Pharmacology

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.

Background

From 2000-2022 there were over 200 new drug and over 500 indication approvals specific to oncology. The rate of approvals has increased exponentially, making it difficult to maintain an up-to-date, standardized practice. Nationally, Veterans Affairs (VA) formulary decisions can take time given a lengthy approval process. Locally, the need was identified to incorporate new drugs and data into practice more rapidly. When bringing requests to the facility Pharmacy and Therapeutics (P&T) Committee, it was recognized that the membership consisting of non-oncology practitioners did not allow for meaningful discussion of utilization. In 2017, a dedicated oncology drug review committee (DRC) comprised of oncology practitioners and a facility formulary representative was created as a P&T workgroup. Purpose: Evaluate and describe the utility of forming a local oncology DRC to incorporate new drugs and data into practice.

Methods

DRC minutes from December 2017 to May 2023 were reviewed. Discussion items were categorized into type of review. Date of local review was compared to national formulary criteria for use publication dates, and date of FDA approval for new drugs or publication date for new data, where applicable. Items were excluded if crucial information was missing from minutes. Descriptive statistics were used.

Results

Over 65 months, 38 meetings were held. Thirty total members include: pharmacists, physicians, fellows, and advanced practice providers. Items reviewed included: 36 new drugs (ND), 36 new indications/data (NI), 14 institutional preferences, 10 new dosage form/biosimilars, 4 drug shortages and 2 others. The median time from ND approval to discussion was 3 months (n= 36, IQR 3-6) and NI from publication was 3 months (n=30, IQR 1-8). Nearly all (34/36, 94%) ND were reviewed prior to national review. Local review was a median of 7 months before national, with 11 drugs currently having no published national criteria for use (n=25, IQR 2-12).

Conclusions

DRC formation has enabled faster incorporation of new drugs/indications into practice. It has also created an appropriate forum for in-depth utilization discussions, pharmacoeconomic stewardship, and sharing of formulary and medication related information. VA Health Systems could consider implementing similar committees to review and implement up-to-date oncology practices.

Background

From 2000-2022 there were over 200 new drug and over 500 indication approvals specific to oncology. The rate of approvals has increased exponentially, making it difficult to maintain an up-to-date, standardized practice. Nationally, Veterans Affairs (VA) formulary decisions can take time given a lengthy approval process. Locally, the need was identified to incorporate new drugs and data into practice more rapidly. When bringing requests to the facility Pharmacy and Therapeutics (P&T) Committee, it was recognized that the membership consisting of non-oncology practitioners did not allow for meaningful discussion of utilization. In 2017, a dedicated oncology drug review committee (DRC) comprised of oncology practitioners and a facility formulary representative was created as a P&T workgroup. Purpose: Evaluate and describe the utility of forming a local oncology DRC to incorporate new drugs and data into practice.

Methods

DRC minutes from December 2017 to May 2023 were reviewed. Discussion items were categorized into type of review. Date of local review was compared to national formulary criteria for use publication dates, and date of FDA approval for new drugs or publication date for new data, where applicable. Items were excluded if crucial information was missing from minutes. Descriptive statistics were used.

Results

Over 65 months, 38 meetings were held. Thirty total members include: pharmacists, physicians, fellows, and advanced practice providers. Items reviewed included: 36 new drugs (ND), 36 new indications/data (NI), 14 institutional preferences, 10 new dosage form/biosimilars, 4 drug shortages and 2 others. The median time from ND approval to discussion was 3 months (n= 36, IQR 3-6) and NI from publication was 3 months (n=30, IQR 1-8). Nearly all (34/36, 94%) ND were reviewed prior to national review. Local review was a median of 7 months before national, with 11 drugs currently having no published national criteria for use (n=25, IQR 2-12).

Conclusions

DRC formation has enabled faster incorporation of new drugs/indications into practice. It has also created an appropriate forum for in-depth utilization discussions, pharmacoeconomic stewardship, and sharing of formulary and medication related information. VA Health Systems could consider implementing similar committees to review and implement up-to-date oncology practices.

Background

From 2000-2022 there were over 200 new drug and over 500 indication approvals specific to oncology. The rate of approvals has increased exponentially, making it difficult to maintain an up-to-date, standardized practice. Nationally, Veterans Affairs (VA) formulary decisions can take time given a lengthy approval process. Locally, the need was identified to incorporate new drugs and data into practice more rapidly. When bringing requests to the facility Pharmacy and Therapeutics (P&T) Committee, it was recognized that the membership consisting of non-oncology practitioners did not allow for meaningful discussion of utilization. In 2017, a dedicated oncology drug review committee (DRC) comprised of oncology practitioners and a facility formulary representative was created as a P&T workgroup. Purpose: Evaluate and describe the utility of forming a local oncology DRC to incorporate new drugs and data into practice.

Methods

DRC minutes from December 2017 to May 2023 were reviewed. Discussion items were categorized into type of review. Date of local review was compared to national formulary criteria for use publication dates, and date of FDA approval for new drugs or publication date for new data, where applicable. Items were excluded if crucial information was missing from minutes. Descriptive statistics were used.

Results

Over 65 months, 38 meetings were held. Thirty total members include: pharmacists, physicians, fellows, and advanced practice providers. Items reviewed included: 36 new drugs (ND), 36 new indications/data (NI), 14 institutional preferences, 10 new dosage form/biosimilars, 4 drug shortages and 2 others. The median time from ND approval to discussion was 3 months (n= 36, IQR 3-6) and NI from publication was 3 months (n=30, IQR 1-8). Nearly all (34/36, 94%) ND were reviewed prior to national review. Local review was a median of 7 months before national, with 11 drugs currently having no published national criteria for use (n=25, IQR 2-12).

Conclusions

DRC formation has enabled faster incorporation of new drugs/indications into practice. It has also created an appropriate forum for in-depth utilization discussions, pharmacoeconomic stewardship, and sharing of formulary and medication related information. VA Health Systems could consider implementing similar committees to review and implement up-to-date oncology practices.

Background

Oral anti-cancer therapies have quickly moved to the forefront of cancer treatment for several oncologic disease states. While these treatments have led to improvements in prognosis and ease of administration, many of these agents carry the risk of serious short- and long-term toxicities affecting the cardiovascular system. This prompted the Journal of the American Heart Association (JAHA) to release special guidance focused on cardiovascular monitoring strategies for anti-cancer agents. The primary objective of this retrospective review was to evaluate compliance with cardiovascular monitoring based on JAHA cardio-oncologic guidelines. The secondary objective was to assess disparities in cardiovascular monitoring based on markers of equity such as race/ ethnicity, rurality, socioeconomic status and gender.

Methods

Patients who initiated pazopanib, cabozantinib, lenvatinib, axitinib, regorafenib, nilotinib, ibrutinib, sorafenib, sunitinib, ponatinib or everolimus between January 1, 2019 and December 31, 2022 at a VHA VISN 12 site with oncology services were followed forward until treatment discontinuation or 12 months of therapy had been completed. Data was acquired utilizing the VA Informatics and Computing Infrastructure (VINCI) and the Corporate Data Warehouse (CDW). The following cardiovascular monitoring markers were recorded at baseline and months 3, 6, 9 and 12 after initiation anti-cancer therapy: blood pressure, blood glucose, cholesterol, ECG and echocardiogram. Descriptive statistics were used to examine all continuous variables, while frequencies were used to examine categorical variables. Univariate statistics were performed on all items respectively.

Results

A total of 219 patients were identified initiating pre-specified oral anti-cancer therapies during the study time period. Of these, a total of n=145 met study inclusion criteria. 97% were male (n=141), 80% (n=116) had a racial background of white, 36% (n=52) live in rural or highly rural locations and 23% (n=34) lived in a high poverty area. Based on the primary endpoint, the mean compliance with recommended cardiovascular monitoring was 44.95% [IQR 12]. There was no statistically significant difference in cardiovascular monitoring based on equity.

Conclusions

Overall uptake of cardiovascular monitoring markers recommended by JAHA guidance is low. We plan to evaluate methods to increase these measures, utilizing clinical pharmacy provider support throughout VISN 12.

Background

Oral anti-cancer therapies have quickly moved to the forefront of cancer treatment for several oncologic disease states. While these treatments have led to improvements in prognosis and ease of administration, many of these agents carry the risk of serious short- and long-term toxicities affecting the cardiovascular system. This prompted the Journal of the American Heart Association (JAHA) to release special guidance focused on cardiovascular monitoring strategies for anti-cancer agents. The primary objective of this retrospective review was to evaluate compliance with cardiovascular monitoring based on JAHA cardio-oncologic guidelines. The secondary objective was to assess disparities in cardiovascular monitoring based on markers of equity such as race/ ethnicity, rurality, socioeconomic status and gender.

Methods

Patients who initiated pazopanib, cabozantinib, lenvatinib, axitinib, regorafenib, nilotinib, ibrutinib, sorafenib, sunitinib, ponatinib or everolimus between January 1, 2019 and December 31, 2022 at a VHA VISN 12 site with oncology services were followed forward until treatment discontinuation or 12 months of therapy had been completed. Data was acquired utilizing the VA Informatics and Computing Infrastructure (VINCI) and the Corporate Data Warehouse (CDW). The following cardiovascular monitoring markers were recorded at baseline and months 3, 6, 9 and 12 after initiation anti-cancer therapy: blood pressure, blood glucose, cholesterol, ECG and echocardiogram. Descriptive statistics were used to examine all continuous variables, while frequencies were used to examine categorical variables. Univariate statistics were performed on all items respectively.

Results

A total of 219 patients were identified initiating pre-specified oral anti-cancer therapies during the study time period. Of these, a total of n=145 met study inclusion criteria. 97% were male (n=141), 80% (n=116) had a racial background of white, 36% (n=52) live in rural or highly rural locations and 23% (n=34) lived in a high poverty area. Based on the primary endpoint, the mean compliance with recommended cardiovascular monitoring was 44.95% [IQR 12]. There was no statistically significant difference in cardiovascular monitoring based on equity.

Conclusions

Overall uptake of cardiovascular monitoring markers recommended by JAHA guidance is low. We plan to evaluate methods to increase these measures, utilizing clinical pharmacy provider support throughout VISN 12.

Background

Oral anti-cancer therapies have quickly moved to the forefront of cancer treatment for several oncologic disease states. While these treatments have led to improvements in prognosis and ease of administration, many of these agents carry the risk of serious short- and long-term toxicities affecting the cardiovascular system. This prompted the Journal of the American Heart Association (JAHA) to release special guidance focused on cardiovascular monitoring strategies for anti-cancer agents. The primary objective of this retrospective review was to evaluate compliance with cardiovascular monitoring based on JAHA cardio-oncologic guidelines. The secondary objective was to assess disparities in cardiovascular monitoring based on markers of equity such as race/ ethnicity, rurality, socioeconomic status and gender.

Methods

Patients who initiated pazopanib, cabozantinib, lenvatinib, axitinib, regorafenib, nilotinib, ibrutinib, sorafenib, sunitinib, ponatinib or everolimus between January 1, 2019 and December 31, 2022 at a VHA VISN 12 site with oncology services were followed forward until treatment discontinuation or 12 months of therapy had been completed. Data was acquired utilizing the VA Informatics and Computing Infrastructure (VINCI) and the Corporate Data Warehouse (CDW). The following cardiovascular monitoring markers were recorded at baseline and months 3, 6, 9 and 12 after initiation anti-cancer therapy: blood pressure, blood glucose, cholesterol, ECG and echocardiogram. Descriptive statistics were used to examine all continuous variables, while frequencies were used to examine categorical variables. Univariate statistics were performed on all items respectively.

Results

A total of 219 patients were identified initiating pre-specified oral anti-cancer therapies during the study time period. Of these, a total of n=145 met study inclusion criteria. 97% were male (n=141), 80% (n=116) had a racial background of white, 36% (n=52) live in rural or highly rural locations and 23% (n=34) lived in a high poverty area. Based on the primary endpoint, the mean compliance with recommended cardiovascular monitoring was 44.95% [IQR 12]. There was no statistically significant difference in cardiovascular monitoring based on equity.

Conclusions

Overall uptake of cardiovascular monitoring markers recommended by JAHA guidance is low. We plan to evaluate methods to increase these measures, utilizing clinical pharmacy provider support throughout VISN 12.

The emergency department (ED) is estimated to provide half of all medical care in the United States, serving as a conduit between ambulatory care and inpatient settings.¹ According to the Centers for Disease Control and Prevention, around 11 million antibiotic prescriptions were written in EDs in 2021.² A previous study conducted at a US Department of Veterans (VA) Affairs medical center found that about 40% of all antimicrobial use in the ED was inappropriate.³ The ED is a critical and high-yield space for antimicrobial stewardship efforts.⁴

Urinary tract infections (UTIs) are one of the most common reasons for ED visits.⁴ In 2018, there were about 3 million UTI discharge diagnoses reported in the US.⁵ Diagnosis and management of UTIs can vary depending on patient sex, upper or lower urinary tract involvement, and the severity of the infection.⁶ Most UTIs are uncomplicated and can be safely treated with oral antibiotics at home; however, if mismanaged, they can lead to increased morbidity and mortality.⁶

Antimicrobial prescribing in the ED is predominantly empiric with challenges such as diverse patient needs, rising antimicrobial resistance, and limited microbiologic data at the time of discharge.⁶ The lack of a standardized process for urine culture follow-up after discharge represents another major complicating factor in the outpatient management of UTIs. Studies have shown that ED pharmacists play a vital role in providing quality follow-up care by optimizing antimicrobial use, resulting in improved patient outcomes in various infectious syndromes, including UTIs.^7-13

Program Description

In June 2021, the VA Greater Los Angeles Healthcare System (VAGLAHS) piloted an ED pharmacist-led aftercare program to optimize postdischarge antimicrobial therapy management of UTIs. After a patient is discharged from the ED, the clinical pharmacist reviews urine culture results, interprets available antimicrobial susceptibility, conducts patient interviews, adjusts for patient-specific factors, and addresses potential antibiotic-associated adverse events. The ED pharmacist is then responsible for managing therapy changes in consultation with an ED health care practitioner (HCP).

Methods

This single center, retrospective chart review included veterans who were discharged with an oral antibiotic for UTI treatment from the VAGLAHS ED and evaluated by clinical pharmacists between June 1, 2021, and June 30, 2022. For patients with multiple ED visits, only the initial ED encounter was reviewed. Patients were excluded if they had a complicated UTI diagnosis requiring intravenous antibiotics or if they were admitted to the hospital. Data were generated through the Corporate Data Warehouse by VAGLAHS Pharmacy Informatics Service. Each patient was assigned a random number using the Microsoft Excel formula =RAND( ) and then sorted in chronological order to ensure randomization at baseline prior to data collection.

The primary aim of this quality improvement project was to characterize the impact of ED pharmacist-led interventions by evaluating the proportion of empiric to targeted therapy adjustments, antibiotic therapy discontinuation, and unmodified index treatment. The secondary objectives evaluated time to ED pharmacist aftercare follow-up, days of antibiotic exposure avoided, 30-day ED visits related to a urinary source, and transition of care documentation. Descriptive statistics were performed; median and IQR were calculated in Microsoft Excel.

A total of 548 ED UTI encounters were identified, including 449 patients with an index ED UTI aftercare follow-up evaluation. Of the 246 randomly screened patients, 200 veterans met inclusion criteria. The median age of included patients was 73 years and most (83.0%) were male (Table 1). One hundred thirty-two patients (66.0%) had a cystitis diagnosis, followed by complicated UTI (14.0%) and catheter-associated UTI (11.0%). The most frequently isolated uropathogen was Escherichia coli (30.5%). ß-lactams were prescribed for empiric treatment to 121 patients (60.5%), followed by 36 fluoroquinolones prescriptions (18.0%). The median treatment duration was 7 days.

The median time to ED pharmacist UTI aftercare evaluation was 2 days (Table 2). Sixty-seven cases required pharmacist intervention, which included 34 transitions to targeted therapy (17.0%) and 33 antibiotic discontinuations (16.5%). A total of 144 days of antibiotic exposure was avoided (ie, days antibiotic was prescribed minus days therapy administered). The majority of cases without modification to index therapy were due to appropriate empiric treatment selection (49.0%). Twelve (6.0%) patients had a subsequent urinary-related ED visit within 30 days due to 8 cases of persistent and/or worsening urinary symptoms (66.7%) and 2 cases of recurrent UTI (16.7%).

Discussion

Outpatient antibiotic prescribing for UTI management in the ED is challenging due to the absence of microbiologic data at time of diagnosis and lack of consistent transition of care follow-up.⁶ The VAGLAHS ED UTI aftercare program piloted a pharmacist-driven protocol for review of all urine cultures and optimization of antibiotic therapy.

Most ED UTI discharges that did not require pharmacist intervention had empiric treatment selection active against the clinical isolates. This suggests that the ED prescribing practices concur with theVAGLAHS antibiogram and treatment guidelines. Clinical pharmacists intervened in about one-third of UTI cases, which included modification or discontinuation of therapy. Further review of these cases demonstrated that about half of those with a subsequent 30-day ED visit related to a urinary source had therapy modification. Most patients with a 30-day ED visit had persistent and/or worsening urinary symptoms, prompting further exploratory workup.

Although this project did not evaluate time from urine culture results to aftercare review, the VAGLAHS ED pharmacists had a median follow-up time of 48 hours. This timeline mirrors the typical duration for urine culture results, suggesting that the pilot program allowed for real time pharmacist review and intervention. Consequently, this initiative resulted in the avoidance of 144 unnecessary days of antibiotic exposure.

While the current protocol highlights the work that ED pharmacists provide postdischarge, there are additional opportunities for pharmacist intervention. For example, one-third of these clinical encounters were completed without HCP notification, indicating an ongoing need to ensure continuity of care. Additionally, all 16 patients diagnosed with asymptomatic bacteriuria were discharged with an oral antibiotic, highlighting an opportunity to further optimize antibiotic prescribing prior to discharge. ED pharmacists continue to play an important role in mitigating inappropriate and unnecessary antibiotic use, which will reduce antibiotic-related adverse drug reactions, Clostridioides difficile infection, and antimicrobial resistance.

Limitations

Inconsistent and incomplete documentation of clinical data in the electronic health record made the characterization of patient encounters challenging. Furthermore, ED HCPs varying clinical practices may have impacted the heterogeneity of UTI diagnosis and management at VAGLAHS.

Conclusions

Implementation of an ED pharmacist-driven UTI aftercare program at VAGLAHS reduced unnecessary antimicrobial exposure, improved antibiotic management, and ensured continuity of care postdischarge. Findings from our project implicate possible future pharmacist involvement predischarge, such as targeting inappropriate asymptomatic bacteriuria treatment.^14-16 This pilot program suggested the feasibility of integrating antimicrobial stewardship practices within the ED setting in an ongoing effort to improve the quality of care for veterans.

The emergency department (ED) is estimated to provide half of all medical care in the United States, serving as a conduit between ambulatory care and inpatient settings.¹ According to the Centers for Disease Control and Prevention, around 11 million antibiotic prescriptions were written in EDs in 2021.² A previous study conducted at a US Department of Veterans (VA) Affairs medical center found that about 40% of all antimicrobial use in the ED was inappropriate.³ The ED is a critical and high-yield space for antimicrobial stewardship efforts.⁴

Urinary tract infections (UTIs) are one of the most common reasons for ED visits.⁴ In 2018, there were about 3 million UTI discharge diagnoses reported in the US.⁵ Diagnosis and management of UTIs can vary depending on patient sex, upper or lower urinary tract involvement, and the severity of the infection.⁶ Most UTIs are uncomplicated and can be safely treated with oral antibiotics at home; however, if mismanaged, they can lead to increased morbidity and mortality.⁶

Antimicrobial prescribing in the ED is predominantly empiric with challenges such as diverse patient needs, rising antimicrobial resistance, and limited microbiologic data at the time of discharge.⁶ The lack of a standardized process for urine culture follow-up after discharge represents another major complicating factor in the outpatient management of UTIs. Studies have shown that ED pharmacists play a vital role in providing quality follow-up care by optimizing antimicrobial use, resulting in improved patient outcomes in various infectious syndromes, including UTIs.^7-13

Program Description

In June 2021, the VA Greater Los Angeles Healthcare System (VAGLAHS) piloted an ED pharmacist-led aftercare program to optimize postdischarge antimicrobial therapy management of UTIs. After a patient is discharged from the ED, the clinical pharmacist reviews urine culture results, interprets available antimicrobial susceptibility, conducts patient interviews, adjusts for patient-specific factors, and addresses potential antibiotic-associated adverse events. The ED pharmacist is then responsible for managing therapy changes in consultation with an ED health care practitioner (HCP).

Methods

This single center, retrospective chart review included veterans who were discharged with an oral antibiotic for UTI treatment from the VAGLAHS ED and evaluated by clinical pharmacists between June 1, 2021, and June 30, 2022. For patients with multiple ED visits, only the initial ED encounter was reviewed. Patients were excluded if they had a complicated UTI diagnosis requiring intravenous antibiotics or if they were admitted to the hospital. Data were generated through the Corporate Data Warehouse by VAGLAHS Pharmacy Informatics Service. Each patient was assigned a random number using the Microsoft Excel formula =RAND( ) and then sorted in chronological order to ensure randomization at baseline prior to data collection.

The primary aim of this quality improvement project was to characterize the impact of ED pharmacist-led interventions by evaluating the proportion of empiric to targeted therapy adjustments, antibiotic therapy discontinuation, and unmodified index treatment. The secondary objectives evaluated time to ED pharmacist aftercare follow-up, days of antibiotic exposure avoided, 30-day ED visits related to a urinary source, and transition of care documentation. Descriptive statistics were performed; median and IQR were calculated in Microsoft Excel.

A total of 548 ED UTI encounters were identified, including 449 patients with an index ED UTI aftercare follow-up evaluation. Of the 246 randomly screened patients, 200 veterans met inclusion criteria. The median age of included patients was 73 years and most (83.0%) were male (Table 1). One hundred thirty-two patients (66.0%) had a cystitis diagnosis, followed by complicated UTI (14.0%) and catheter-associated UTI (11.0%). The most frequently isolated uropathogen was Escherichia coli (30.5%). ß-lactams were prescribed for empiric treatment to 121 patients (60.5%), followed by 36 fluoroquinolones prescriptions (18.0%). The median treatment duration was 7 days.

The median time to ED pharmacist UTI aftercare evaluation was 2 days (Table 2). Sixty-seven cases required pharmacist intervention, which included 34 transitions to targeted therapy (17.0%) and 33 antibiotic discontinuations (16.5%). A total of 144 days of antibiotic exposure was avoided (ie, days antibiotic was prescribed minus days therapy administered). The majority of cases without modification to index therapy were due to appropriate empiric treatment selection (49.0%). Twelve (6.0%) patients had a subsequent urinary-related ED visit within 30 days due to 8 cases of persistent and/or worsening urinary symptoms (66.7%) and 2 cases of recurrent UTI (16.7%).

Discussion

Outpatient antibiotic prescribing for UTI management in the ED is challenging due to the absence of microbiologic data at time of diagnosis and lack of consistent transition of care follow-up.⁶ The VAGLAHS ED UTI aftercare program piloted a pharmacist-driven protocol for review of all urine cultures and optimization of antibiotic therapy.

Most ED UTI discharges that did not require pharmacist intervention had empiric treatment selection active against the clinical isolates. This suggests that the ED prescribing practices concur with theVAGLAHS antibiogram and treatment guidelines. Clinical pharmacists intervened in about one-third of UTI cases, which included modification or discontinuation of therapy. Further review of these cases demonstrated that about half of those with a subsequent 30-day ED visit related to a urinary source had therapy modification. Most patients with a 30-day ED visit had persistent and/or worsening urinary symptoms, prompting further exploratory workup.

Although this project did not evaluate time from urine culture results to aftercare review, the VAGLAHS ED pharmacists had a median follow-up time of 48 hours. This timeline mirrors the typical duration for urine culture results, suggesting that the pilot program allowed for real time pharmacist review and intervention. Consequently, this initiative resulted in the avoidance of 144 unnecessary days of antibiotic exposure.

While the current protocol highlights the work that ED pharmacists provide postdischarge, there are additional opportunities for pharmacist intervention. For example, one-third of these clinical encounters were completed without HCP notification, indicating an ongoing need to ensure continuity of care. Additionally, all 16 patients diagnosed with asymptomatic bacteriuria were discharged with an oral antibiotic, highlighting an opportunity to further optimize antibiotic prescribing prior to discharge. ED pharmacists continue to play an important role in mitigating inappropriate and unnecessary antibiotic use, which will reduce antibiotic-related adverse drug reactions, Clostridioides difficile infection, and antimicrobial resistance.

Limitations

Inconsistent and incomplete documentation of clinical data in the electronic health record made the characterization of patient encounters challenging. Furthermore, ED HCPs varying clinical practices may have impacted the heterogeneity of UTI diagnosis and management at VAGLAHS.

Conclusions

Implementation of an ED pharmacist-driven UTI aftercare program at VAGLAHS reduced unnecessary antimicrobial exposure, improved antibiotic management, and ensured continuity of care postdischarge. Findings from our project implicate possible future pharmacist involvement predischarge, such as targeting inappropriate asymptomatic bacteriuria treatment.^14-16 This pilot program suggested the feasibility of integrating antimicrobial stewardship practices within the ED setting in an ongoing effort to improve the quality of care for veterans.

The emergency department (ED) is estimated to provide half of all medical care in the United States, serving as a conduit between ambulatory care and inpatient settings.¹ According to the Centers for Disease Control and Prevention, around 11 million antibiotic prescriptions were written in EDs in 2021.² A previous study conducted at a US Department of Veterans (VA) Affairs medical center found that about 40% of all antimicrobial use in the ED was inappropriate.³ The ED is a critical and high-yield space for antimicrobial stewardship efforts.⁴

Urinary tract infections (UTIs) are one of the most common reasons for ED visits.⁴ In 2018, there were about 3 million UTI discharge diagnoses reported in the US.⁵ Diagnosis and management of UTIs can vary depending on patient sex, upper or lower urinary tract involvement, and the severity of the infection.⁶ Most UTIs are uncomplicated and can be safely treated with oral antibiotics at home; however, if mismanaged, they can lead to increased morbidity and mortality.⁶

Antimicrobial prescribing in the ED is predominantly empiric with challenges such as diverse patient needs, rising antimicrobial resistance, and limited microbiologic data at the time of discharge.⁶ The lack of a standardized process for urine culture follow-up after discharge represents another major complicating factor in the outpatient management of UTIs. Studies have shown that ED pharmacists play a vital role in providing quality follow-up care by optimizing antimicrobial use, resulting in improved patient outcomes in various infectious syndromes, including UTIs.^7-13

Program Description

In June 2021, the VA Greater Los Angeles Healthcare System (VAGLAHS) piloted an ED pharmacist-led aftercare program to optimize postdischarge antimicrobial therapy management of UTIs. After a patient is discharged from the ED, the clinical pharmacist reviews urine culture results, interprets available antimicrobial susceptibility, conducts patient interviews, adjusts for patient-specific factors, and addresses potential antibiotic-associated adverse events. The ED pharmacist is then responsible for managing therapy changes in consultation with an ED health care practitioner (HCP).

Methods

This single center, retrospective chart review included veterans who were discharged with an oral antibiotic for UTI treatment from the VAGLAHS ED and evaluated by clinical pharmacists between June 1, 2021, and June 30, 2022. For patients with multiple ED visits, only the initial ED encounter was reviewed. Patients were excluded if they had a complicated UTI diagnosis requiring intravenous antibiotics or if they were admitted to the hospital. Data were generated through the Corporate Data Warehouse by VAGLAHS Pharmacy Informatics Service. Each patient was assigned a random number using the Microsoft Excel formula =RAND( ) and then sorted in chronological order to ensure randomization at baseline prior to data collection.

The primary aim of this quality improvement project was to characterize the impact of ED pharmacist-led interventions by evaluating the proportion of empiric to targeted therapy adjustments, antibiotic therapy discontinuation, and unmodified index treatment. The secondary objectives evaluated time to ED pharmacist aftercare follow-up, days of antibiotic exposure avoided, 30-day ED visits related to a urinary source, and transition of care documentation. Descriptive statistics were performed; median and IQR were calculated in Microsoft Excel.

A total of 548 ED UTI encounters were identified, including 449 patients with an index ED UTI aftercare follow-up evaluation. Of the 246 randomly screened patients, 200 veterans met inclusion criteria. The median age of included patients was 73 years and most (83.0%) were male (Table 1). One hundred thirty-two patients (66.0%) had a cystitis diagnosis, followed by complicated UTI (14.0%) and catheter-associated UTI (11.0%). The most frequently isolated uropathogen was Escherichia coli (30.5%). ß-lactams were prescribed for empiric treatment to 121 patients (60.5%), followed by 36 fluoroquinolones prescriptions (18.0%). The median treatment duration was 7 days.

The median time to ED pharmacist UTI aftercare evaluation was 2 days (Table 2). Sixty-seven cases required pharmacist intervention, which included 34 transitions to targeted therapy (17.0%) and 33 antibiotic discontinuations (16.5%). A total of 144 days of antibiotic exposure was avoided (ie, days antibiotic was prescribed minus days therapy administered). The majority of cases without modification to index therapy were due to appropriate empiric treatment selection (49.0%). Twelve (6.0%) patients had a subsequent urinary-related ED visit within 30 days due to 8 cases of persistent and/or worsening urinary symptoms (66.7%) and 2 cases of recurrent UTI (16.7%).

Discussion

Outpatient antibiotic prescribing for UTI management in the ED is challenging due to the absence of microbiologic data at time of diagnosis and lack of consistent transition of care follow-up.⁶ The VAGLAHS ED UTI aftercare program piloted a pharmacist-driven protocol for review of all urine cultures and optimization of antibiotic therapy.

Most ED UTI discharges that did not require pharmacist intervention had empiric treatment selection active against the clinical isolates. This suggests that the ED prescribing practices concur with theVAGLAHS antibiogram and treatment guidelines. Clinical pharmacists intervened in about one-third of UTI cases, which included modification or discontinuation of therapy. Further review of these cases demonstrated that about half of those with a subsequent 30-day ED visit related to a urinary source had therapy modification. Most patients with a 30-day ED visit had persistent and/or worsening urinary symptoms, prompting further exploratory workup.

Although this project did not evaluate time from urine culture results to aftercare review, the VAGLAHS ED pharmacists had a median follow-up time of 48 hours. This timeline mirrors the typical duration for urine culture results, suggesting that the pilot program allowed for real time pharmacist review and intervention. Consequently, this initiative resulted in the avoidance of 144 unnecessary days of antibiotic exposure.

While the current protocol highlights the work that ED pharmacists provide postdischarge, there are additional opportunities for pharmacist intervention. For example, one-third of these clinical encounters were completed without HCP notification, indicating an ongoing need to ensure continuity of care. Additionally, all 16 patients diagnosed with asymptomatic bacteriuria were discharged with an oral antibiotic, highlighting an opportunity to further optimize antibiotic prescribing prior to discharge. ED pharmacists continue to play an important role in mitigating inappropriate and unnecessary antibiotic use, which will reduce antibiotic-related adverse drug reactions, Clostridioides difficile infection, and antimicrobial resistance.

Limitations

Inconsistent and incomplete documentation of clinical data in the electronic health record made the characterization of patient encounters challenging. Furthermore, ED HCPs varying clinical practices may have impacted the heterogeneity of UTI diagnosis and management at VAGLAHS.

Conclusions

Implementation of an ED pharmacist-driven UTI aftercare program at VAGLAHS reduced unnecessary antimicrobial exposure, improved antibiotic management, and ensured continuity of care postdischarge. Findings from our project implicate possible future pharmacist involvement predischarge, such as targeting inappropriate asymptomatic bacteriuria treatment.^14-16 This pilot program suggested the feasibility of integrating antimicrobial stewardship practices within the ED setting in an ongoing effort to improve the quality of care for veterans.

Background

Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.^1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.^8-18

Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.^19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.²⁰ It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.²¹ Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.¹⁹ Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.^22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.^19-32

One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.^2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.

Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.^3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.^33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.^33,53

Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.^19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.⁵⁴ Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.⁵⁵ Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.⁵⁶ In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.⁵⁷ Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.^58-64

The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.^65-67

The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

METHODS

The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.

Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.⁷⁰ Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

RESULTS

The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).

There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).

Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).

Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).

The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.

MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).

The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).

DISCUSSION

As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.

Paclitaxel

Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.^20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.^19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.^22-27

The generic name is not the same as a generic drug, which may have slight differences from the brand name product.⁷¹ The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.⁷² During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.

Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.^73-76

Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.

Discontinued Treatment

Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.^19-24,77-81

Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.^82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.

Antidepressants and Other Drugs

Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.⁸⁵ CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.

Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).

Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.

The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).^86-129

Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).^65-67

Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.^57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.

Conclusions

This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.

Background

Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.^1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.^8-18

Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.^19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.²⁰ It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.²¹ Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.¹⁹ Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.^22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.^19-32

One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.^2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.

Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.^3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.^33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.^33,53

Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.^19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.⁵⁴ Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.⁵⁵ Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.⁵⁶ In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.⁵⁷ Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.^58-64

The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.^65-67

The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

METHODS

The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.

Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.⁷⁰ Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

RESULTS

The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).

There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).

Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).

Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).

The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.

MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).

The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).

DISCUSSION

As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.

Paclitaxel

Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.^20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.^19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.^22-27

The generic name is not the same as a generic drug, which may have slight differences from the brand name product.⁷¹ The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.⁷² During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.

Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.^73-76

Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.

Discontinued Treatment

Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.^19-24,77-81

Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.^82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.

Antidepressants and Other Drugs

Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.⁸⁵ CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.

Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).

Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.

The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).^86-129

Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).^65-67

Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.^57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.

Conclusions

This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.

Background

Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.^1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.^8-18

Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.^19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.²⁰ It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.²¹ Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.¹⁹ Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.^22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.^19-32

One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.^2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.

Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.^3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.^33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.^33,53

Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.^19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.⁵⁴ Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.⁵⁵ Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.⁵⁶ In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.⁵⁷ Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.^58-64

The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.^65-67

The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.

METHODS

The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.

Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.

Data Extraction Design

The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.

Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).

Data Extraction Analysis

The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.^68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.

In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.⁷⁰ Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.

RESULTS

The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).

There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).

Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).

Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).

Management Analysis and Reporting Tool Database

MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).

The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.

MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).

The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).

DISCUSSION

As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.

Paclitaxel

Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.^20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.^19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.^22-27

The generic name is not the same as a generic drug, which may have slight differences from the brand name product.⁷¹ The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.⁷² During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.

Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.^73-76

Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.

Discontinued Treatment

Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.^19-24,77-81

Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.^82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.

Antidepressants and Other Drugs

Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.⁸⁵ CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.

Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).

Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.

The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).^86-129

Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).^65-67

Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.^57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.

Conclusions

This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.

Acknowledgments

The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.