mental health services, and transportation across other health care systems may aid in characterizing and mitigating racial and gender disparities in oncologic care.  

Acknowledgments

Portions of this work were presented at the November 2020 ASTRO conference. ⁴⁰

To the Editor:

Psoriasis affects 2% to 3% of the US population and is one of the more commonly diagnosed dermatologic conditions.^1-3 Experts agree that common cutaneous diseases such as psoriasis present differently in patients with skin of color (SOC) compared to non-SOC patients.^3,4 Despite the prevalence of psoriasis, data on these morphologic differences are limited.^3-5 We performed a retrospective chart review comparing characteristics of psoriasis in SOC and non-SOC patients.

Through a search of electronic health records, we identified patients with an International Classification of Diseases, 10th Revision, diagnosis of psoriasis who were 18 years or older and were evaluated in the dermatology department between August 2015 and June 2020 at University Medical Center, an academic institution in New Orleans, Louisiana. Photographs and descriptions of lesions from these patients were reviewed. Patient data collected included age, sex, psoriasis classification, insurance status, self-identified race and ethnicity, location of lesion(s), biopsy, final diagnosis, and average number of visits or days required for accurate diagnosis. Self-identified SOC race and ethnicity categories included Black or African American, Hispanic, Asian, American Indian and Alaskan Native, Native Hawaiian and Other Pacific Islander, and “other.”

All analyses were conducted using R-4.0.1 statistics software. Categorical variables were compared in SOC and non-SOC groups using Fisher exact tests. Continuous covariates were conducted using a Wilcoxon rank sum test.

In total, we reviewed 557 charts. Four patients who declined to identify their race or ethnicity were excluded, yielding 286 SOC and 267 non-SOC patients (N=553). A total of 276 patients (131 SOC; 145 non-SOC) with a prior diagnosis of psoriasis were excluded in the days to diagnosis analysis. Twenty patients (15, SOC; 5, non-SOC) were given a diagnosis of a disease other than psoriasis when evaluated in the dermatology department.

Distributions between racial groups differed for insurance status, sex, psoriasis classification, biopsy status, and days between first dermatology visit and diagnosis. Skin of color patients had significantly longer days between initial presentation to dermatology and final diagnosis vs non-SOC patients (180.11 and 60.27 days, respectively; P=.001). Skin of color patients had a higher rate of palmoplantar psoriasis and severe plaque psoriasis (ie, >10% body surface area involvement) at presentation.

Several multivariable regression analyses were performed. Skin of color patients had significantly higher odds of biopsy compared to non-SOC patients (adjusted odds ratio [95% CI]=4 [2.05-7.82]; P<.001)(Figure 1). There were no significant predictors for severe plaque psoriasis involving more than 10% body surface area. Skin of color patients had a significantly longer time to diagnosis than non-SOC patients (P=.006)(Figure 2). On average, patients with SOC waited 3.23 times longer for a diagnosis than their non-SOC counterparts (95% CI, 1.42-7.36).

Our data reveal striking racial disparities in psoriasis care. Worse outcomes for patients with SOC compared to non-SOC patients may result from physicians’ inadequate familiarity with diverse presentations of psoriasis, including more frequent involvement of special body sites in SOC. Other likely contributing factors that we did not evaluate include socioeconomic barriers to health care, lack of physician diversity, missed appointments, and a paucity of literature on the topic of differentiating morphologies of psoriasis in SOC and non-SOC patients. Our study did not examine the effects of sex, tobacco use, or prior or current therapy, and it excluded pediatric patients.

To improve dermatologic outcomes for our increasingly diverse patient population, more studies must be undertaken to elucidate and document disparities in care for SOC populations.

To the Editor:

Psoriasis affects 2% to 3% of the US population and is one of the more commonly diagnosed dermatologic conditions.^1-3 Experts agree that common cutaneous diseases such as psoriasis present differently in patients with skin of color (SOC) compared to non-SOC patients.^3,4 Despite the prevalence of psoriasis, data on these morphologic differences are limited.^3-5 We performed a retrospective chart review comparing characteristics of psoriasis in SOC and non-SOC patients.

Through a search of electronic health records, we identified patients with an International Classification of Diseases, 10th Revision, diagnosis of psoriasis who were 18 years or older and were evaluated in the dermatology department between August 2015 and June 2020 at University Medical Center, an academic institution in New Orleans, Louisiana. Photographs and descriptions of lesions from these patients were reviewed. Patient data collected included age, sex, psoriasis classification, insurance status, self-identified race and ethnicity, location of lesion(s), biopsy, final diagnosis, and average number of visits or days required for accurate diagnosis. Self-identified SOC race and ethnicity categories included Black or African American, Hispanic, Asian, American Indian and Alaskan Native, Native Hawaiian and Other Pacific Islander, and “other.”

All analyses were conducted using R-4.0.1 statistics software. Categorical variables were compared in SOC and non-SOC groups using Fisher exact tests. Continuous covariates were conducted using a Wilcoxon rank sum test.

In total, we reviewed 557 charts. Four patients who declined to identify their race or ethnicity were excluded, yielding 286 SOC and 267 non-SOC patients (N=553). A total of 276 patients (131 SOC; 145 non-SOC) with a prior diagnosis of psoriasis were excluded in the days to diagnosis analysis. Twenty patients (15, SOC; 5, non-SOC) were given a diagnosis of a disease other than psoriasis when evaluated in the dermatology department.

Distributions between racial groups differed for insurance status, sex, psoriasis classification, biopsy status, and days between first dermatology visit and diagnosis. Skin of color patients had significantly longer days between initial presentation to dermatology and final diagnosis vs non-SOC patients (180.11 and 60.27 days, respectively; P=.001). Skin of color patients had a higher rate of palmoplantar psoriasis and severe plaque psoriasis (ie, >10% body surface area involvement) at presentation.

Several multivariable regression analyses were performed. Skin of color patients had significantly higher odds of biopsy compared to non-SOC patients (adjusted odds ratio [95% CI]=4 [2.05-7.82]; P<.001)(Figure 1). There were no significant predictors for severe plaque psoriasis involving more than 10% body surface area. Skin of color patients had a significantly longer time to diagnosis than non-SOC patients (P=.006)(Figure 2). On average, patients with SOC waited 3.23 times longer for a diagnosis than their non-SOC counterparts (95% CI, 1.42-7.36).

Our data reveal striking racial disparities in psoriasis care. Worse outcomes for patients with SOC compared to non-SOC patients may result from physicians’ inadequate familiarity with diverse presentations of psoriasis, including more frequent involvement of special body sites in SOC. Other likely contributing factors that we did not evaluate include socioeconomic barriers to health care, lack of physician diversity, missed appointments, and a paucity of literature on the topic of differentiating morphologies of psoriasis in SOC and non-SOC patients. Our study did not examine the effects of sex, tobacco use, or prior or current therapy, and it excluded pediatric patients.

To improve dermatologic outcomes for our increasingly diverse patient population, more studies must be undertaken to elucidate and document disparities in care for SOC populations.

To the Editor:

Psoriasis affects 2% to 3% of the US population and is one of the more commonly diagnosed dermatologic conditions.^1-3 Experts agree that common cutaneous diseases such as psoriasis present differently in patients with skin of color (SOC) compared to non-SOC patients.^3,4 Despite the prevalence of psoriasis, data on these morphologic differences are limited.^3-5 We performed a retrospective chart review comparing characteristics of psoriasis in SOC and non-SOC patients.

Through a search of electronic health records, we identified patients with an International Classification of Diseases, 10th Revision, diagnosis of psoriasis who were 18 years or older and were evaluated in the dermatology department between August 2015 and June 2020 at University Medical Center, an academic institution in New Orleans, Louisiana. Photographs and descriptions of lesions from these patients were reviewed. Patient data collected included age, sex, psoriasis classification, insurance status, self-identified race and ethnicity, location of lesion(s), biopsy, final diagnosis, and average number of visits or days required for accurate diagnosis. Self-identified SOC race and ethnicity categories included Black or African American, Hispanic, Asian, American Indian and Alaskan Native, Native Hawaiian and Other Pacific Islander, and “other.”

All analyses were conducted using R-4.0.1 statistics software. Categorical variables were compared in SOC and non-SOC groups using Fisher exact tests. Continuous covariates were conducted using a Wilcoxon rank sum test.

In total, we reviewed 557 charts. Four patients who declined to identify their race or ethnicity were excluded, yielding 286 SOC and 267 non-SOC patients (N=553). A total of 276 patients (131 SOC; 145 non-SOC) with a prior diagnosis of psoriasis were excluded in the days to diagnosis analysis. Twenty patients (15, SOC; 5, non-SOC) were given a diagnosis of a disease other than psoriasis when evaluated in the dermatology department.

Distributions between racial groups differed for insurance status, sex, psoriasis classification, biopsy status, and days between first dermatology visit and diagnosis. Skin of color patients had significantly longer days between initial presentation to dermatology and final diagnosis vs non-SOC patients (180.11 and 60.27 days, respectively; P=.001). Skin of color patients had a higher rate of palmoplantar psoriasis and severe plaque psoriasis (ie, >10% body surface area involvement) at presentation.

Several multivariable regression analyses were performed. Skin of color patients had significantly higher odds of biopsy compared to non-SOC patients (adjusted odds ratio [95% CI]=4 [2.05-7.82]; P<.001)(Figure 1). There were no significant predictors for severe plaque psoriasis involving more than 10% body surface area. Skin of color patients had a significantly longer time to diagnosis than non-SOC patients (P=.006)(Figure 2). On average, patients with SOC waited 3.23 times longer for a diagnosis than their non-SOC counterparts (95% CI, 1.42-7.36).

Our data reveal striking racial disparities in psoriasis care. Worse outcomes for patients with SOC compared to non-SOC patients may result from physicians’ inadequate familiarity with diverse presentations of psoriasis, including more frequent involvement of special body sites in SOC. Other likely contributing factors that we did not evaluate include socioeconomic barriers to health care, lack of physician diversity, missed appointments, and a paucity of literature on the topic of differentiating morphologies of psoriasis in SOC and non-SOC patients. Our study did not examine the effects of sex, tobacco use, or prior or current therapy, and it excluded pediatric patients.

To improve dermatologic outcomes for our increasingly diverse patient population, more studies must be undertaken to elucidate and document disparities in care for SOC populations.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

 

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

 

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.

Keratinocyte carcinoma (KC), or nonmelanoma skin cancer, is the most commonly diagnosed cancer in the United States.¹ Basal cell carcinoma comprises the majority of all KCs.^2,3 Squamous cell carcinoma is the second most common skin cancer, representing approximately 20% of KCs and accounting for the majority of KC-related deaths.^4-7 Malignant melanoma represents the majority of all skin cancer–related deaths.⁸ The incidence of basal cell carcinoma, squamous cell carcinoma, and malignant melanoma in the United States is on the rise and carries substantial morbidity and mortality with notable social and economic burdens.^1,8-10

Prevention is necessary to reduce skin cancer morbidity and mortality as well as rising treatment costs. The most commonly used skin cancer screening method among dermatologists is the visual full-body skin examination (FBSE), which is a noninvasive, safe, quick, and cost-effective method of early detection and prevention.¹¹ To effectively confront the growing incidence and health care burden of skin cancer, primary care providers (PCPs) must join dermatologists in conducting FBSEs.^12,13

Despite being the predominant means of secondary skin cancer prevention, the US Preventive Services Task Force (USPSTF) issued an I rating for insufficient evidence to assess the benefits vs harms of screening the adult general population by PCPs.^14,15 A major barrier to studying screening is the lack of a standardized method for conducting and reporting FBSEs.¹³ Systematic thorough skin examination generally is not performed in the primary care setting.^16-18

We aimed to investigate what occurs during an FBSE in the primary care setting and how often they are performed. We examined whether there was potential variation in the execution of the examination, what was perceived by the patient vs reported by the physician, and what was ultimately included in the medical record. Miscommunication between patient and provider regarding performance of FBSEs has previously been noted,^17-19 and we sought to characterize and quantify that miscommunication. We hypothesized that there would be lower patient-reported FBSEs compared to physicians and patient medical records. We also hypothesized that there would be variability in how physicians screened for skin cancer.

METHODS

This study was cross-sectional and was conducted based on interviews and a review of medical records at secondary- and tertiary-level units (clinics and hospitals) across the United States. We examined baseline data from a randomized controlled trial of a Web-based skin cancer early detection continuing education course—the Basic Skin Cancer Triage curriculum. Complete details have been described elsewhere.¹² This study was approved by the institutional review boards of the Providence Veterans Affairs Medical Center, Rhode Island Hospital, and Brown University (all in Providence, Rhode Island), as well as those of all recruitment sites.

Data were collected from 2005 to 2008 and included physician online surveys, patient telephone interviews, and patient medical record data abstracted by research assistants. Primary care providers included in the study were general internists, family physicians, or medicine-pediatrics practitioners who were recruited from 4 collaborating centers across the United States in the mid-Atlantic region, Ohio, Kansas, and southern California, and who had been in practice for at least a year. Patients were recruited from participating physician practices and selected by research assistants who traveled to each clinic for coordination, recruitment, and performance of medical record reviews. Patients were selected as having minimal risk of melanoma (eg, no signs of severe photodamage to the skin). Patients completed structured telephone surveys within 1 to 2 weeks of the office visit regarding the practices observed and clinical questions asked during their recent clinical encounter with their PCP.

Measures

Demographics—Demographic variables asked of physicians included age, sex, ethnicity, academic degree (MD vs DO), years in practice, training, and prior dermatology training. Demographic information asked of patients included age, sex, ethnicity, education, and household income.

 

Physician-Reported Examination and Counseling Variables—Physicians were asked to characterize their clinical practices, prompted by questions regarding performance of FBSEs: “Please think of a typical month and using the scale below, indicate how frequently you perform a total body skin exam during an annual exam (eg, periodic follow-up exam).” Physicians responded to 3 questions on a 5-point scale (1=never, 2=sometimes, 3=about half, 4=often, 5=almost always).

Patient-Reported Examination Variables—Patients also were asked to characterize the skin examination experienced in their clinical encounter with their PCP, including: “During your last visit, as far as you could tell, did your physician: (1) look at the skin on your back? (2) look at the skin on your belly area? (3) look at the skin on the back of your legs?” Patient responses were coded as yes, no, don’t know, or refused. Participants who refused were excluded from analysis; participants who responded are detailed in Table 1. In addition, patients also reported the level of undress with their physician by answering the following question: “During your last medical exam, did you: 1=keep your clothes on; 2=partially undress; 3=totally undress except for undergarments; 4=totally undress, including all undergarments?”

Patient Medical Record–Extracted Data—Research assistants used a structured abstract form to extract the information from the patient’s medical record and graded it as 0 (absence) or 1 (presence) from the medical record.

Statistical Analysis

Descriptive statistics included mean and standard deviation (SD) for continuous variables as well as frequency and percentage for categorical variables. Logit/logistic regression analysis was used to predict the odds of patient-reported outcomes that were binary with physician-reported variables as the predictor. Linear regression analysis was used to assess the association between 2 continuous variables. All analyses were conducted using SPSS version 24 (IBM).²⁰ Significance criterion was set at α of .05.

RESULTS Demographics

The final sample included data from 53 physicians and 3343 patients. The study sample mean age (SD) was 50.3 (9.9) years for PCPs (n=53) and 59.8 (16.9) years for patients (n=3343). The physician sample was 36% female and predominantly White (83%). Ninety-one percent of the PCPs had an MD (the remaining had a DO degree), and the mean (SD) years practicing was 21.8 (10.6) years. Seventeen percent of PCPs were trained in internal medicine, 4% in internal medicine and pediatrics, and 79% family medicine; 79% of PCPs had received prior training in dermatology. The patient sample was 58% female, predominantly White (84%), non-Hispanic/Latinx (95%), had completed high school (94%), and earned more than $40,000 annually (66%).

Physician- and Patient-Reported FBSEs

Physicians reported performing FBSEs with variable frequency. Among PCPs who conducted FBSEs with greater frequency, there was a modest increase in the odds that patients reported a particular body part was examined (back: odds ratio [OR], 24.5% [95% CI, 1.18-1.31; P<.001]; abdomen: OR, 23.3% [95% CI, 1.17-1.30; P<.001]; backs of legs: OR, 20.4% [95% CI, 1.13-1.28; P<.001])(Table 1). The patient-reported level of undress during examination was significantly associated with physician-reported FBSE (β=0.16 [95% CI, 0.13-0.18; P<.001])(Table 2).

Because of the bimodal distribution of scores in the physician-reported frequency of FBSEs, particularly pertaining to the extreme points of the scale, we further repeated analysis with only the never and almost always groups (Table 1). Primary care providers who reported almost always for FBSE had 29.6% increased odds of patient-reported back examination (95% CI, 1.00-1.68; P=.048) and 59.3% increased odds of patient-reported abdomen examination (95% CI, 1.23-2.06; P<.001). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having never conducted an FBSE were 56%, 40%, and 26%, respectively. The raw percentages of patients who reported having their back, abdomen, and backs of legs examined when the PCP reported having almost always conducted an FBSE were 52%, 51%, and 30%, respectively. Raw percentages were calculated by dividing the number of "yes" responses by participants for each body part examined by thetotal number of participant responses (“yes” and “no”) for each respective body part. There was no significant change in odds of patient-reported backs of legs examined with PCP-reported never vs almost always conducting an FBSE. In addition, a greater patient-reported level of undress was associated with 20.2% increased odds of PCPs reporting almost always conducting an FBSE (95% CI, 1.08-1.34; P=.001).

 

 

FBSEs in Patient Medical Records

When comparing PCP-reported FBSE and report of FBSE in patient medical records, there was a 39.0% increased odds of the patient medical record indicating FBSE when physicians reported conducting an FBSE with greater frequency (95% CI, 1.30-1.48; P<.001)(eTable 1). When examining PCP-reported never vs almost always conducting an FBSE, a report of almost always was associated with 79.0% increased odds of the patient medical record indicating that an FBSE was conducted (95% CI, 1.28-2.49; P=.001). The raw percentage of the patient medical record indicating an FBSE was conducted when the PCP reported having never conducted an FBSE was 17% and 26% when the PCP reported having almost always conducted an FBSE.

When comparing the patient-reported body part examined with patient FBSE medical record documentation, an indication of yes for FBSE on the patient medical record was associated with a considerable increase in odds that patients reported a particular body part was examined (back: 91.4% [95% CI, 1.59-2.31; P<.001]; abdomen: 75.0% [95% CI, 1.45-2.11; P<.001]; backs of legs: 91.6% [95% CI, 1.56-2.36; P<.001])(eTable 2). The raw percentages of patients who reported having their back, abdomen, and backs of legs examined vs not examined when the patient medical record indicated an FBSE was completed were 24% vs 14%, 23% vs 15%, and 26% vs 16%, respectively. An increase in patient-reported level of undress was associated with a 57.0% increased odds of their medical record indicating an FBSE was conducted (95% CI, 1.45-1.70; P<.001).

COMMENT How PCPs Perform FBSEs Varies

We found that PCPs performed FBSEs with variable frequency, and among those who did, the patient report of their examination varied considerably (Table 1). There appears to be considerable ambiguity in each of these means of determining the extent to which the skin was inspected for skin cancer, which may render the task of improving such inspection more difficult. We asked patients whether their back, abdomen, and backs of legs were examined as an assessment of some of the variety of areas inspected during an FBSE. During a general well-visit appointment, a patient’s back and abdomen may be examined for multiple reasons. Patients may have misinterpreted elements of the pulmonary, cardiac, abdominal, or musculoskeletal examinations as being part of the FBSE. The back and abdomen—the least specific features of the FBSE—were reported by patients to be the most often examined. Conversely, the backs of the legs—the most specific feature of the FBSE—had the lowest odds of being examined (Table 1).

In addition to the potential limitations of patient awareness of physician activity, our results also could be explained by differences among PCPs in how they performed FBSEs. There is no standardized method of conducting an FBSE. Furthermore, not all medical students and residents are exposed to dermatology training. In our sample of 53 physicians, 79% had reported receiving dermatology training; however, we did not assess the extent to which they had been trained in conducting an FBSE and/or identifying malignant lesions. In an American survey of 659 medical students, more than two-thirds of students had never been trained or never examined a patient for skin cancer.²¹ In another American survey of 342 internal medicine, family medicine, pediatrics, and obstetrics/gynecology residents across 7 medical schools and 4 residency programs, more than three-quarters of residents had never been trained in skin cancer screening.²² Our findings reflect insufficient and inconsistent training in skin cancer screening and underscore the need for mandatory education to ensure quality FBSEs are performed in the primary care setting.

Frequency of PCPs Performing FBSEs

Similar to prior studies analyzing the frequency of FBSE performance in the primary care setting,^16,19,23,24 more than half of our PCP sample reported sometimes to never conducting FBSEs. The percentage of physicians who reported conducting FBSEs in our sample was greater than the proportion reported by the National Health Interview Survey, in which only 8% of patients received an FBSE in the prior year by a PCP or obstetrician/gynecologist,¹⁶ but similar to a smaller patient study.¹⁹ In that study, 87% of patients, regardless of their skin cancer history, also reported that they would like their PCP to perform an FBSE regularly.¹⁹ Although some of our patient participants may have declined an FBSE, it is unlikely that that would have entirely accounted for the relatively low number of PCPs who reported frequently performing FBSEs.

Documentation in Medical Records of FBSEs

Compared to PCP self-reported performance of FBSEs, considerably fewer PCPs marked the patient medical record as having completed an FBSE. Among patients with medical records that indicated an FBSE had been conducted, they reported higher odds of all 3 body parts being examined, the highest being the backs of the legs. Also, when the patient medical record indicated an FBSE had been completed, the odds that the PCP reported an FBSE also were higher. The relatively low medical record documentation of FBSEs highlights the need for more rigorous enforcement of accurate documentation. However, among the cases that were recorded, it appeared that the content of the examinations was more consistent.

Benefits of PCP-Led FBSEs

Although the USPSTF issued an I rating for PCP-led FBSEs,¹⁴ multiple national medical societies, including the American Cancer Society,²⁵ American Academy of Dermatology,²⁶ and Skin Cancer Foundation,²⁷ as well as international guidelines in Germany,²⁸ Australia,^29,30 and New Zealand,³¹ recommend regular FBSEs among the general or at-risk population; New Zealand and Australia have the highest incidence and prevalence of melanoma in the world.⁸ The benefits of physician-led FBSEs on detection of early-stage skin cancer, and in particular, melanoma detection, have been documented in numerous studies.^30,32-38 However, the variability and often poor quality of skin screening may contribute in part to the just as numerous null results from prior skin screening studies,¹⁵ perpetuating the insufficient status of skin examinations by USPSTF standards.¹⁴ Our study underscores both the variability in frequency and content of PCP-administered FBSEs. It also highlights the need for standardization of screening examinations at the medical student, trainee, and physician level.

 

 

Study Limitations

The present study has several limitations. First, there was an unknown time lag between the FBSEs and physician self-reported surveys. Similarly, there was a variable time lag between the patient examination encounter and subsequent telephone survey. Both the physician and patient survey data may have been affected by recall bias. Second, patients were not asked directly whether an FBSE had been conducted. Furthermore, patients may not have appreciated whether the body part examined was part of the FBSE or another examination. Also, screenings often were not recorded in the medical record, assuming that the patient report and/or physician report was more accurate than the medical record.

Our study also was limited by demographics; our patient sample was largely comprised of White, educated, US adults, potentially limiting the generalizability of our findings. Conversely, a notable strength of our study was that our participants were recruited from 4 geographically diverse centers. Furthermore, we had a comparatively large sample size of patients and physicians. Also, the independent assessment of provider-reported examinations, objective assessment of medical records, and patient reports of their encounters provides a strong foundation for assessing the independent contributions of each data source.

CONCLUSION

Our study highlights the challenges future studies face in promoting skin cancer screening in the primary care setting. Our findings underscore the need for a standardized FBSE as well as clear clinical expectations regarding skin cancer screening that is expected of PCPs.

As long as skin cancer screening rates remain low in the United States, patients will be subject to potential delays and missed diagnoses, impacting morbidity and mortality.⁸ There are burgeoning resources and efforts in place to increase skin cancer screening. For example, free validated online training is available for early detection of melanoma and other skin cancers (https://www.visualdx.com/skin-cancer-education/).^39-42 Future directions for bolstering screening numbers must focus on educating PCPs about skin cancer prevention and perhaps narrowing the screening population by age-appropriate risk assessments.

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Treatment with autologous HSCT was defined by Current Procedural Terminology and ICD-9 Clinical Modification procedure codes for bone marrow and autologous HSCT occurring at any time in the CDW (eAppendix). Days elapsed from MM diagnosis to HSCT were calculated.

 

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

During fiscal years 2010 to 2015, 68% of our cohort had a diagnosis of MGUS (n = 11,112; 9105 had MGUS only), 44% had MM (n = 7261; 5254 had MM only), and 12% of these were transformation patients (n = 2007). AO exposure characterized 3102 MGUS-only patients (34%), 1886 MM-only patients (36%), and 695 transformation patients (35%) (χ² = 4.92, P = .09). Among 5683 AO-exposed patients, 695 (12.2%) underwent MGUS-to-MM transformation. Among 10,683 nonexposed veterans, 1312 (12.3%) experienced transformation.

Comorbidity in the year leading up to the index MGUS/MM date determined using CCI was a mean (SD) of 1.9 (2.1) (range, 0-14). Among disorders not included in the CCI, 71% were diagnosed with hypertension, 57% with lipid disorders, 22% with nicotine dependence, 14% with major depressive disorder, 13% with PTSD, and 9% with AUD. Overweight (BMI 25 to < 30) and obesity (BMI ≥ 30) were common (35% and 41%, respectively). For 98% of patients, weight was measured within 90 days of their index MGUS/MM date. Most of the cohort (70%) were in Vietnam in 1961 to 1968.

HSCT was provided to 632 patients with MM (8.7%), including 441 patients who were treated after their index date and 219 patients treated before their index date. From fiscal years 2010 to 2015, the median (IQR) number of days from MM index date to HSCT receipt was 349 (243-650) days. Historical HSCT occurred a median (IQR) of 857 (353-1592) days before the index date, per data available back to October 1999; this median suggests long histories of MM in this cohort.

The unadjusted survival model found a very small inverse association of mortality with AO exposure in the total sample, meaning patients with documented AO exposure lived longer (HR, 0.85; 95% CI, 0.81-0.89; Table 2; Figure). Among 11,112 MGUS patients, AO was similarly associated with mortality (HR, 0.79; 95% CI, 0.74-0.84). The effect was also seen among 7269 patients with MM (HR, 0.86; 95% CI, 0.81-0.91).

In the adjusted model of the total sample, the mortality hazard was greater for veterans who were older, with AUD and nicotine dependence, greater comorbidity per the CCI, diagnosis of MM, and transformation from MGUS to MM. Protective effects were noted for AO exposure, female sex, Black race, obesity, overweight, PTSD, and HSCT.

After adjusting for covariates, AO exposure was still associated with lower mortality among 11,112 patients with MGUS (HR, 0.85; 95% CI, 0.80-0.91). Risk factors were older age, nicotine dependence, AUD, the adapted CCI score (HR, 1.23 per point increase in the index; 95% CI, 1.22-1.25), and transformation to MM (HR, 1.76; 95% CI, 1.65-1.88). Additional protective factors were female sex, Black race, obesity, overweight, and PTSD.

After adjusting for covariates and limiting the analytic cohort to MM patients, the effect of AO exposure persisted (HR, 0.89; 95% CI, 0.84-0.95). Mortality risk factors were older age, nicotine dependence, AUD, and higher CCI score. Also protective were female sex, Black race, obesity, overweight, diagnosis of MGUS (transformation), and HSCT.

In the final model on patients with MM, the interaction term of AO exposure with transformation was significant. The combination of AO exposure with MGUS transformation had a greater protective effect than either AO exposure alone or MGUS without prior AO exposure. Additional protective factors were female sex, Black race, obesity, overweight, and HSCT. Older age, AUD, nicotine dependence, and greater comorbidity increased mortality risk.

 

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

 

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Treatment with autologous HSCT was defined by Current Procedural Terminology and ICD-9 Clinical Modification procedure codes for bone marrow and autologous HSCT occurring at any time in the CDW (eAppendix). Days elapsed from MM diagnosis to HSCT were calculated.

 

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

During fiscal years 2010 to 2015, 68% of our cohort had a diagnosis of MGUS (n = 11,112; 9105 had MGUS only), 44% had MM (n = 7261; 5254 had MM only), and 12% of these were transformation patients (n = 2007). AO exposure characterized 3102 MGUS-only patients (34%), 1886 MM-only patients (36%), and 695 transformation patients (35%) (χ² = 4.92, P = .09). Among 5683 AO-exposed patients, 695 (12.2%) underwent MGUS-to-MM transformation. Among 10,683 nonexposed veterans, 1312 (12.3%) experienced transformation.

Comorbidity in the year leading up to the index MGUS/MM date determined using CCI was a mean (SD) of 1.9 (2.1) (range, 0-14). Among disorders not included in the CCI, 71% were diagnosed with hypertension, 57% with lipid disorders, 22% with nicotine dependence, 14% with major depressive disorder, 13% with PTSD, and 9% with AUD. Overweight (BMI 25 to < 30) and obesity (BMI ≥ 30) were common (35% and 41%, respectively). For 98% of patients, weight was measured within 90 days of their index MGUS/MM date. Most of the cohort (70%) were in Vietnam in 1961 to 1968.

HSCT was provided to 632 patients with MM (8.7%), including 441 patients who were treated after their index date and 219 patients treated before their index date. From fiscal years 2010 to 2015, the median (IQR) number of days from MM index date to HSCT receipt was 349 (243-650) days. Historical HSCT occurred a median (IQR) of 857 (353-1592) days before the index date, per data available back to October 1999; this median suggests long histories of MM in this cohort.

The unadjusted survival model found a very small inverse association of mortality with AO exposure in the total sample, meaning patients with documented AO exposure lived longer (HR, 0.85; 95% CI, 0.81-0.89; Table 2; Figure). Among 11,112 MGUS patients, AO was similarly associated with mortality (HR, 0.79; 95% CI, 0.74-0.84). The effect was also seen among 7269 patients with MM (HR, 0.86; 95% CI, 0.81-0.91).

In the adjusted model of the total sample, the mortality hazard was greater for veterans who were older, with AUD and nicotine dependence, greater comorbidity per the CCI, diagnosis of MM, and transformation from MGUS to MM. Protective effects were noted for AO exposure, female sex, Black race, obesity, overweight, PTSD, and HSCT.

After adjusting for covariates, AO exposure was still associated with lower mortality among 11,112 patients with MGUS (HR, 0.85; 95% CI, 0.80-0.91). Risk factors were older age, nicotine dependence, AUD, the adapted CCI score (HR, 1.23 per point increase in the index; 95% CI, 1.22-1.25), and transformation to MM (HR, 1.76; 95% CI, 1.65-1.88). Additional protective factors were female sex, Black race, obesity, overweight, and PTSD.

After adjusting for covariates and limiting the analytic cohort to MM patients, the effect of AO exposure persisted (HR, 0.89; 95% CI, 0.84-0.95). Mortality risk factors were older age, nicotine dependence, AUD, and higher CCI score. Also protective were female sex, Black race, obesity, overweight, diagnosis of MGUS (transformation), and HSCT.

In the final model on patients with MM, the interaction term of AO exposure with transformation was significant. The combination of AO exposure with MGUS transformation had a greater protective effect than either AO exposure alone or MGUS without prior AO exposure. Additional protective factors were female sex, Black race, obesity, overweight, and HSCT. Older age, AUD, nicotine dependence, and greater comorbidity increased mortality risk.

 

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

 

Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.¹ MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.²

Background

Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.³

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.^4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.⁶

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.⁷ Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.^8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.¹⁰ To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.¹¹

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.

Methods

This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.

Measures

Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.^12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).¹⁴

Treatment with autologous HSCT was defined by Current Procedural Terminology and ICD-9 Clinical Modification procedure codes for bone marrow and autologous HSCT occurring at any time in the CDW (eAppendix). Days elapsed from MM diagnosis to HSCT were calculated.

 

Statistical Analysis

Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ² test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.

Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.

Results

We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.

The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.

During fiscal years 2010 to 2015, 68% of our cohort had a diagnosis of MGUS (n = 11,112; 9105 had MGUS only), 44% had MM (n = 7261; 5254 had MM only), and 12% of these were transformation patients (n = 2007). AO exposure characterized 3102 MGUS-only patients (34%), 1886 MM-only patients (36%), and 695 transformation patients (35%) (χ² = 4.92, P = .09). Among 5683 AO-exposed patients, 695 (12.2%) underwent MGUS-to-MM transformation. Among 10,683 nonexposed veterans, 1312 (12.3%) experienced transformation.

Comorbidity in the year leading up to the index MGUS/MM date determined using CCI was a mean (SD) of 1.9 (2.1) (range, 0-14). Among disorders not included in the CCI, 71% were diagnosed with hypertension, 57% with lipid disorders, 22% with nicotine dependence, 14% with major depressive disorder, 13% with PTSD, and 9% with AUD. Overweight (BMI 25 to < 30) and obesity (BMI ≥ 30) were common (35% and 41%, respectively). For 98% of patients, weight was measured within 90 days of their index MGUS/MM date. Most of the cohort (70%) were in Vietnam in 1961 to 1968.

HSCT was provided to 632 patients with MM (8.7%), including 441 patients who were treated after their index date and 219 patients treated before their index date. From fiscal years 2010 to 2015, the median (IQR) number of days from MM index date to HSCT receipt was 349 (243-650) days. Historical HSCT occurred a median (IQR) of 857 (353-1592) days before the index date, per data available back to October 1999; this median suggests long histories of MM in this cohort.

The unadjusted survival model found a very small inverse association of mortality with AO exposure in the total sample, meaning patients with documented AO exposure lived longer (HR, 0.85; 95% CI, 0.81-0.89; Table 2; Figure). Among 11,112 MGUS patients, AO was similarly associated with mortality (HR, 0.79; 95% CI, 0.74-0.84). The effect was also seen among 7269 patients with MM (HR, 0.86; 95% CI, 0.81-0.91).

In the adjusted model of the total sample, the mortality hazard was greater for veterans who were older, with AUD and nicotine dependence, greater comorbidity per the CCI, diagnosis of MM, and transformation from MGUS to MM. Protective effects were noted for AO exposure, female sex, Black race, obesity, overweight, PTSD, and HSCT.

After adjusting for covariates, AO exposure was still associated with lower mortality among 11,112 patients with MGUS (HR, 0.85; 95% CI, 0.80-0.91). Risk factors were older age, nicotine dependence, AUD, the adapted CCI score (HR, 1.23 per point increase in the index; 95% CI, 1.22-1.25), and transformation to MM (HR, 1.76; 95% CI, 1.65-1.88). Additional protective factors were female sex, Black race, obesity, overweight, and PTSD.

After adjusting for covariates and limiting the analytic cohort to MM patients, the effect of AO exposure persisted (HR, 0.89; 95% CI, 0.84-0.95). Mortality risk factors were older age, nicotine dependence, AUD, and higher CCI score. Also protective were female sex, Black race, obesity, overweight, diagnosis of MGUS (transformation), and HSCT.

In the final model on patients with MM, the interaction term of AO exposure with transformation was significant. The combination of AO exposure with MGUS transformation had a greater protective effect than either AO exposure alone or MGUS without prior AO exposure. Additional protective factors were female sex, Black race, obesity, overweight, and HSCT. Older age, AUD, nicotine dependence, and greater comorbidity increased mortality risk.

 

Disscussion

Elucidating the pathophysiology and risk of transformation from MGUS to MM is an ongoing endeavor, even 35 years after the end of US involvement in the Vietnam War. Our study sought to understand a relationship between AO exposure, risk of MGUS transforming to MM, and associated mortality in US Vietnam War veterans. The rate of transformation (MGUS progressing to active MM) is well cited at 1% per year.¹⁵ Here, we found 12% of our cohort had undergone this transformation over 10 years.

Vietnam War era veterans who were exposed to AO during the Operation Ranch Hand period had 2.4 times greater risk of developing MGUS compared with veterans not exposed to AO.⁸ Our study was not designed to look at this association of AO exposure and MGUS/MM as this was a retrospective review to assess the difference in outcomes based on AO exposure. We found that AO exposure is associated with a decrease in mortality in contrast to a prior study showing worse survival with individuals with AO exposure.¹⁰ Another single center study found no association between AO exposure and overall survival, but it did identify an increased risk of progression from MGUS to MM.¹¹ Our study did not show increased risk of transformation but did show positive effect on survival.

Black individuals have twice the risk of developing MM compared with White individuals and are diagnosed at a younger age (66 vs 70 years, respectively).¹⁶ Interestingly, Black race was a protective factor in our study. Given the length of time (35 years) elapsed since the Vietnam War ended, it is likely that most vulnerable Black veterans did not survive until our observation period.

HSCT, as expected, was a protective factor for veterans undergoing this treatment modality, but it is unclear why such a small number (8%) underwent HSCT as this is a standard of care in the management of MM. Obesity was also found to be a protective factor in a prior study, which was also seen in our study cohort.⁸

Limitations

This study was limited by its retrospective review of survivors among the Vietnam-era cohort several decades after the exposure of concern. Clinician notes and full historical data, such as date of onset for any disorder, were unavailable. These data also relied on the practitioners caring for the veterans to make the correct diagnosis with the associated code so that the data could be captured. Neither AO exposure nor diagnoses codes were verified against other sources of data; however, validation studies over the years have supported the accuracy of the diagnosis codes recorded in the VA EHR.

Conclusions

Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and substance use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies will look at the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to learn how best to identify their disease course and optimize their care in the latter part of their life.

Acknowledgments

This research was supported by the Central Texas Veterans Health Care System and Baylor Scott and White Health, both in Temple and Veterans Affairs Central Western Massachusetts Healthcare System, Leeds.

 

To the Editor:

There is increasing demand for medical care in the United States due to expanded health care coverage; an aging population; and advancements in diagnostics, treatment, and technology.¹ It is predicted that by 2050 the number of dermatologists will be 24.4% short of the expected estimate of demand.²

Accordingly, dermatologists are increasingly practicing in team-based care delivery models that incorporate nonphysician clinicians (NPCs), including nurse practitioners and physician assistants.¹ Despite recognition that NPCs are taking a larger role in medical teams, there is, to our knowledge, limited training for dermatologists and dermatologists in-training to optimize this professional alliance.

The objectives of this study included (1) determining whether residency programs adequately prepare residents to work with or supervise NPCs and (2) understanding the relationship between NPCs and dermatology residents across residency programs in the United States.

An anonymous cross-sectional, Internet-based survey designed using Google Forms survey creation and administration software was distributed to 117 dermatology residency program directors through email, with a request for further dissemination to residents through self-maintained listserves. Four email reminders about completing and disseminating the survey were sent to program directors between August and November 2020. The study was approved by the Emory University institutional review board. All respondents consented to participate in this survey prior to completing it.

The survey included questions pertaining to demographic information, residents’ experiences working with NPCs, residency program training specific to working with NPCs, and residents’ and residency program directors’ opinions on NPCs’ impact on education and patient care. Program directors were asked to respond N/A to 6 questions on the survey because data from those questions represented residents’ opinions only. Questions relating to residents’ and residency program directors’ opinions were based on a 5-point scale of impact (1=strongly impact in a negative way; 5=strongly impact in a positive way) or importance (1=not at all important; 5=extremely important). The survey was not previously validated.

Descriptive analysis and a paired t test were conducted when appropriate. Missing data were excluded.

There were 81 respondents to the survey. Demographic information is shown Table 1. Thirty-five dermatology residency program directors (29.9% of 117 programs) responded. Of the 45 residents or recent graduates, 29 (64.4%) reported that they foresaw the need to work with or supervise NPCs in the future (Table 2). Currently, 29 (64.4%) residents also reported that (1) they do not feel adequately trained to provide supervision of or to work with NPCs or (2) were uncertain whether they could do so. Sixty-five (80.2%) respondents stated that there was no formalized training in their program for supervising or working with NPCs; 45 (55.6%) respondents noted that they do not think that their program provided adequate training in supervising NPCs.

 

Regarding NPCs impact on care, residency program directors who completed the survey were more likely to rank NPCs as having a more significant positive impact on patient care than residents (mean score, 3.43 vs 2.78; P=.043; 95% CI, –1.28 to –0.20)(Table 3).

This study demonstrated a lack of dermatology training related to working with NPCs in a professional setting and highlighted residents’ perception that formal education in working with and supervising NPCs could be of benefit to their education. Furthermore, residency directors perceived NPCs as having a greater positive impact on patient care than residents did, underscoring the importance of the continued need to educate residents on working synergistically with NPCs to optimize patient care. Ultimately, these results suggest a potential area for further development of residency curricula.

There are approximately 360,000 NPCs serving as integral members of interdisciplinary medical teams across the United States.^3,4 In a 2014 survey, 46% of 2001 dermatologists noted that they already employed 1 or more NPCs, a number that has increased over time and is likely to continue to do so.⁵ Although the number of NPCs in dermatology has increased, there remain limited formal training and certificate programs for these providers.^1,6

Furthermore, the American Academy of Dermatology recommends that “[w]hen practicing in a dermatological setting, non-dermatologist physicians and non-physician clinicians . . . should be directly supervised by a board-certified dermatologist.”⁷ Therefore, the responsibility for a dermatology-specific education can fall on the dermatologist, necessitating adequate supervision and training of NPCs.

The findings of this study were limited by a small sample size; response bias because distribution of the survey relied on program directors disseminating the instrument to their residents, thereby limiting generalizability; and a lack of predissemination validation of the survey. Additional research in this area should focus on survey validation and distribution directly to dermatology residents, instead of relying on dermatology program directors to disseminate the survey.

To the Editor:

There is increasing demand for medical care in the United States due to expanded health care coverage; an aging population; and advancements in diagnostics, treatment, and technology.¹ It is predicted that by 2050 the number of dermatologists will be 24.4% short of the expected estimate of demand.²

Accordingly, dermatologists are increasingly practicing in team-based care delivery models that incorporate nonphysician clinicians (NPCs), including nurse practitioners and physician assistants.¹ Despite recognition that NPCs are taking a larger role in medical teams, there is, to our knowledge, limited training for dermatologists and dermatologists in-training to optimize this professional alliance.

The objectives of this study included (1) determining whether residency programs adequately prepare residents to work with or supervise NPCs and (2) understanding the relationship between NPCs and dermatology residents across residency programs in the United States.

An anonymous cross-sectional, Internet-based survey designed using Google Forms survey creation and administration software was distributed to 117 dermatology residency program directors through email, with a request for further dissemination to residents through self-maintained listserves. Four email reminders about completing and disseminating the survey were sent to program directors between August and November 2020. The study was approved by the Emory University institutional review board. All respondents consented to participate in this survey prior to completing it.

The survey included questions pertaining to demographic information, residents’ experiences working with NPCs, residency program training specific to working with NPCs, and residents’ and residency program directors’ opinions on NPCs’ impact on education and patient care. Program directors were asked to respond N/A to 6 questions on the survey because data from those questions represented residents’ opinions only. Questions relating to residents’ and residency program directors’ opinions were based on a 5-point scale of impact (1=strongly impact in a negative way; 5=strongly impact in a positive way) or importance (1=not at all important; 5=extremely important). The survey was not previously validated.

Descriptive analysis and a paired t test were conducted when appropriate. Missing data were excluded.

There were 81 respondents to the survey. Demographic information is shown Table 1. Thirty-five dermatology residency program directors (29.9% of 117 programs) responded. Of the 45 residents or recent graduates, 29 (64.4%) reported that they foresaw the need to work with or supervise NPCs in the future (Table 2). Currently, 29 (64.4%) residents also reported that (1) they do not feel adequately trained to provide supervision of or to work with NPCs or (2) were uncertain whether they could do so. Sixty-five (80.2%) respondents stated that there was no formalized training in their program for supervising or working with NPCs; 45 (55.6%) respondents noted that they do not think that their program provided adequate training in supervising NPCs.

 

Regarding NPCs impact on care, residency program directors who completed the survey were more likely to rank NPCs as having a more significant positive impact on patient care than residents (mean score, 3.43 vs 2.78; P=.043; 95% CI, –1.28 to –0.20)(Table 3).

This study demonstrated a lack of dermatology training related to working with NPCs in a professional setting and highlighted residents’ perception that formal education in working with and supervising NPCs could be of benefit to their education. Furthermore, residency directors perceived NPCs as having a greater positive impact on patient care than residents did, underscoring the importance of the continued need to educate residents on working synergistically with NPCs to optimize patient care. Ultimately, these results suggest a potential area for further development of residency curricula.

There are approximately 360,000 NPCs serving as integral members of interdisciplinary medical teams across the United States.^3,4 In a 2014 survey, 46% of 2001 dermatologists noted that they already employed 1 or more NPCs, a number that has increased over time and is likely to continue to do so.⁵ Although the number of NPCs in dermatology has increased, there remain limited formal training and certificate programs for these providers.^1,6

Furthermore, the American Academy of Dermatology recommends that “[w]hen practicing in a dermatological setting, non-dermatologist physicians and non-physician clinicians . . . should be directly supervised by a board-certified dermatologist.”⁷ Therefore, the responsibility for a dermatology-specific education can fall on the dermatologist, necessitating adequate supervision and training of NPCs.

The findings of this study were limited by a small sample size; response bias because distribution of the survey relied on program directors disseminating the instrument to their residents, thereby limiting generalizability; and a lack of predissemination validation of the survey. Additional research in this area should focus on survey validation and distribution directly to dermatology residents, instead of relying on dermatology program directors to disseminate the survey.

To the Editor:

There is increasing demand for medical care in the United States due to expanded health care coverage; an aging population; and advancements in diagnostics, treatment, and technology.¹ It is predicted that by 2050 the number of dermatologists will be 24.4% short of the expected estimate of demand.²

Accordingly, dermatologists are increasingly practicing in team-based care delivery models that incorporate nonphysician clinicians (NPCs), including nurse practitioners and physician assistants.¹ Despite recognition that NPCs are taking a larger role in medical teams, there is, to our knowledge, limited training for dermatologists and dermatologists in-training to optimize this professional alliance.

The objectives of this study included (1) determining whether residency programs adequately prepare residents to work with or supervise NPCs and (2) understanding the relationship between NPCs and dermatology residents across residency programs in the United States.

An anonymous cross-sectional, Internet-based survey designed using Google Forms survey creation and administration software was distributed to 117 dermatology residency program directors through email, with a request for further dissemination to residents through self-maintained listserves. Four email reminders about completing and disseminating the survey were sent to program directors between August and November 2020. The study was approved by the Emory University institutional review board. All respondents consented to participate in this survey prior to completing it.

The survey included questions pertaining to demographic information, residents’ experiences working with NPCs, residency program training specific to working with NPCs, and residents’ and residency program directors’ opinions on NPCs’ impact on education and patient care. Program directors were asked to respond N/A to 6 questions on the survey because data from those questions represented residents’ opinions only. Questions relating to residents’ and residency program directors’ opinions were based on a 5-point scale of impact (1=strongly impact in a negative way; 5=strongly impact in a positive way) or importance (1=not at all important; 5=extremely important). The survey was not previously validated.

Descriptive analysis and a paired t test were conducted when appropriate. Missing data were excluded.

There were 81 respondents to the survey. Demographic information is shown Table 1. Thirty-five dermatology residency program directors (29.9% of 117 programs) responded. Of the 45 residents or recent graduates, 29 (64.4%) reported that they foresaw the need to work with or supervise NPCs in the future (Table 2). Currently, 29 (64.4%) residents also reported that (1) they do not feel adequately trained to provide supervision of or to work with NPCs or (2) were uncertain whether they could do so. Sixty-five (80.2%) respondents stated that there was no formalized training in their program for supervising or working with NPCs; 45 (55.6%) respondents noted that they do not think that their program provided adequate training in supervising NPCs.

 

Regarding NPCs impact on care, residency program directors who completed the survey were more likely to rank NPCs as having a more significant positive impact on patient care than residents (mean score, 3.43 vs 2.78; P=.043; 95% CI, –1.28 to –0.20)(Table 3).

This study demonstrated a lack of dermatology training related to working with NPCs in a professional setting and highlighted residents’ perception that formal education in working with and supervising NPCs could be of benefit to their education. Furthermore, residency directors perceived NPCs as having a greater positive impact on patient care than residents did, underscoring the importance of the continued need to educate residents on working synergistically with NPCs to optimize patient care. Ultimately, these results suggest a potential area for further development of residency curricula.

There are approximately 360,000 NPCs serving as integral members of interdisciplinary medical teams across the United States.^3,4 In a 2014 survey, 46% of 2001 dermatologists noted that they already employed 1 or more NPCs, a number that has increased over time and is likely to continue to do so.⁵ Although the number of NPCs in dermatology has increased, there remain limited formal training and certificate programs for these providers.^1,6

Furthermore, the American Academy of Dermatology recommends that “[w]hen practicing in a dermatological setting, non-dermatologist physicians and non-physician clinicians . . . should be directly supervised by a board-certified dermatologist.”⁷ Therefore, the responsibility for a dermatology-specific education can fall on the dermatologist, necessitating adequate supervision and training of NPCs.

The findings of this study were limited by a small sample size; response bias because distribution of the survey relied on program directors disseminating the instrument to their residents, thereby limiting generalizability; and a lack of predissemination validation of the survey. Additional research in this area should focus on survey validation and distribution directly to dermatology residents, instead of relying on dermatology program directors to disseminate the survey.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

 

NMSCs are often asymptomatic and not immediately life threatening. Although NMSCs tend to have a favorable prognosis, studies have found that NMSC may be a marker for other poor health outcomes. A significant increased risk for all-cause mortality was found for patients with a history of SCC, which may be attributed to immune status.¹¹ The aging veteran population has more complex health care needs to be considered when developing surgical treatment plans. These medical problems may limit their life expectancy much sooner than the skin cancer will become symptomatic. We found that individuals aged ≥ 80 years who had CAD, CHF, or dementia had a relative risk of 3 or higher for 5-year mortality. The leading cause of death in the United States in years 2011 to 2015 was heart disease. Alzheimer disease was the sixth leading cause of death in those same years.^12-14
Skin cancer excisions do not typically require general anesthesia, deep sedation, or large fluid shifts; however, studies have found that when frail patients undergo low-risk procedures, they tend to have a higher mortality rate than their healthier counterparts.¹⁵ Frailty is a concept that identifies patients who are at increased risk of dying in 6 to 60 months due to a decline in their physical reserve. Frail patients have increased rates of perioperative mortality and complications. Various tools have been used to assess the components of physical performance, speed, mobility, nutrition status, mental health, and cognition.¹⁶ Frailty screening has been initiated in several VA hospitals, including our own in Gainesville, Florida, with the goal of decreasing postoperative morbidity and mortality in older adult patients.¹⁷ The patients are given a 1-page screening assessment that asks about their living situation, medical conditions, nutrition status, cognition, and activities of daily living. The results can trigger the clinician to rethink the surgical plan and mobilize more resources to optimize the patient’s health. This study period precedes the initiative at our institution.

The plastic surgery service’s routine practice is to excise skin cancers in the operating room if sedation or general anesthesia will be needed (Figure 1A), for optimal control of bleeding (Figure 1B) in a patient who cannot safely stop blood thinners, or for excision of a highly vascularized area such as the scalp. Surgery is offered in an office-based setting if the area can be closed primarily, left open to close secondarily, or closed with a small skin graft under local anesthesia only (Figure 2). We prefer treating frail patients in the minor procedure clinic, when possible, to avoid the risks of sedation and the additional preoperative visits and transportation requirements. NMSC with unclear margins (Figure 3A) or in cosmetically sensitive areas where tissue needs to be preserved (Figure 3B) are referred to the Mohs dermatologist. The skin cancers in this study were most frequently found on the face, scalp, hands, and forearms based on referral patterns.

Other treatment options for NMSC include curettage and electrodessication, cryotherapy, and radiation; however, ours is a surgical service and patients are typically referred to us by primary care or dermatology when those are not reasonable or desirable options.¹⁸ Published complication rates of patients having skin cancer surgery without age restriction have a rate of 3% to 6%, which is consistent with our study of 5%.^19-21 Two bleeding complications that needed to be admitted did not require more than a bedside procedure and neither required transfusions. One patient had been instructed to continue taking coumadin during the perioperative office-based procedure due to a recent carotid stent placement in the setting of a rapidly growing basal cell on an easily accessible location.

The most noted comorbidity in patients with wound complications was found to be DM; however, this was not found to be a statistically significant risk factor for wound complications (P = .10). We do not have a set rule for advising for or against NMSC surgery. We do counsel frail patients and their families that not all cancer is immediately life threatening and will work with them to do whatever makes the most sense to achieve their goals, occasionally accepting positive margins in order to debulk a symptomatic growth. The objective of this paper is to contribute to the discussion of performing invasive procedures on older adult veterans with life-limiting comorbidities. Patients and their families will have different thresholds for what they feel needs intervention, especially if other medical problems are consuming much of their time. We also have the community care referral option for patients whose treatment decisions are being dictated by travel hardships.

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

 

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

 

NMSCs are often asymptomatic and not immediately life threatening. Although NMSCs tend to have a favorable prognosis, studies have found that NMSC may be a marker for other poor health outcomes. A significant increased risk for all-cause mortality was found for patients with a history of SCC, which may be attributed to immune status.¹¹ The aging veteran population has more complex health care needs to be considered when developing surgical treatment plans. These medical problems may limit their life expectancy much sooner than the skin cancer will become symptomatic. We found that individuals aged ≥ 80 years who had CAD, CHF, or dementia had a relative risk of 3 or higher for 5-year mortality. The leading cause of death in the United States in years 2011 to 2015 was heart disease. Alzheimer disease was the sixth leading cause of death in those same years.^12-14
Skin cancer excisions do not typically require general anesthesia, deep sedation, or large fluid shifts; however, studies have found that when frail patients undergo low-risk procedures, they tend to have a higher mortality rate than their healthier counterparts.¹⁵ Frailty is a concept that identifies patients who are at increased risk of dying in 6 to 60 months due to a decline in their physical reserve. Frail patients have increased rates of perioperative mortality and complications. Various tools have been used to assess the components of physical performance, speed, mobility, nutrition status, mental health, and cognition.¹⁶ Frailty screening has been initiated in several VA hospitals, including our own in Gainesville, Florida, with the goal of decreasing postoperative morbidity and mortality in older adult patients.¹⁷ The patients are given a 1-page screening assessment that asks about their living situation, medical conditions, nutrition status, cognition, and activities of daily living. The results can trigger the clinician to rethink the surgical plan and mobilize more resources to optimize the patient’s health. This study period precedes the initiative at our institution.

The plastic surgery service’s routine practice is to excise skin cancers in the operating room if sedation or general anesthesia will be needed (Figure 1A), for optimal control of bleeding (Figure 1B) in a patient who cannot safely stop blood thinners, or for excision of a highly vascularized area such as the scalp. Surgery is offered in an office-based setting if the area can be closed primarily, left open to close secondarily, or closed with a small skin graft under local anesthesia only (Figure 2). We prefer treating frail patients in the minor procedure clinic, when possible, to avoid the risks of sedation and the additional preoperative visits and transportation requirements. NMSC with unclear margins (Figure 3A) or in cosmetically sensitive areas where tissue needs to be preserved (Figure 3B) are referred to the Mohs dermatologist. The skin cancers in this study were most frequently found on the face, scalp, hands, and forearms based on referral patterns.

Other treatment options for NMSC include curettage and electrodessication, cryotherapy, and radiation; however, ours is a surgical service and patients are typically referred to us by primary care or dermatology when those are not reasonable or desirable options.¹⁸ Published complication rates of patients having skin cancer surgery without age restriction have a rate of 3% to 6%, which is consistent with our study of 5%.^19-21 Two bleeding complications that needed to be admitted did not require more than a bedside procedure and neither required transfusions. One patient had been instructed to continue taking coumadin during the perioperative office-based procedure due to a recent carotid stent placement in the setting of a rapidly growing basal cell on an easily accessible location.

The most noted comorbidity in patients with wound complications was found to be DM; however, this was not found to be a statistically significant risk factor for wound complications (P = .10). We do not have a set rule for advising for or against NMSC surgery. We do counsel frail patients and their families that not all cancer is immediately life threatening and will work with them to do whatever makes the most sense to achieve their goals, occasionally accepting positive margins in order to debulk a symptomatic growth. The objective of this paper is to contribute to the discussion of performing invasive procedures on older adult veterans with life-limiting comorbidities. Patients and their families will have different thresholds for what they feel needs intervention, especially if other medical problems are consuming much of their time. We also have the community care referral option for patients whose treatment decisions are being dictated by travel hardships.

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

 

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Skin cancer is the most diagnosed cancer in the United States. Nonmelanoma skin cancers (NMSC), which include basal cell carcinoma and squamous cell carcinoma, are usually cured with removal.¹ The incidence of NMSC increases with age and is commonly found in nursing homes and geriatric units. These cancers are not usually metastatic or fatal but can cause local destruction and disfigurement if neglected.² The current standard of care is to treat diagnosed NMSC; however, the dermatology and geriatric care literature have questioned the logic of treating asymptomatic skin cancers that will not affect a patient’s life expectancy.^2-4

Forty-seven percent of the current living veteran population is aged ≥ 65 years.⁵ Older adult patients are frequently referred to the US Department of Veterans Affairs (VA) surgical service for the treatment of NMSC. The veteran population includes a higher percentage of individuals at an elevated risk of skin cancers (older, White, and male) compared with the general population.⁶ World War II veterans deployed in regions closer to the equator have been found to have an elevated risk of melanoma and nonmelanoma skin carcinomas.⁷ A retrospective study of Vietnam veterans exposed to Agent Orange (2,3,7,8-tetrachlorodibenzodioxin) found a significantly higher risk of invasive NMSC in Fitzpatrick skin types I-IV compared with an age-matched subset of the general population.⁸ Younger veterans who were deployed in Afghanistan and Iraq for Operation Enduring Freedom/Operation Iraqi Freedom worked at more equatorial latitudes than the rest of the US population and may be at increased risk of NMSC. Inadequate sunscreen access, immediate safety concerns, outdoor recreational activities, harsh weather, and insufficient emphasis on sun protection have created a multifactorial challenge for the military population. Riemenschneider and colleagues recommended targeted screening for at-risk veteran patients and prioritizing annual skin cancer screenings during medical mission physical examinations for active military.⁷

The plastic surgery service regularly receives consults from dermatology, general surgery, and primary care to remove skin cancers on the face, scalp, hands, and forearms. Skin cancer treatment can create serious hardships for older adult patients and their families with multiple appointments for the consult, procedure, and follow-up. Patients are often told to hold their anticoagulant medications when the surgery will be performed on a highly vascular region, such as the scalp or face. This can create wide swings in their laboratory test values and result in life-threatening complications from either bleeding or clotting. The appropriateness of offering surgery to patients with serious comorbidities and a limited life expectancy has been questioned.^2-4 The purpose of this study was to measure the morbidity and unrelated 5-year mortality for patients with skin cancer referred to the plastic surgery service to help patients and families make a more informed treatment decision, particularly when the patients are aged > 80 years and have significant life-threatening comorbidities.

Methods

The University of Florida and Malcom Randall VA Medical Center Institutional review board in Gainesville, approved a retrospective review of all consults completed by the plastic surgery service for the treatment of NMSC performed from July 1, 2011 to June 30, 2015. Data collected included age and common life-limiting comorbidities at the time of referral. Morbidities were found on the electronic health record, including coronary artery disease (CAD), congestive heart failure (CHF), cerebral vascular disease (CVD), peripheral vascular disease, dementia, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), tobacco use, diabetes mellitus (DM), liver disease, alcohol use, and obstructive sleep apnea.

Treatment, complications, and 5-year mortality were recorded. A χ² analysis with P value < .05 was used to determine statistical significance between individual risk factors and 5-year mortality. The relative risk of 5-year mortality was calculated by combining advanced age (aged > 80 years) with the individual comorbidities.

Results

Over 4 years, 800 consults for NMSC were completed by the plastic surgery service. Treatment decisions included 210 excisions (with or without reconstruction) in the operating room, 402 excisions (with or without reconstruction) under local anesthesia in clinic, 55 Mohs surgical dermatology referrals, 21 other service or hospital referrals, and 112 patient who were observed, declined intervention, or died prior to intervention. Five-year mortality was 28.6%. No patients died of NMSC. The median age at consult submission for patients deceased 5 years later was 78 years. Complication rate was 5% and included wound infection, dehiscence, bleeding, or graft loss. Two patients, both deceased within 5 years, had unplanned admissions due to bleeding from either a skin graft donor site or recipient bleeding. Aged ≥ 80 years, CAD, CHF, CVD, peripheral vascular disease, dementia, CKD, COPD, and DM were all found individually to be statistically significant predictors of 5-year mortality (Table 1). Combining aged ≥ 80 years plus CAD, CHF, or dementia all increased the 5-year mortality by a relative risk of > 3 (Table 2).

Discussion

The standard of care is to treat NMSC. Most NMSCs are treated surgically without consideration of patient age or life expectancy.^2,4,9,10 A prospective cohort study involving a university-based private practice and a VA medical center in San Francisco found a 22.6% overall 5-year mortality and a 43.3% mortality in the group defined as limited life expectancy (LLE) based on age (≥ 85 years) and medical comorbidities. None died due to the NMSC. Leading cause of death was cardiac, cerebrovascular, and respiratory disease, lung and prostate cancer, and Alzheimer disease. The authors suggested the LLE group may be exposed to wound complications without benefiting from the treatment.⁴

Another study of 440 patients receiving excision for biopsy-proven facial NMSC at the Roudebush VA Medical Center in Indianapolis, Indiana, found no residual carcinoma in 35.3% of excisions, and in patients aged > 90 years, more than half of the excisions had no residual carcinoma. More than half of the patients aged > 90 years died within 1 year, not as a result of the NMSC. The authors argued for watchful waiting in select patients to maximize comfort and outcomes.¹⁰

 

NMSCs are often asymptomatic and not immediately life threatening. Although NMSCs tend to have a favorable prognosis, studies have found that NMSC may be a marker for other poor health outcomes. A significant increased risk for all-cause mortality was found for patients with a history of SCC, which may be attributed to immune status.¹¹ The aging veteran population has more complex health care needs to be considered when developing surgical treatment plans. These medical problems may limit their life expectancy much sooner than the skin cancer will become symptomatic. We found that individuals aged ≥ 80 years who had CAD, CHF, or dementia had a relative risk of 3 or higher for 5-year mortality. The leading cause of death in the United States in years 2011 to 2015 was heart disease. Alzheimer disease was the sixth leading cause of death in those same years.^12-14
Skin cancer excisions do not typically require general anesthesia, deep sedation, or large fluid shifts; however, studies have found that when frail patients undergo low-risk procedures, they tend to have a higher mortality rate than their healthier counterparts.¹⁵ Frailty is a concept that identifies patients who are at increased risk of dying in 6 to 60 months due to a decline in their physical reserve. Frail patients have increased rates of perioperative mortality and complications. Various tools have been used to assess the components of physical performance, speed, mobility, nutrition status, mental health, and cognition.¹⁶ Frailty screening has been initiated in several VA hospitals, including our own in Gainesville, Florida, with the goal of decreasing postoperative morbidity and mortality in older adult patients.¹⁷ The patients are given a 1-page screening assessment that asks about their living situation, medical conditions, nutrition status, cognition, and activities of daily living. The results can trigger the clinician to rethink the surgical plan and mobilize more resources to optimize the patient’s health. This study period precedes the initiative at our institution.

The plastic surgery service’s routine practice is to excise skin cancers in the operating room if sedation or general anesthesia will be needed (Figure 1A), for optimal control of bleeding (Figure 1B) in a patient who cannot safely stop blood thinners, or for excision of a highly vascularized area such as the scalp. Surgery is offered in an office-based setting if the area can be closed primarily, left open to close secondarily, or closed with a small skin graft under local anesthesia only (Figure 2). We prefer treating frail patients in the minor procedure clinic, when possible, to avoid the risks of sedation and the additional preoperative visits and transportation requirements. NMSC with unclear margins (Figure 3A) or in cosmetically sensitive areas where tissue needs to be preserved (Figure 3B) are referred to the Mohs dermatologist. The skin cancers in this study were most frequently found on the face, scalp, hands, and forearms based on referral patterns.

Other treatment options for NMSC include curettage and electrodessication, cryotherapy, and radiation; however, ours is a surgical service and patients are typically referred to us by primary care or dermatology when those are not reasonable or desirable options.¹⁸ Published complication rates of patients having skin cancer surgery without age restriction have a rate of 3% to 6%, which is consistent with our study of 5%.^19-21 Two bleeding complications that needed to be admitted did not require more than a bedside procedure and neither required transfusions. One patient had been instructed to continue taking coumadin during the perioperative office-based procedure due to a recent carotid stent placement in the setting of a rapidly growing basal cell on an easily accessible location.

The most noted comorbidity in patients with wound complications was found to be DM; however, this was not found to be a statistically significant risk factor for wound complications (P = .10). We do not have a set rule for advising for or against NMSC surgery. We do counsel frail patients and their families that not all cancer is immediately life threatening and will work with them to do whatever makes the most sense to achieve their goals, occasionally accepting positive margins in order to debulk a symptomatic growth. The objective of this paper is to contribute to the discussion of performing invasive procedures on older adult veterans with life-limiting comorbidities. Patients and their families will have different thresholds for what they feel needs intervention, especially if other medical problems are consuming much of their time. We also have the community care referral option for patients whose treatment decisions are being dictated by travel hardships.

Strengths and Limitations

A strength of this study is that the data were obtained from a closed system. Patients tend to stay long-term within the VA and their health record is accessible throughout the country as long as they are seen at a VA facility. Complications, therefore, return to the treating service or primary care, who would route the patient back to the surgeon.

One limitation of the study is that this is a retrospective review from 2011. The authors are limited to data that are recorded in the patient record. Multiple health care professionals saw the patients and notes lack consistency in detail. Size of the lesions were not consistently recorded and did not get logged into our database for that reason.

 

Conclusions

Treatment of NMSC in older adult patients has a low morbidity but needs to be balanced against a patient and family’s goals when the patient presents with life-limiting comorbidities. An elevated 5-year mortality in patients aged > 80 years with serious unrelated medical conditions is intuitive, but this study may help put treatment plans into perspective for families and health care professionals who want to provide an indicated service while maximizing patient quality of life.

Acknowledgments

This manuscript is the result of work supported with resources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

 

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

 

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

 

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

 

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

 

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

 

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

 

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

 

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

 

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

To the Editor:

In response to the challenges of the COVID-19 pandemic, iPLEDGE announced that they would accept results from home pregnancy tests and explicitly permit telemedicine.¹ Given the financial and logistical burdens associated with iPLEDGE, these changes have the potential to increase access.² However, it is unclear whether these modifications will be allowed to continue. We sought to evaluate clinician perspectives on the role of telemedicine and home pregnancy testing for iPLEDGE.

After piloting among several clinicians, a 13-question survey was distributed using the Qualtrics platform to members of the American Acne & Rosacea Society between April 14, 2021, and June 14, 2021. This survey consisted of items addressing provider practices and perspectives on telemedicine and home pregnancy testing for patients taking isotretinoin (eTable). Respondents were asked whether they think telemedicine and home pregnancy testing have improved access to care and whether they would like to continue these practices going forward. In addition, participants were asked about their concerns with home pregnancy testing and how comfortable they feel with home pregnancy testing for various contraceptive strategies (abstinence, condoms, combined oral contraceptives, and long-acting reversible contraception). This study was deemed exempt (category 2) by the University of Pennsylvania (Philadelphia, Pennsylvania) institutional review board (Protocol #844549).

Among 70 clinicians who completed the survey (response rate, 6.4%), 33 (47.1%) practiced in an academic setting. At the peak of the COVID-19 pandemic, clinicians reported using telemedicine for a median of 90% (IQR=50%–100%) of their patients on isotretinoin, and 57 respondents (81.4%) reported having patients use a home pregnancy test for iPLEDGE (Table 1). More than 75% (55/70) agreed that they would like to continue to use telemedicine for patients on isotretinoin, and more than 75% (54/70) agreed that they would like to continue using home pregnancy testing for patients outside the setting of the COVID-19 pandemic. More than 75% (54/70) agreed that telemedicine has increased access for their patients, and more than 70% (52/70) agreed that home pregnancy testing has increased access (Table 2). Clinicians agreed that they would be comfortable using home pregnancy testing for patients choosing long-acting reversible contraception (63/70 [90.0%]), combined oral contraceptives (61/69 [88.4%]), condoms (47/70 [67.1%]), or abstinence (48/70 [68.6%])(Table 3).

The most common concerns about home pregnancy testing were patient deception (39/70 [55.7%]), logistical challenges with reviewing results (19/70 [27.1%]), accuracy of the tests (19/70 [27.1%]), and patient ability to interpret tests appropriately (18/70 [25.7%]). To document testing results, 50 respondents (73.5%) would require a picture of results, 4 (5.9%) would accept a written report from the patient, and 14 (20.6%) would accept a verbal report from the patient (Table 2).

In this survey, clinicians expressed interest in continuing to use telemedicine and home pregnancy testing to care for patients with acne treated with isotretinoin. More than 75% agreed that these changes have increased access, which is notable, as several studies have identified that female and minority patients may face iPLEDGE-associated access barriers.^3,4 Continuing to allow home pregnancy testing and explicitly permitting telemedicine can enable clinicians to provide patient-centered care.²

Although clinicians felt comfortable with a variety of contraceptive strategies, particularly those with high reported effectiveness,⁵ there were concerns about deception and interpretation of test results. Future studies are needed to identify optimal workflows for home pregnancy testing and whether patients should be required to provide a photograph of the results.

This survey study is limited by the possibility of sampling and response bias due to the low response rate. Although the use of national listservs was employed to maximize the generalizability of the results, given the response rate, future studies are needed to evaluate whether these findings generalize to other settings. In addition, given iPLEDGE-associated access barriers, further research is needed to examine how changes such as telemedicine and home pregnancy testing influence both access to isotretinoin and pregnancy prevention.

Acknowledgments—We would like to thank Stacey Moore (Montclair, New Jersey) and the American Acne & Rosacea Society for their help distributing the survey.

To the Editor:

In response to the challenges of the COVID-19 pandemic, iPLEDGE announced that they would accept results from home pregnancy tests and explicitly permit telemedicine.¹ Given the financial and logistical burdens associated with iPLEDGE, these changes have the potential to increase access.² However, it is unclear whether these modifications will be allowed to continue. We sought to evaluate clinician perspectives on the role of telemedicine and home pregnancy testing for iPLEDGE.

After piloting among several clinicians, a 13-question survey was distributed using the Qualtrics platform to members of the American Acne & Rosacea Society between April 14, 2021, and June 14, 2021. This survey consisted of items addressing provider practices and perspectives on telemedicine and home pregnancy testing for patients taking isotretinoin (eTable). Respondents were asked whether they think telemedicine and home pregnancy testing have improved access to care and whether they would like to continue these practices going forward. In addition, participants were asked about their concerns with home pregnancy testing and how comfortable they feel with home pregnancy testing for various contraceptive strategies (abstinence, condoms, combined oral contraceptives, and long-acting reversible contraception). This study was deemed exempt (category 2) by the University of Pennsylvania (Philadelphia, Pennsylvania) institutional review board (Protocol #844549).

Among 70 clinicians who completed the survey (response rate, 6.4%), 33 (47.1%) practiced in an academic setting. At the peak of the COVID-19 pandemic, clinicians reported using telemedicine for a median of 90% (IQR=50%–100%) of their patients on isotretinoin, and 57 respondents (81.4%) reported having patients use a home pregnancy test for iPLEDGE (Table 1). More than 75% (55/70) agreed that they would like to continue to use telemedicine for patients on isotretinoin, and more than 75% (54/70) agreed that they would like to continue using home pregnancy testing for patients outside the setting of the COVID-19 pandemic. More than 75% (54/70) agreed that telemedicine has increased access for their patients, and more than 70% (52/70) agreed that home pregnancy testing has increased access (Table 2). Clinicians agreed that they would be comfortable using home pregnancy testing for patients choosing long-acting reversible contraception (63/70 [90.0%]), combined oral contraceptives (61/69 [88.4%]), condoms (47/70 [67.1%]), or abstinence (48/70 [68.6%])(Table 3).

The most common concerns about home pregnancy testing were patient deception (39/70 [55.7%]), logistical challenges with reviewing results (19/70 [27.1%]), accuracy of the tests (19/70 [27.1%]), and patient ability to interpret tests appropriately (18/70 [25.7%]). To document testing results, 50 respondents (73.5%) would require a picture of results, 4 (5.9%) would accept a written report from the patient, and 14 (20.6%) would accept a verbal report from the patient (Table 2).

In this survey, clinicians expressed interest in continuing to use telemedicine and home pregnancy testing to care for patients with acne treated with isotretinoin. More than 75% agreed that these changes have increased access, which is notable, as several studies have identified that female and minority patients may face iPLEDGE-associated access barriers.^3,4 Continuing to allow home pregnancy testing and explicitly permitting telemedicine can enable clinicians to provide patient-centered care.²

Although clinicians felt comfortable with a variety of contraceptive strategies, particularly those with high reported effectiveness,⁵ there were concerns about deception and interpretation of test results. Future studies are needed to identify optimal workflows for home pregnancy testing and whether patients should be required to provide a photograph of the results.

This survey study is limited by the possibility of sampling and response bias due to the low response rate. Although the use of national listservs was employed to maximize the generalizability of the results, given the response rate, future studies are needed to evaluate whether these findings generalize to other settings. In addition, given iPLEDGE-associated access barriers, further research is needed to examine how changes such as telemedicine and home pregnancy testing influence both access to isotretinoin and pregnancy prevention.

Acknowledgments—We would like to thank Stacey Moore (Montclair, New Jersey) and the American Acne & Rosacea Society for their help distributing the survey.

To the Editor:

In response to the challenges of the COVID-19 pandemic, iPLEDGE announced that they would accept results from home pregnancy tests and explicitly permit telemedicine.¹ Given the financial and logistical burdens associated with iPLEDGE, these changes have the potential to increase access.² However, it is unclear whether these modifications will be allowed to continue. We sought to evaluate clinician perspectives on the role of telemedicine and home pregnancy testing for iPLEDGE.

After piloting among several clinicians, a 13-question survey was distributed using the Qualtrics platform to members of the American Acne & Rosacea Society between April 14, 2021, and June 14, 2021. This survey consisted of items addressing provider practices and perspectives on telemedicine and home pregnancy testing for patients taking isotretinoin (eTable). Respondents were asked whether they think telemedicine and home pregnancy testing have improved access to care and whether they would like to continue these practices going forward. In addition, participants were asked about their concerns with home pregnancy testing and how comfortable they feel with home pregnancy testing for various contraceptive strategies (abstinence, condoms, combined oral contraceptives, and long-acting reversible contraception). This study was deemed exempt (category 2) by the University of Pennsylvania (Philadelphia, Pennsylvania) institutional review board (Protocol #844549).

Among 70 clinicians who completed the survey (response rate, 6.4%), 33 (47.1%) practiced in an academic setting. At the peak of the COVID-19 pandemic, clinicians reported using telemedicine for a median of 90% (IQR=50%–100%) of their patients on isotretinoin, and 57 respondents (81.4%) reported having patients use a home pregnancy test for iPLEDGE (Table 1). More than 75% (55/70) agreed that they would like to continue to use telemedicine for patients on isotretinoin, and more than 75% (54/70) agreed that they would like to continue using home pregnancy testing for patients outside the setting of the COVID-19 pandemic. More than 75% (54/70) agreed that telemedicine has increased access for their patients, and more than 70% (52/70) agreed that home pregnancy testing has increased access (Table 2). Clinicians agreed that they would be comfortable using home pregnancy testing for patients choosing long-acting reversible contraception (63/70 [90.0%]), combined oral contraceptives (61/69 [88.4%]), condoms (47/70 [67.1%]), or abstinence (48/70 [68.6%])(Table 3).

The most common concerns about home pregnancy testing were patient deception (39/70 [55.7%]), logistical challenges with reviewing results (19/70 [27.1%]), accuracy of the tests (19/70 [27.1%]), and patient ability to interpret tests appropriately (18/70 [25.7%]). To document testing results, 50 respondents (73.5%) would require a picture of results, 4 (5.9%) would accept a written report from the patient, and 14 (20.6%) would accept a verbal report from the patient (Table 2).

In this survey, clinicians expressed interest in continuing to use telemedicine and home pregnancy testing to care for patients with acne treated with isotretinoin. More than 75% agreed that these changes have increased access, which is notable, as several studies have identified that female and minority patients may face iPLEDGE-associated access barriers.^3,4 Continuing to allow home pregnancy testing and explicitly permitting telemedicine can enable clinicians to provide patient-centered care.²

Although clinicians felt comfortable with a variety of contraceptive strategies, particularly those with high reported effectiveness,⁵ there were concerns about deception and interpretation of test results. Future studies are needed to identify optimal workflows for home pregnancy testing and whether patients should be required to provide a photograph of the results.

This survey study is limited by the possibility of sampling and response bias due to the low response rate. Although the use of national listservs was employed to maximize the generalizability of the results, given the response rate, future studies are needed to evaluate whether these findings generalize to other settings. In addition, given iPLEDGE-associated access barriers, further research is needed to examine how changes such as telemedicine and home pregnancy testing influence both access to isotretinoin and pregnancy prevention.

Acknowledgments—We would like to thank Stacey Moore (Montclair, New Jersey) and the American Acne & Rosacea Society for their help distributing the survey.

Isotretinoin is the most effective treatment of recalcitrant acne, but because of its teratogenicity and potential association with psychiatric adverse effects, it has been heavily regulated by the US Food and Drug Administration (FDA) through the iPLEDGE program since 2006.^1,2 To manage the risk of teratogenicity associated with isotretinoin, various pregnancy prevention programs have been developed, but none of these programs have demonstrated a zero fetal exposure rate. The FDA reported 122 isotretinoin-exposed pregnancies during the first year iPLEDGE was implemented, which was a slight increase from the 120 pregnancies reported the year after the implementation of the System to Manage Accutane-Related Teratogenicity program, iPLEDGE’s predecessor.³ The iPLEDGE program requires registration of all wholesalers distributing isotretinoin, all health care providers prescribing isotretinoin, all pharmacies dispensing isotretinoin, and all female and male patients prescribed isotretinoin to create a verifiable link that only enables patients who have met all criteria to pick up their prescriptions. For patients of reproductive potential, there are additional qualification criteria and monthly requirements; before receiving their prescription every month, patients of reproductive potential must undergo a urine or serum pregnancy test with negative results, and patients must be counseled by prescribers regarding the risks of the drug and verify they are using 2 methods of contraception (or practicing abstinence) each month before completing online questions that test their understanding of the drug’s side effects and their chosen methods of contraception.⁴ These requirements place burdens on both patients and prescribers. Studies have shown that in the 2 years after the implementation of iPLEDGE, there was a 29% decrease in isotretinoin prescriptions.^1-3

We conducted a survey study to see if clinicians chose not to prescribe isotretinoin to appropriate candidates specifically because of the administrative burden of iPLEDGE. Secondarily, we investigated the medications these clinicians would prescribe instead of isotretinoin.

Methods

In March 2020, we administered an anonymous online survey consisting of 12 multiple-choice questions to verified board-certified dermatologists in the United States using a social media group. The University of Rochester’s (Rochester, New York) institutional review board determined that our protocol met criteria for exemption (IRB STUDY00004693).

Statistical Analysis—Primary analyses used Pearson χ² tests to identify significant differences among respondent groups, practice settings, age of respondents, and time spent registering patients for iPLEDGE.

Results

Survey results from 510 respondents are summarized in the Table.

Burden of iPLEDGE—Of the respondents, 336 (65.9%) were frequent prescribers of isotretinoin, 166 (32.5%) were infrequent prescribers, and 8 (1.6%) were never prescribers. Significantly more isotretinoin prescribers estimated that their offices spend 16 to 30 minutes registering a new isotretinoin patient with the iPLEDGE program (289 [57.6%]) compared with 0 to 15 minutes (140 [27.9%]), 31 to 45 minutes (57 [11.3%]), and morethan 45 minutes (16 [3.2%])(χ²₃=22.09, P<.0001). Furthermore, 150 dermatologists reported sometimes not prescribing, and 2 reported never prescribing isotretinoin because of the burden of iPLEDGE.

Systemic Agents Prescribed Instead of Isotretinoin—Of the respondents, 73.0% (n=111) prescribed spironolactone to female patients and 88.8% (n=135) prescribed oral antibiotics to male patients instead of isotretinoin. Spironolactone typically is not prescribed to male patients with acne because of its feminizing side effects, such as gynecomastia.⁵ According to the American Academy of Dermatology guidelines on acne, systemic antibiotic usage should be limited to the shortest possible duration (ie, less than 3–4 months) because of potential bacterial resistance and reported associations with inflammatory bowel disease, Clostridium difficile infection, and candidiasis.^6,7

 

Prescriber Demographics—The frequency of not prescribing isotretinoin did not vary by practice setting (χ ²₄=6.44, P=.1689) but did vary by age of the dermatologist (χ²₃=15.57, P=.0014). Dermatologists younger than 46 years were more likely (Figure) to report not prescribing isotretinoin because of the administrative burden of iPLEDGE. We speculate that this is because younger dermatologists are less established in their practices and therefore may have less support to complete registration without interruption of clinic workflow.

Comment

The results of our survey suggest that the administrative burden of iPLEDGE may be compelling prescribers to refrain from prescribing isotretinoin therapy to appropriate candidates when it would otherwise be the drug of choice.

Recent Changes to iPLEDGE—The FDA recently approved a modification to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) program based on the advocacy efforts from the American Academy of Dermatology. Starting December 13, 2021, the 3 patient risk categories were consolidated into 2 gender-neutral categories: patients who can get pregnant and patients who cannot get pregnant.⁸ The iPLEDGE website was transitioned to a new system, and all iPLEDGE REMS users had to update their iPLEDGE accounts. After the implementation of the modified program, user access issues arose, leading to delayed treatment when patients, providers, and pharmacists were all locked out of the online system; users also experienced long hold times with the call center.⁸ This change highlights the ongoing critical need for a streamlined program that increases patient access to isotretinoin while maintaining safety.

Study Limitations—The main limitation of this study was the inability to calculate a true response rate to our survey. We distributed the survey via social media to maintain anonymity of the respondents. We could not track how many saw the link to compare with the number of respondents. Therefore, the only way we could calculate a response rate was with the total number of members in the group, which fluctuated around 4000 at the time we administered the survey. We calculated that we would need at least 351 responses to have a 5% margin of error at 95% confidence for our results to be generalizable and significant. We ultimately received 510 responses, which gave us a 4.05% margin of error at 95% confidence and an estimated 12.7% response rate. Since some members of the group are not active and did not see the survey link, our true response rate was likely higher. Therefore, we concluded that the survey was successful, and our significant responses were representative of US dermatologists.

Suggestions to Improve iPLEDGE Process—Our survey study should facilitate further discussions on the importance of simplifying iPLEDGE. One suggestion for improving iPLEDGE is to remove the initial registration month so care is not delayed. Currently, a patient who can get pregnant must be on 2 forms of contraception for 30 days after they register as a patient before they are eligible to fill their prescription.⁴ This process is unnecessarily long and arduous and could be eliminated as long as the patient has already been on an effective form of contraception and has a negative pregnancy test on the day of registration. The need to repeat contraception comprehension questions monthly is redundant and also could be removed. Another suggestion is to remove the category of patients who cannot become pregnant from the system entirely. Isotretinoin does not appear to be associated with adverse psychiatric effects as shown through the systematic review and meta-analysis of numerous studies.⁹ If anything, the treatment of acne with isotretinoin appears to mitigate depressive symptoms. The iPLEDGE program does not manage this largely debunked idea. Because the program’s sole goal is to manage the risk of isotretinoin’s teratogenicity, the category of those who cannot become pregnant should not be included.

Conclusion

This survey highlights the burdens of iPLEDGE for dermatologists and the need for a more streamlined risk management program. The burden was felt equally among all practice types but especially by younger dermatologists (<46 years). This time-consuming program is deterring some dermatologists from prescribing isotretinoin and ultimately limiting patient access to an effective medication.

Acknowledgment—The authors thank all of the responding clinicians who provided insight into the impact of iPLEDGE on their isotretinoin prescribing patterns.

Isotretinoin is the most effective treatment of recalcitrant acne, but because of its teratogenicity and potential association with psychiatric adverse effects, it has been heavily regulated by the US Food and Drug Administration (FDA) through the iPLEDGE program since 2006.^1,2 To manage the risk of teratogenicity associated with isotretinoin, various pregnancy prevention programs have been developed, but none of these programs have demonstrated a zero fetal exposure rate. The FDA reported 122 isotretinoin-exposed pregnancies during the first year iPLEDGE was implemented, which was a slight increase from the 120 pregnancies reported the year after the implementation of the System to Manage Accutane-Related Teratogenicity program, iPLEDGE’s predecessor.³ The iPLEDGE program requires registration of all wholesalers distributing isotretinoin, all health care providers prescribing isotretinoin, all pharmacies dispensing isotretinoin, and all female and male patients prescribed isotretinoin to create a verifiable link that only enables patients who have met all criteria to pick up their prescriptions. For patients of reproductive potential, there are additional qualification criteria and monthly requirements; before receiving their prescription every month, patients of reproductive potential must undergo a urine or serum pregnancy test with negative results, and patients must be counseled by prescribers regarding the risks of the drug and verify they are using 2 methods of contraception (or practicing abstinence) each month before completing online questions that test their understanding of the drug’s side effects and their chosen methods of contraception.⁴ These requirements place burdens on both patients and prescribers. Studies have shown that in the 2 years after the implementation of iPLEDGE, there was a 29% decrease in isotretinoin prescriptions.^1-3

We conducted a survey study to see if clinicians chose not to prescribe isotretinoin to appropriate candidates specifically because of the administrative burden of iPLEDGE. Secondarily, we investigated the medications these clinicians would prescribe instead of isotretinoin.

Methods

In March 2020, we administered an anonymous online survey consisting of 12 multiple-choice questions to verified board-certified dermatologists in the United States using a social media group. The University of Rochester’s (Rochester, New York) institutional review board determined that our protocol met criteria for exemption (IRB STUDY00004693).

Statistical Analysis—Primary analyses used Pearson χ² tests to identify significant differences among respondent groups, practice settings, age of respondents, and time spent registering patients for iPLEDGE.

Results

Survey results from 510 respondents are summarized in the Table.

Burden of iPLEDGE—Of the respondents, 336 (65.9%) were frequent prescribers of isotretinoin, 166 (32.5%) were infrequent prescribers, and 8 (1.6%) were never prescribers. Significantly more isotretinoin prescribers estimated that their offices spend 16 to 30 minutes registering a new isotretinoin patient with the iPLEDGE program (289 [57.6%]) compared with 0 to 15 minutes (140 [27.9%]), 31 to 45 minutes (57 [11.3%]), and morethan 45 minutes (16 [3.2%])(χ²₃=22.09, P<.0001). Furthermore, 150 dermatologists reported sometimes not prescribing, and 2 reported never prescribing isotretinoin because of the burden of iPLEDGE.

Systemic Agents Prescribed Instead of Isotretinoin—Of the respondents, 73.0% (n=111) prescribed spironolactone to female patients and 88.8% (n=135) prescribed oral antibiotics to male patients instead of isotretinoin. Spironolactone typically is not prescribed to male patients with acne because of its feminizing side effects, such as gynecomastia.⁵ According to the American Academy of Dermatology guidelines on acne, systemic antibiotic usage should be limited to the shortest possible duration (ie, less than 3–4 months) because of potential bacterial resistance and reported associations with inflammatory bowel disease, Clostridium difficile infection, and candidiasis.^6,7

 

Prescriber Demographics—The frequency of not prescribing isotretinoin did not vary by practice setting (χ ²₄=6.44, P=.1689) but did vary by age of the dermatologist (χ²₃=15.57, P=.0014). Dermatologists younger than 46 years were more likely (Figure) to report not prescribing isotretinoin because of the administrative burden of iPLEDGE. We speculate that this is because younger dermatologists are less established in their practices and therefore may have less support to complete registration without interruption of clinic workflow.

Comment

The results of our survey suggest that the administrative burden of iPLEDGE may be compelling prescribers to refrain from prescribing isotretinoin therapy to appropriate candidates when it would otherwise be the drug of choice.

Recent Changes to iPLEDGE—The FDA recently approved a modification to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) program based on the advocacy efforts from the American Academy of Dermatology. Starting December 13, 2021, the 3 patient risk categories were consolidated into 2 gender-neutral categories: patients who can get pregnant and patients who cannot get pregnant.⁸ The iPLEDGE website was transitioned to a new system, and all iPLEDGE REMS users had to update their iPLEDGE accounts. After the implementation of the modified program, user access issues arose, leading to delayed treatment when patients, providers, and pharmacists were all locked out of the online system; users also experienced long hold times with the call center.⁸ This change highlights the ongoing critical need for a streamlined program that increases patient access to isotretinoin while maintaining safety.

Study Limitations—The main limitation of this study was the inability to calculate a true response rate to our survey. We distributed the survey via social media to maintain anonymity of the respondents. We could not track how many saw the link to compare with the number of respondents. Therefore, the only way we could calculate a response rate was with the total number of members in the group, which fluctuated around 4000 at the time we administered the survey. We calculated that we would need at least 351 responses to have a 5% margin of error at 95% confidence for our results to be generalizable and significant. We ultimately received 510 responses, which gave us a 4.05% margin of error at 95% confidence and an estimated 12.7% response rate. Since some members of the group are not active and did not see the survey link, our true response rate was likely higher. Therefore, we concluded that the survey was successful, and our significant responses were representative of US dermatologists.

Suggestions to Improve iPLEDGE Process—Our survey study should facilitate further discussions on the importance of simplifying iPLEDGE. One suggestion for improving iPLEDGE is to remove the initial registration month so care is not delayed. Currently, a patient who can get pregnant must be on 2 forms of contraception for 30 days after they register as a patient before they are eligible to fill their prescription.⁴ This process is unnecessarily long and arduous and could be eliminated as long as the patient has already been on an effective form of contraception and has a negative pregnancy test on the day of registration. The need to repeat contraception comprehension questions monthly is redundant and also could be removed. Another suggestion is to remove the category of patients who cannot become pregnant from the system entirely. Isotretinoin does not appear to be associated with adverse psychiatric effects as shown through the systematic review and meta-analysis of numerous studies.⁹ If anything, the treatment of acne with isotretinoin appears to mitigate depressive symptoms. The iPLEDGE program does not manage this largely debunked idea. Because the program’s sole goal is to manage the risk of isotretinoin’s teratogenicity, the category of those who cannot become pregnant should not be included.

Conclusion

This survey highlights the burdens of iPLEDGE for dermatologists and the need for a more streamlined risk management program. The burden was felt equally among all practice types but especially by younger dermatologists (<46 years). This time-consuming program is deterring some dermatologists from prescribing isotretinoin and ultimately limiting patient access to an effective medication.

Acknowledgment—The authors thank all of the responding clinicians who provided insight into the impact of iPLEDGE on their isotretinoin prescribing patterns.

Isotretinoin is the most effective treatment of recalcitrant acne, but because of its teratogenicity and potential association with psychiatric adverse effects, it has been heavily regulated by the US Food and Drug Administration (FDA) through the iPLEDGE program since 2006.^1,2 To manage the risk of teratogenicity associated with isotretinoin, various pregnancy prevention programs have been developed, but none of these programs have demonstrated a zero fetal exposure rate. The FDA reported 122 isotretinoin-exposed pregnancies during the first year iPLEDGE was implemented, which was a slight increase from the 120 pregnancies reported the year after the implementation of the System to Manage Accutane-Related Teratogenicity program, iPLEDGE’s predecessor.³ The iPLEDGE program requires registration of all wholesalers distributing isotretinoin, all health care providers prescribing isotretinoin, all pharmacies dispensing isotretinoin, and all female and male patients prescribed isotretinoin to create a verifiable link that only enables patients who have met all criteria to pick up their prescriptions. For patients of reproductive potential, there are additional qualification criteria and monthly requirements; before receiving their prescription every month, patients of reproductive potential must undergo a urine or serum pregnancy test with negative results, and patients must be counseled by prescribers regarding the risks of the drug and verify they are using 2 methods of contraception (or practicing abstinence) each month before completing online questions that test their understanding of the drug’s side effects and their chosen methods of contraception.⁴ These requirements place burdens on both patients and prescribers. Studies have shown that in the 2 years after the implementation of iPLEDGE, there was a 29% decrease in isotretinoin prescriptions.^1-3

We conducted a survey study to see if clinicians chose not to prescribe isotretinoin to appropriate candidates specifically because of the administrative burden of iPLEDGE. Secondarily, we investigated the medications these clinicians would prescribe instead of isotretinoin.

Methods

In March 2020, we administered an anonymous online survey consisting of 12 multiple-choice questions to verified board-certified dermatologists in the United States using a social media group. The University of Rochester’s (Rochester, New York) institutional review board determined that our protocol met criteria for exemption (IRB STUDY00004693).

Statistical Analysis—Primary analyses used Pearson χ² tests to identify significant differences among respondent groups, practice settings, age of respondents, and time spent registering patients for iPLEDGE.

Results

Survey results from 510 respondents are summarized in the Table.

Burden of iPLEDGE—Of the respondents, 336 (65.9%) were frequent prescribers of isotretinoin, 166 (32.5%) were infrequent prescribers, and 8 (1.6%) were never prescribers. Significantly more isotretinoin prescribers estimated that their offices spend 16 to 30 minutes registering a new isotretinoin patient with the iPLEDGE program (289 [57.6%]) compared with 0 to 15 minutes (140 [27.9%]), 31 to 45 minutes (57 [11.3%]), and morethan 45 minutes (16 [3.2%])(χ²₃=22.09, P<.0001). Furthermore, 150 dermatologists reported sometimes not prescribing, and 2 reported never prescribing isotretinoin because of the burden of iPLEDGE.

Systemic Agents Prescribed Instead of Isotretinoin—Of the respondents, 73.0% (n=111) prescribed spironolactone to female patients and 88.8% (n=135) prescribed oral antibiotics to male patients instead of isotretinoin. Spironolactone typically is not prescribed to male patients with acne because of its feminizing side effects, such as gynecomastia.⁵ According to the American Academy of Dermatology guidelines on acne, systemic antibiotic usage should be limited to the shortest possible duration (ie, less than 3–4 months) because of potential bacterial resistance and reported associations with inflammatory bowel disease, Clostridium difficile infection, and candidiasis.^6,7

 

Prescriber Demographics—The frequency of not prescribing isotretinoin did not vary by practice setting (χ ²₄=6.44, P=.1689) but did vary by age of the dermatologist (χ²₃=15.57, P=.0014). Dermatologists younger than 46 years were more likely (Figure) to report not prescribing isotretinoin because of the administrative burden of iPLEDGE. We speculate that this is because younger dermatologists are less established in their practices and therefore may have less support to complete registration without interruption of clinic workflow.

Comment

The results of our survey suggest that the administrative burden of iPLEDGE may be compelling prescribers to refrain from prescribing isotretinoin therapy to appropriate candidates when it would otherwise be the drug of choice.

Recent Changes to iPLEDGE—The FDA recently approved a modification to the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) program based on the advocacy efforts from the American Academy of Dermatology. Starting December 13, 2021, the 3 patient risk categories were consolidated into 2 gender-neutral categories: patients who can get pregnant and patients who cannot get pregnant.⁸ The iPLEDGE website was transitioned to a new system, and all iPLEDGE REMS users had to update their iPLEDGE accounts. After the implementation of the modified program, user access issues arose, leading to delayed treatment when patients, providers, and pharmacists were all locked out of the online system; users also experienced long hold times with the call center.⁸ This change highlights the ongoing critical need for a streamlined program that increases patient access to isotretinoin while maintaining safety.

Study Limitations—The main limitation of this study was the inability to calculate a true response rate to our survey. We distributed the survey via social media to maintain anonymity of the respondents. We could not track how many saw the link to compare with the number of respondents. Therefore, the only way we could calculate a response rate was with the total number of members in the group, which fluctuated around 4000 at the time we administered the survey. We calculated that we would need at least 351 responses to have a 5% margin of error at 95% confidence for our results to be generalizable and significant. We ultimately received 510 responses, which gave us a 4.05% margin of error at 95% confidence and an estimated 12.7% response rate. Since some members of the group are not active and did not see the survey link, our true response rate was likely higher. Therefore, we concluded that the survey was successful, and our significant responses were representative of US dermatologists.

Suggestions to Improve iPLEDGE Process—Our survey study should facilitate further discussions on the importance of simplifying iPLEDGE. One suggestion for improving iPLEDGE is to remove the initial registration month so care is not delayed. Currently, a patient who can get pregnant must be on 2 forms of contraception for 30 days after they register as a patient before they are eligible to fill their prescription.⁴ This process is unnecessarily long and arduous and could be eliminated as long as the patient has already been on an effective form of contraception and has a negative pregnancy test on the day of registration. The need to repeat contraception comprehension questions monthly is redundant and also could be removed. Another suggestion is to remove the category of patients who cannot become pregnant from the system entirely. Isotretinoin does not appear to be associated with adverse psychiatric effects as shown through the systematic review and meta-analysis of numerous studies.⁹ If anything, the treatment of acne with isotretinoin appears to mitigate depressive symptoms. The iPLEDGE program does not manage this largely debunked idea. Because the program’s sole goal is to manage the risk of isotretinoin’s teratogenicity, the category of those who cannot become pregnant should not be included.

Conclusion

This survey highlights the burdens of iPLEDGE for dermatologists and the need for a more streamlined risk management program. The burden was felt equally among all practice types but especially by younger dermatologists (<46 years). This time-consuming program is deterring some dermatologists from prescribing isotretinoin and ultimately limiting patient access to an effective medication.

Acknowledgment—The authors thank all of the responding clinicians who provided insight into the impact of iPLEDGE on their isotretinoin prescribing patterns.