Melanoma

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

To the Editor:

Genital lentiginosis (also known as mucosal melanotic macules, vulvar melanosis, penile melanosis, and penile lentigines) occurs in men and women.¹ Lesions present in adult life as multifocal, asymmetrical, pigmented patches that can have a mottled appearance or exhibit skip areas. The irregular appearance of the pigmented areas often raises concern for melanoma. Biopsy reveals increased pigmentation along the basal layer of the epidermis; the irregular distribution of single melanocytes and pagetoid spread typical of melanoma in situ is not identified.

Genital lentiginosis usually occurs as an isolated finding; however, the condition can be a manifestation of Laugier-Hunziker syndrome, Carney complex, and Bannayan-Riley-Ruvalcaba syndrome.^1-3 When it occurs as an isolated finding, the patient can be reassured and treatment is unnecessary. Because genital lentiginosis may mimic the appearance of melanoma, it is important for physicians to differentiate the two and make a correct diagnosis. We present a case of genital lentiginosis that mimicked vulvar melanoma.

A 64-year-old woman was referred by her gynecologist to dermatology to rule out vulvar melanoma. The patient had a history of hypothyroidism and hypercholesterolemia but was otherwise in good health. Genital examination revealed asymptomatic pigmented macules and patches of unknown duration (Figure 1). Specimens were taken from 3 areas by punch biopsy to clarify the diagnosis. All 3 specimens showed identical features including basilar pigmentation, occasional melanophages in the papillary dermis, and no evidence of nests or pagetoid spread of atypical melanocytes (Figures 2 and 3). Histologic findings were diagnostic for genital lentiginosis. The patient was reassured, and no treatment was provided. At 6-month follow-up there was no change in clinical appearance.

Genital lentiginosis is characterized by brown lesions that can have a mottled appearance and often are associated with skip areas.¹ Lesions can be strikingly irregular and darkly pigmented.

Although the lesions of genital lentiginosis most often are isolated findings, they can be a clue to several uncommon syndromes such as autosomal-dominant Bannayan-Riley-Ruvalcaba syndrome, which is associated with genital lentiginosis, intestinal polyposis, and macrocephaly.³ Vascular malformations, lipomatosis, verrucal keratoses, and acrochordons can occur. Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome may share genetic linkage; mutations in the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) has been implicated in both syndromes.⁴ Underlying Carney complex should be excluded when genital lentiginosis is encountered.

Genital lentiginosis is idiopathic in most instances, but reports of lesions occurring after annular lichen planus suggest a possible mechanism.⁵ The disappearance of lentigines after imatinib therapy suggests a role for c-kit, a receptor tyrosine kinase that is involved in intracellular signaling, in some cases.⁶ At times, lesions can simulate trichrome vitiligo or have a reticulate pattern.⁷

Men and women present at different points in the course of disease. Men often present with penile lesions 14 years after onset, on average; they notice a gradual increase in the size of lesions. Because women can have greater difficulty self-examining the genital region, they tend to present much later in the course but often within a few months after initial inspection.^1,8

Genital lentiginosis can mimic melanoma with nonhomogeneous pigmentation, asymmetry, and unilateral distribution, which makes dermoscopic assessment of colors helpful in narrowing the differential diagnosis. Melanoma is associated with combinations of gray, red, blue, and white, which are not found in genital lentiginosis.⁹

Biopsy of a genital lentigo is diagnostic, distinguishing the lesion from melanoma—failing to reveal the atypical melanocytes and pagetoid spread characteristic of melanoma in situ. Histologic findings can cause diagnostic difficulties when concurrent lichen sclerosus is associated with genital lentigines or nevi.¹⁰

Lentigines on sun-damaged skin or in the setting of xeroderma pigmentosum have been associated with melanoma,^11-13 but genital lentigines are not considered a form of precancerous melanosis. In women, early diagnosis is important when there is concern for melanoma because the prognosis for vulvar melanoma is improved in thin lesions.¹⁴

Other entities in the differential include secondary syphilis, which commonly presents as macules and scaly papules and can be found on mucosal surfaces such as the oral cavity,¹⁵ as well as Kaposi sarcoma, which is characterized by purplish, brown, or black macules, plaques, and nodules, more commonly in immunosuppressed patients.¹⁶

To avoid unwarranted concern and unnecessary surgery, dermatologists should be aware of genital lentigines and their characteristic presentation in adults.

A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.

The Indiana statewide study, conducted at the beginning of the pandemic, found that unvaccinated adults with cancer and SARS-CoV-2 infection were nearly seven times more likely to die from any cause than uninfected adults with cancer.

“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.

The study was published online in JMIR Cancer.

Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.

A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”

Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.

In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.

Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).

During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.

In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).

During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).

When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).

Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.

Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).

“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.

“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.

Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.

The Indiana statewide study, conducted at the beginning of the pandemic, found that unvaccinated adults with cancer and SARS-CoV-2 infection were nearly seven times more likely to die from any cause than uninfected adults with cancer.

“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.

The study was published online in JMIR Cancer.

Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.

A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”

Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.

In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.

Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).

During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.

In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).

During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).

When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).

Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.

Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).

“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.

“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.

Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.

The Indiana statewide study, conducted at the beginning of the pandemic, found that unvaccinated adults with cancer and SARS-CoV-2 infection were nearly seven times more likely to die from any cause than uninfected adults with cancer.

“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.

The study was published online in JMIR Cancer.

Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.

A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”

Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.

In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.

Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).

During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.

In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).

During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).

When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).

Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.

Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).

“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.

“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.

Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Mohs micrographic surgery (MMS) is most commonly used for the surgical management of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) in high-risk locations. The ability for 100% margin evaluation with MMS also has shown lower recurrence rates compared with wide local excision for less common and/or more aggressive tumors. However, there is a lack of standardization on initial and subsequent margin size when treating these less common skin tumors, such as dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and sebaceous carcinoma.

Because Mohs surgeons must balance normal tissue preservation with the importance of tumor clearance in the context of comprehensive margin control, we aimed to assess the practice patterns of Mohs surgeons regarding margin size for these unique tumors. The average margin size for each Mohs layer has been reported to be 1 to 3 mm for BCC compared with 3 to 6 mm or larger for other skin cancers, such as melanoma in situ (MIS).^1-3 We hypothesized that the initial margin size would vary among surgeons and likely be greater for more aggressive and rarer malignancies as well as for lesions on the trunk and extremities.

Methods

A descriptive survey was created using SurveyMonkey and distributed to members of the American College of Mohs Surgery (ACMS). Survey participants and their responses were anonymous. Demographic information on survey participants was collected in addition to initial and subsequent MMS margin size for DFSP, AFX, MIS, invasive melanoma, sebaceous carcinoma, microcystic adnexal carcinoma (MAC), poorly differentiated SCC, Merkel cell carcinoma, extramammary Paget disease, leiomyosarcoma, and endocrine mucin-producing sweat gland carcinoma. Survey participants were asked to choose from a range of margin sizes: 1 to 3 mm, 4 to 6 mm, 7 to 9 mm, and greater than 9 mm. This study was approved by the University of Texas Southwest Medical Center (Dallas, Texas) institutional review board.

Results

Eighty-seven respondents from the ACMS listserve completed the survey (response rate <10%). Of these, 58 respondents (66.7%) reported practicing for more than 5 years, and 58 (66.7%) were male. Practice setting was primarily private/community (71.3% [62/87]), and survey respondents were located across the United States. More than 50% of survey respondents treated the following tumors on the head and neck in their respective practices: DFSP (80.9% [55/68]), AFX (95.6% [65/68]), MIS (67.7% [46/68]), sebaceous carcinoma (92.7% [63/68]), MAC (83.8% [57/68]), poorly differentiated SCC (97.1% [66/68]), and endocrine mucin-producing sweat gland carcinoma (51.5% [35/68]). More than 50% of survey respondents treated the following tumors on the trunk and extremities: DFSP (90.3% [47/52]), AFX (86.4% [45/52]), MIS (55.8% [29/52]), sebaceous carcinoma (80.8% [42/52]), MAC (73.1% [38/52]), poorly differentiated SCC (94.2% [49/52]), and extramammary Paget disease (53.9% [28/52]). Invasive melanoma, Merkel cell carcinoma, and leiomyosarcoma were overall less commonly treated.

In general, respondent Mohs surgeons were more likely to take larger initial and subsequent margins for tumors treated on the trunk and extremities compared with the head and neck (Table). In addition, initial margin size often was larger than the 1- to 3-mm margin commonly used in Mohs surgery for BCCs and less aggressive SCCs (Table). A larger initial margin size (>9 mm) and subsequent margin size (4–6 mm) was more commonly reported for certain tumors known to be more aggressive and/or have extensive subclinical extension, such as DFSP and invasive melanoma. Of note, most respondents performed 4- to 6-mm margins (37/67 [55.2%]) for poorly differentiated SCC. Overall, there was a high range of margin size variability among Mohs surgeons for these unique and/or more aggressive skin tumors.

Comment

Given that no guidelines exist on margins with MMS for less commonly treated skin tumors, this study helps give Mohs surgeons perspective on current practice patterns for both initial and subsequent Mohs margin sizes. High margin-size variability among Mohs surgeons is expected, as surgeons also need to account for high-risk features of the tumor or specific locations where tissue sparing is critical. Overall, Mohs surgeons are more likely to take larger initial margins for these less common skin tumors compared with BCCs or SCCs. Initial margin size was consistently larger on the trunk and extremities where tissue sparing often is less critical.

Our survey was limited by a small sample size and incomplete response of the ACMS membership. In addition, most respondents practiced in a private/community setting, which may have led to bias, as academic centers may manage rare malignancies more commonly and/or have increased access to immunostains and multispecialty care. Future registries for rare skin malignancies will hopefully be developed that will allow for further consensus on standardized margins. Additional studies on the average number of stages required to clear these less common tumors also are warranted.

Mohs micrographic surgery (MMS) is most commonly used for the surgical management of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) in high-risk locations. The ability for 100% margin evaluation with MMS also has shown lower recurrence rates compared with wide local excision for less common and/or more aggressive tumors. However, there is a lack of standardization on initial and subsequent margin size when treating these less common skin tumors, such as dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and sebaceous carcinoma.

Because Mohs surgeons must balance normal tissue preservation with the importance of tumor clearance in the context of comprehensive margin control, we aimed to assess the practice patterns of Mohs surgeons regarding margin size for these unique tumors. The average margin size for each Mohs layer has been reported to be 1 to 3 mm for BCC compared with 3 to 6 mm or larger for other skin cancers, such as melanoma in situ (MIS).^1-3 We hypothesized that the initial margin size would vary among surgeons and likely be greater for more aggressive and rarer malignancies as well as for lesions on the trunk and extremities.

Methods

A descriptive survey was created using SurveyMonkey and distributed to members of the American College of Mohs Surgery (ACMS). Survey participants and their responses were anonymous. Demographic information on survey participants was collected in addition to initial and subsequent MMS margin size for DFSP, AFX, MIS, invasive melanoma, sebaceous carcinoma, microcystic adnexal carcinoma (MAC), poorly differentiated SCC, Merkel cell carcinoma, extramammary Paget disease, leiomyosarcoma, and endocrine mucin-producing sweat gland carcinoma. Survey participants were asked to choose from a range of margin sizes: 1 to 3 mm, 4 to 6 mm, 7 to 9 mm, and greater than 9 mm. This study was approved by the University of Texas Southwest Medical Center (Dallas, Texas) institutional review board.

Results

Eighty-seven respondents from the ACMS listserve completed the survey (response rate <10%). Of these, 58 respondents (66.7%) reported practicing for more than 5 years, and 58 (66.7%) were male. Practice setting was primarily private/community (71.3% [62/87]), and survey respondents were located across the United States. More than 50% of survey respondents treated the following tumors on the head and neck in their respective practices: DFSP (80.9% [55/68]), AFX (95.6% [65/68]), MIS (67.7% [46/68]), sebaceous carcinoma (92.7% [63/68]), MAC (83.8% [57/68]), poorly differentiated SCC (97.1% [66/68]), and endocrine mucin-producing sweat gland carcinoma (51.5% [35/68]). More than 50% of survey respondents treated the following tumors on the trunk and extremities: DFSP (90.3% [47/52]), AFX (86.4% [45/52]), MIS (55.8% [29/52]), sebaceous carcinoma (80.8% [42/52]), MAC (73.1% [38/52]), poorly differentiated SCC (94.2% [49/52]), and extramammary Paget disease (53.9% [28/52]). Invasive melanoma, Merkel cell carcinoma, and leiomyosarcoma were overall less commonly treated.

In general, respondent Mohs surgeons were more likely to take larger initial and subsequent margins for tumors treated on the trunk and extremities compared with the head and neck (Table). In addition, initial margin size often was larger than the 1- to 3-mm margin commonly used in Mohs surgery for BCCs and less aggressive SCCs (Table). A larger initial margin size (>9 mm) and subsequent margin size (4–6 mm) was more commonly reported for certain tumors known to be more aggressive and/or have extensive subclinical extension, such as DFSP and invasive melanoma. Of note, most respondents performed 4- to 6-mm margins (37/67 [55.2%]) for poorly differentiated SCC. Overall, there was a high range of margin size variability among Mohs surgeons for these unique and/or more aggressive skin tumors.

Comment

Given that no guidelines exist on margins with MMS for less commonly treated skin tumors, this study helps give Mohs surgeons perspective on current practice patterns for both initial and subsequent Mohs margin sizes. High margin-size variability among Mohs surgeons is expected, as surgeons also need to account for high-risk features of the tumor or specific locations where tissue sparing is critical. Overall, Mohs surgeons are more likely to take larger initial margins for these less common skin tumors compared with BCCs or SCCs. Initial margin size was consistently larger on the trunk and extremities where tissue sparing often is less critical.

Our survey was limited by a small sample size and incomplete response of the ACMS membership. In addition, most respondents practiced in a private/community setting, which may have led to bias, as academic centers may manage rare malignancies more commonly and/or have increased access to immunostains and multispecialty care. Future registries for rare skin malignancies will hopefully be developed that will allow for further consensus on standardized margins. Additional studies on the average number of stages required to clear these less common tumors also are warranted.

Mohs micrographic surgery (MMS) is most commonly used for the surgical management of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) in high-risk locations. The ability for 100% margin evaluation with MMS also has shown lower recurrence rates compared with wide local excision for less common and/or more aggressive tumors. However, there is a lack of standardization on initial and subsequent margin size when treating these less common skin tumors, such as dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and sebaceous carcinoma.

Because Mohs surgeons must balance normal tissue preservation with the importance of tumor clearance in the context of comprehensive margin control, we aimed to assess the practice patterns of Mohs surgeons regarding margin size for these unique tumors. The average margin size for each Mohs layer has been reported to be 1 to 3 mm for BCC compared with 3 to 6 mm or larger for other skin cancers, such as melanoma in situ (MIS).^1-3 We hypothesized that the initial margin size would vary among surgeons and likely be greater for more aggressive and rarer malignancies as well as for lesions on the trunk and extremities.

Methods

A descriptive survey was created using SurveyMonkey and distributed to members of the American College of Mohs Surgery (ACMS). Survey participants and their responses were anonymous. Demographic information on survey participants was collected in addition to initial and subsequent MMS margin size for DFSP, AFX, MIS, invasive melanoma, sebaceous carcinoma, microcystic adnexal carcinoma (MAC), poorly differentiated SCC, Merkel cell carcinoma, extramammary Paget disease, leiomyosarcoma, and endocrine mucin-producing sweat gland carcinoma. Survey participants were asked to choose from a range of margin sizes: 1 to 3 mm, 4 to 6 mm, 7 to 9 mm, and greater than 9 mm. This study was approved by the University of Texas Southwest Medical Center (Dallas, Texas) institutional review board.

Results

Eighty-seven respondents from the ACMS listserve completed the survey (response rate <10%). Of these, 58 respondents (66.7%) reported practicing for more than 5 years, and 58 (66.7%) were male. Practice setting was primarily private/community (71.3% [62/87]), and survey respondents were located across the United States. More than 50% of survey respondents treated the following tumors on the head and neck in their respective practices: DFSP (80.9% [55/68]), AFX (95.6% [65/68]), MIS (67.7% [46/68]), sebaceous carcinoma (92.7% [63/68]), MAC (83.8% [57/68]), poorly differentiated SCC (97.1% [66/68]), and endocrine mucin-producing sweat gland carcinoma (51.5% [35/68]). More than 50% of survey respondents treated the following tumors on the trunk and extremities: DFSP (90.3% [47/52]), AFX (86.4% [45/52]), MIS (55.8% [29/52]), sebaceous carcinoma (80.8% [42/52]), MAC (73.1% [38/52]), poorly differentiated SCC (94.2% [49/52]), and extramammary Paget disease (53.9% [28/52]). Invasive melanoma, Merkel cell carcinoma, and leiomyosarcoma were overall less commonly treated.

In general, respondent Mohs surgeons were more likely to take larger initial and subsequent margins for tumors treated on the trunk and extremities compared with the head and neck (Table). In addition, initial margin size often was larger than the 1- to 3-mm margin commonly used in Mohs surgery for BCCs and less aggressive SCCs (Table). A larger initial margin size (>9 mm) and subsequent margin size (4–6 mm) was more commonly reported for certain tumors known to be more aggressive and/or have extensive subclinical extension, such as DFSP and invasive melanoma. Of note, most respondents performed 4- to 6-mm margins (37/67 [55.2%]) for poorly differentiated SCC. Overall, there was a high range of margin size variability among Mohs surgeons for these unique and/or more aggressive skin tumors.

Comment

Given that no guidelines exist on margins with MMS for less commonly treated skin tumors, this study helps give Mohs surgeons perspective on current practice patterns for both initial and subsequent Mohs margin sizes. High margin-size variability among Mohs surgeons is expected, as surgeons also need to account for high-risk features of the tumor or specific locations where tissue sparing is critical. Overall, Mohs surgeons are more likely to take larger initial margins for these less common skin tumors compared with BCCs or SCCs. Initial margin size was consistently larger on the trunk and extremities where tissue sparing often is less critical.

Our survey was limited by a small sample size and incomplete response of the ACMS membership. In addition, most respondents practiced in a private/community setting, which may have led to bias, as academic centers may manage rare malignancies more commonly and/or have increased access to immunostains and multispecialty care. Future registries for rare skin malignancies will hopefully be developed that will allow for further consensus on standardized margins. Additional studies on the average number of stages required to clear these less common tumors also are warranted.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.

John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?

Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.

He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.

And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
 

Interprofessional teamwork is fundamental to treat ‘total pain’

None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?

Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.

But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.

You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
 

Teamwork improves quality of life

My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.

Cancer, as one of my patients once remarked to me, is a “full-contact sport.” Living with advanced cancer touches nearly every aspect of a person’s life. The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.