Melanoma

Patients treated with ipilimumab for metastatic melanoma should be prepared for immune-related adverse effects, and physicians should expect to treat them early and aggressively, according to a report published online Aug. 17 in Journal of Clinical Oncology.

Severe immune-related adverse effects such as diarrhea, hepatitis, and hypophysitis were common in a retrospective analysis of the medical records of 298 patients treated during a 27-month period at Memorial Sloan Kettering Cancer Center, New York. Corticosteroids were not adequate to control symptoms in a substantial number of cases, and additional systemic immunosuppressive therapy was required, said Dr. Troy Z. Horvat of Memorial Sloan Kettering and his associates.

From their institutional experience, the investigators suspected that the incidence of clinically significant adverse effects of ipilimumab was higher than has been previously reported and higher than would be expected just by counting the number of events qualifying as grade 3 or higher by National Cancer Institute criteria. They also suspected that the need for immunosuppressive therapy was greater than generally expected. Previous studies showed adverse event rates ranging from 6% to 19%, and did not give any information regarding corticosteroid use.

Their analysis confirmed these suspicions, showing that 31% of patients developed grade 3, 4, or 5 adverse effects and 35% required corticosteroid therapy. This is more than twice the rate of grade 3 or higher toxicity reported in clinical trials of ipilimumab. Adverse effects included diarrhea (50 patients), which led to bowel perforation in 3 patients; hepatitis (22 patients); dermatitis (21 patients); endocrinopathies (14); hypophysitis (6); uveitis (2); pneumonitis (1); seizure (1); arthritis (1); and hearing loss (1). These effects were severe enough to cause 19% of patients to discontinue ipilimumab.

About one-third of the patients who received systemic corticosteroids – 10% of the total study population – required additional immunotherapy, including infliximab, mycophenolate, or adalimumab, Dr. Horvat and his associates said (J Clin Oncol 2015 Aug 17 [doi:10.1200/JCO.2015.60.8448]).

This study’s higher rates of adverse events, of corticosteroid therapy, and of further immunosuppressive therapy are likely attributable to the treatment team’s considerable experience with ipilimumab in real-world patients. As clinicians gain such experience, they become more familiar with associated adverse events, allowing earlier identification and intervention, the investigators said.

“In our experience, if improvement in ipilimumab-related adverse effects is not evident early in the treatment with high-dose systemic corticosteroids, more prolonged treatment rarely leads to benefit, and patients usually end up requiring infliximab anyway. ... We believe the overall risk-to-benefit ratio favors the early use of infliximab rather than prolonged treatment with corticosteroids,” they noted.

The median overall survival and median time to treatment failure were not affected by either the occurrence of adverse events or the use of corticosteroids. Overall, 12% of these patients achieved long-term disease control and didn’t require further melanoma treatment. Based on their findings and those of another research group, “we believe that patients and physicians should not be concerned that ipilimumab-related adverse events requiring systemic immunosuppression will compromise the therapeutic benefit,” Dr. Horvat and his associates said.

Patients treated with ipilimumab for metastatic melanoma should be prepared for immune-related adverse effects, and physicians should expect to treat them early and aggressively, according to a report published online Aug. 17 in Journal of Clinical Oncology.

Severe immune-related adverse effects such as diarrhea, hepatitis, and hypophysitis were common in a retrospective analysis of the medical records of 298 patients treated during a 27-month period at Memorial Sloan Kettering Cancer Center, New York. Corticosteroids were not adequate to control symptoms in a substantial number of cases, and additional systemic immunosuppressive therapy was required, said Dr. Troy Z. Horvat of Memorial Sloan Kettering and his associates.

From their institutional experience, the investigators suspected that the incidence of clinically significant adverse effects of ipilimumab was higher than has been previously reported and higher than would be expected just by counting the number of events qualifying as grade 3 or higher by National Cancer Institute criteria. They also suspected that the need for immunosuppressive therapy was greater than generally expected. Previous studies showed adverse event rates ranging from 6% to 19%, and did not give any information regarding corticosteroid use.

Their analysis confirmed these suspicions, showing that 31% of patients developed grade 3, 4, or 5 adverse effects and 35% required corticosteroid therapy. This is more than twice the rate of grade 3 or higher toxicity reported in clinical trials of ipilimumab. Adverse effects included diarrhea (50 patients), which led to bowel perforation in 3 patients; hepatitis (22 patients); dermatitis (21 patients); endocrinopathies (14); hypophysitis (6); uveitis (2); pneumonitis (1); seizure (1); arthritis (1); and hearing loss (1). These effects were severe enough to cause 19% of patients to discontinue ipilimumab.

About one-third of the patients who received systemic corticosteroids – 10% of the total study population – required additional immunotherapy, including infliximab, mycophenolate, or adalimumab, Dr. Horvat and his associates said (J Clin Oncol 2015 Aug 17 [doi:10.1200/JCO.2015.60.8448]).

This study’s higher rates of adverse events, of corticosteroid therapy, and of further immunosuppressive therapy are likely attributable to the treatment team’s considerable experience with ipilimumab in real-world patients. As clinicians gain such experience, they become more familiar with associated adverse events, allowing earlier identification and intervention, the investigators said.

“In our experience, if improvement in ipilimumab-related adverse effects is not evident early in the treatment with high-dose systemic corticosteroids, more prolonged treatment rarely leads to benefit, and patients usually end up requiring infliximab anyway. ... We believe the overall risk-to-benefit ratio favors the early use of infliximab rather than prolonged treatment with corticosteroids,” they noted.

The median overall survival and median time to treatment failure were not affected by either the occurrence of adverse events or the use of corticosteroids. Overall, 12% of these patients achieved long-term disease control and didn’t require further melanoma treatment. Based on their findings and those of another research group, “we believe that patients and physicians should not be concerned that ipilimumab-related adverse events requiring systemic immunosuppression will compromise the therapeutic benefit,” Dr. Horvat and his associates said.

Patients treated with ipilimumab for metastatic melanoma should be prepared for immune-related adverse effects, and physicians should expect to treat them early and aggressively, according to a report published online Aug. 17 in Journal of Clinical Oncology.

Severe immune-related adverse effects such as diarrhea, hepatitis, and hypophysitis were common in a retrospective analysis of the medical records of 298 patients treated during a 27-month period at Memorial Sloan Kettering Cancer Center, New York. Corticosteroids were not adequate to control symptoms in a substantial number of cases, and additional systemic immunosuppressive therapy was required, said Dr. Troy Z. Horvat of Memorial Sloan Kettering and his associates.

From their institutional experience, the investigators suspected that the incidence of clinically significant adverse effects of ipilimumab was higher than has been previously reported and higher than would be expected just by counting the number of events qualifying as grade 3 or higher by National Cancer Institute criteria. They also suspected that the need for immunosuppressive therapy was greater than generally expected. Previous studies showed adverse event rates ranging from 6% to 19%, and did not give any information regarding corticosteroid use.

Their analysis confirmed these suspicions, showing that 31% of patients developed grade 3, 4, or 5 adverse effects and 35% required corticosteroid therapy. This is more than twice the rate of grade 3 or higher toxicity reported in clinical trials of ipilimumab. Adverse effects included diarrhea (50 patients), which led to bowel perforation in 3 patients; hepatitis (22 patients); dermatitis (21 patients); endocrinopathies (14); hypophysitis (6); uveitis (2); pneumonitis (1); seizure (1); arthritis (1); and hearing loss (1). These effects were severe enough to cause 19% of patients to discontinue ipilimumab.

About one-third of the patients who received systemic corticosteroids – 10% of the total study population – required additional immunotherapy, including infliximab, mycophenolate, or adalimumab, Dr. Horvat and his associates said (J Clin Oncol 2015 Aug 17 [doi:10.1200/JCO.2015.60.8448]).

This study’s higher rates of adverse events, of corticosteroid therapy, and of further immunosuppressive therapy are likely attributable to the treatment team’s considerable experience with ipilimumab in real-world patients. As clinicians gain such experience, they become more familiar with associated adverse events, allowing earlier identification and intervention, the investigators said.

“In our experience, if improvement in ipilimumab-related adverse effects is not evident early in the treatment with high-dose systemic corticosteroids, more prolonged treatment rarely leads to benefit, and patients usually end up requiring infliximab anyway. ... We believe the overall risk-to-benefit ratio favors the early use of infliximab rather than prolonged treatment with corticosteroids,” they noted.

The median overall survival and median time to treatment failure were not affected by either the occurrence of adverse events or the use of corticosteroids. Overall, 12% of these patients achieved long-term disease control and didn’t require further melanoma treatment. Based on their findings and those of another research group, “we believe that patients and physicians should not be concerned that ipilimumab-related adverse events requiring systemic immunosuppression will compromise the therapeutic benefit,” Dr. Horvat and his associates said.

VANCOUVER, B.C. – Why should dermatologists care about the role of sentinel lymph node biopsy in melanoma patients? Because SNLB results will inform the use of an explosion of immunotherapies and targeted therapies emerging for melanoma and – because even after melanoma patients have been referred to a comprehensive cancer center – patients will continue to view dermatologists as the primary care providers with respect to the cancer, Dr. Timothy M. Johnson said in a plenary address at the World Congress of Dermatology.

“I guarantee you of that” scenario, predicted Dr. Johnson, professor of dermatology and clinical director of the multidisciplinary melanoma program at the University of Michigan, Ann Arbor, where more than 2,000 melanoma patients are seen each year.

Bruce Jancin/Frontline Medical News

New melanoma therapies are “coming in waves. They seem to be coming weekly,” he said. In June, the National Cancer Institute listed 218 therapeutic clinical trials for advanced melanoma in the United States alone. And some of these new treatments for stage IV melanoma are already starting to make their way into the adjuvant setting for stage III melanoma.

“The first round of adjuvant therapy trials has been done, and the data are being analyzed now. A new round is coming like gangbusters,” Dr. Johnson said. “This is one of the most exciting times ever in melanoma.”

Should some of these novel agents prove safe and effective as adjuvant therapy, SLNB results will determine the need for such therapy based upon individualized patient prognosis. And the SLNB results will determine the type of adjuvant therapy that’s most appropriate based upon the tumor molecular profile.

“Once we have effective adjuvant therapy, it will eradicate the need for total lymph node dissection in patients with a positive node on SLNB. Those with a positive node will likely undergo systemic therapy based on a personalized approach,” he predicted.

For the present, in Dr. Johnson’s view, much of the best guidance on when and how to employ SLNB in melanoma patients comes from the landmark National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial (MSLT-1).

The MSLT-1 results (N Engl J Med. 2014 Feb 13;370:599-609) are deemed controversial by some, Dr. Johnson noted. But they provide a strong case for widespread application of SLNB for accurate staging and regional control of the nodal basin based upon the findings in 1,270 participants with intermediate-thickness melanomas of 1.2-3.5 mm and 290 others with melanomas greater than 3.5 mm thick, he said. Both groups showed significant benefit in terms of 10-year melanoma-specific survival if randomized to SLNB with immediate total lymph node dissection if SLNB positive, as opposed to watchful waiting for an occult nodal metastasis to become clinically evident.

An important finding was that roughly 27% of patients in the observation arms who experienced a clinically evident nodal metastasis during follow-up and then underwent completion total lymph node dissection had four or more positive nodes at that time, compared to 1.6% of those with a positive SLNB who underwent immediate completion dissection.

“If an occult metastasis is present in the lymph node it’s going to grow to the point of becoming clinically evident in an average of 2-3 years. You can deal with it now or you can deal with it later, but you’re likely going to have to deal with it. Failure to detect and treat that disease early will result in increased tumor burden upon completion lymph node dissection, increased morbidity and side effects in order to remove those nodes, and a small but increased likelihood of dying from that disease. That’s a very powerful conversation to have with patients and families to help them make the best informed decision for themselves,” Dr. Johnson said.

At the University of Michigan melanoma program – the nation’s largest – patients are counseled to seriously consider SLNB if they have a clinically localized melanoma 1 mm or more in thickness provided their functional status is favorable. In contrast, there is essentially no evidence to support SLNB in patients with a melanoma less than 0.75 mm in thickness.

In patients with a melanoma thickness of 0.75-0.99 mm, however, Dr. Johnson and his colleagues may recommend SLNB in the presence of certain predictors of increased likelihood of a positive biopsy: ulceration, angiolymphatic invasion, younger age, a positive deep margin on a shave biopsy, extensive dermal regression in excess of 1 mm, and/or a mitotic rate of at least 1 mm². Age and mitotic rate are continuous variables: The younger the patient and the higher the mitotic rate, the greater the likelihood of a positive SLNB in the setting of a thin melanoma.

At present, the decision regarding whether to recommend SLNB in a patient with a thin melanoma is based upon a general gestalt, said Dr. Johnson. He and his colleagues have received a grant to study more than 2,000 cases of thin melanoma in an effort to develop a system for weighting the individual risk factors.

“As dermatologists – you, me, we – should be one of the lead dogs with respect to melanoma advancement, knowledge, management, and guidance. To do that most effectively, you must learn from and work closely with other specialists – collegially, collaboratively, and humbly,” he concluded.

Dr. Johnson reported having no financial conflicts of interest regarding his talk.

[email protected]

VANCOUVER, B.C. – Why should dermatologists care about the role of sentinel lymph node biopsy in melanoma patients? Because SNLB results will inform the use of an explosion of immunotherapies and targeted therapies emerging for melanoma and – because even after melanoma patients have been referred to a comprehensive cancer center – patients will continue to view dermatologists as the primary care providers with respect to the cancer, Dr. Timothy M. Johnson said in a plenary address at the World Congress of Dermatology.

“I guarantee you of that” scenario, predicted Dr. Johnson, professor of dermatology and clinical director of the multidisciplinary melanoma program at the University of Michigan, Ann Arbor, where more than 2,000 melanoma patients are seen each year.

Bruce Jancin/Frontline Medical News

New melanoma therapies are “coming in waves. They seem to be coming weekly,” he said. In June, the National Cancer Institute listed 218 therapeutic clinical trials for advanced melanoma in the United States alone. And some of these new treatments for stage IV melanoma are already starting to make their way into the adjuvant setting for stage III melanoma.

“The first round of adjuvant therapy trials has been done, and the data are being analyzed now. A new round is coming like gangbusters,” Dr. Johnson said. “This is one of the most exciting times ever in melanoma.”

Should some of these novel agents prove safe and effective as adjuvant therapy, SLNB results will determine the need for such therapy based upon individualized patient prognosis. And the SLNB results will determine the type of adjuvant therapy that’s most appropriate based upon the tumor molecular profile.

“Once we have effective adjuvant therapy, it will eradicate the need for total lymph node dissection in patients with a positive node on SLNB. Those with a positive node will likely undergo systemic therapy based on a personalized approach,” he predicted.

For the present, in Dr. Johnson’s view, much of the best guidance on when and how to employ SLNB in melanoma patients comes from the landmark National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial (MSLT-1).

The MSLT-1 results (N Engl J Med. 2014 Feb 13;370:599-609) are deemed controversial by some, Dr. Johnson noted. But they provide a strong case for widespread application of SLNB for accurate staging and regional control of the nodal basin based upon the findings in 1,270 participants with intermediate-thickness melanomas of 1.2-3.5 mm and 290 others with melanomas greater than 3.5 mm thick, he said. Both groups showed significant benefit in terms of 10-year melanoma-specific survival if randomized to SLNB with immediate total lymph node dissection if SLNB positive, as opposed to watchful waiting for an occult nodal metastasis to become clinically evident.

An important finding was that roughly 27% of patients in the observation arms who experienced a clinically evident nodal metastasis during follow-up and then underwent completion total lymph node dissection had four or more positive nodes at that time, compared to 1.6% of those with a positive SLNB who underwent immediate completion dissection.

“If an occult metastasis is present in the lymph node it’s going to grow to the point of becoming clinically evident in an average of 2-3 years. You can deal with it now or you can deal with it later, but you’re likely going to have to deal with it. Failure to detect and treat that disease early will result in increased tumor burden upon completion lymph node dissection, increased morbidity and side effects in order to remove those nodes, and a small but increased likelihood of dying from that disease. That’s a very powerful conversation to have with patients and families to help them make the best informed decision for themselves,” Dr. Johnson said.

At the University of Michigan melanoma program – the nation’s largest – patients are counseled to seriously consider SLNB if they have a clinically localized melanoma 1 mm or more in thickness provided their functional status is favorable. In contrast, there is essentially no evidence to support SLNB in patients with a melanoma less than 0.75 mm in thickness.

In patients with a melanoma thickness of 0.75-0.99 mm, however, Dr. Johnson and his colleagues may recommend SLNB in the presence of certain predictors of increased likelihood of a positive biopsy: ulceration, angiolymphatic invasion, younger age, a positive deep margin on a shave biopsy, extensive dermal regression in excess of 1 mm, and/or a mitotic rate of at least 1 mm². Age and mitotic rate are continuous variables: The younger the patient and the higher the mitotic rate, the greater the likelihood of a positive SLNB in the setting of a thin melanoma.

At present, the decision regarding whether to recommend SLNB in a patient with a thin melanoma is based upon a general gestalt, said Dr. Johnson. He and his colleagues have received a grant to study more than 2,000 cases of thin melanoma in an effort to develop a system for weighting the individual risk factors.

“As dermatologists – you, me, we – should be one of the lead dogs with respect to melanoma advancement, knowledge, management, and guidance. To do that most effectively, you must learn from and work closely with other specialists – collegially, collaboratively, and humbly,” he concluded.

Dr. Johnson reported having no financial conflicts of interest regarding his talk.

[email protected]

VANCOUVER, B.C. – Why should dermatologists care about the role of sentinel lymph node biopsy in melanoma patients? Because SNLB results will inform the use of an explosion of immunotherapies and targeted therapies emerging for melanoma and – because even after melanoma patients have been referred to a comprehensive cancer center – patients will continue to view dermatologists as the primary care providers with respect to the cancer, Dr. Timothy M. Johnson said in a plenary address at the World Congress of Dermatology.

“I guarantee you of that” scenario, predicted Dr. Johnson, professor of dermatology and clinical director of the multidisciplinary melanoma program at the University of Michigan, Ann Arbor, where more than 2,000 melanoma patients are seen each year.

Bruce Jancin/Frontline Medical News

New melanoma therapies are “coming in waves. They seem to be coming weekly,” he said. In June, the National Cancer Institute listed 218 therapeutic clinical trials for advanced melanoma in the United States alone. And some of these new treatments for stage IV melanoma are already starting to make their way into the adjuvant setting for stage III melanoma.

“The first round of adjuvant therapy trials has been done, and the data are being analyzed now. A new round is coming like gangbusters,” Dr. Johnson said. “This is one of the most exciting times ever in melanoma.”

Should some of these novel agents prove safe and effective as adjuvant therapy, SLNB results will determine the need for such therapy based upon individualized patient prognosis. And the SLNB results will determine the type of adjuvant therapy that’s most appropriate based upon the tumor molecular profile.

“Once we have effective adjuvant therapy, it will eradicate the need for total lymph node dissection in patients with a positive node on SLNB. Those with a positive node will likely undergo systemic therapy based on a personalized approach,” he predicted.

For the present, in Dr. Johnson’s view, much of the best guidance on when and how to employ SLNB in melanoma patients comes from the landmark National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial (MSLT-1).

The MSLT-1 results (N Engl J Med. 2014 Feb 13;370:599-609) are deemed controversial by some, Dr. Johnson noted. But they provide a strong case for widespread application of SLNB for accurate staging and regional control of the nodal basin based upon the findings in 1,270 participants with intermediate-thickness melanomas of 1.2-3.5 mm and 290 others with melanomas greater than 3.5 mm thick, he said. Both groups showed significant benefit in terms of 10-year melanoma-specific survival if randomized to SLNB with immediate total lymph node dissection if SLNB positive, as opposed to watchful waiting for an occult nodal metastasis to become clinically evident.

An important finding was that roughly 27% of patients in the observation arms who experienced a clinically evident nodal metastasis during follow-up and then underwent completion total lymph node dissection had four or more positive nodes at that time, compared to 1.6% of those with a positive SLNB who underwent immediate completion dissection.

“If an occult metastasis is present in the lymph node it’s going to grow to the point of becoming clinically evident in an average of 2-3 years. You can deal with it now or you can deal with it later, but you’re likely going to have to deal with it. Failure to detect and treat that disease early will result in increased tumor burden upon completion lymph node dissection, increased morbidity and side effects in order to remove those nodes, and a small but increased likelihood of dying from that disease. That’s a very powerful conversation to have with patients and families to help them make the best informed decision for themselves,” Dr. Johnson said.

At the University of Michigan melanoma program – the nation’s largest – patients are counseled to seriously consider SLNB if they have a clinically localized melanoma 1 mm or more in thickness provided their functional status is favorable. In contrast, there is essentially no evidence to support SLNB in patients with a melanoma less than 0.75 mm in thickness.

In patients with a melanoma thickness of 0.75-0.99 mm, however, Dr. Johnson and his colleagues may recommend SLNB in the presence of certain predictors of increased likelihood of a positive biopsy: ulceration, angiolymphatic invasion, younger age, a positive deep margin on a shave biopsy, extensive dermal regression in excess of 1 mm, and/or a mitotic rate of at least 1 mm². Age and mitotic rate are continuous variables: The younger the patient and the higher the mitotic rate, the greater the likelihood of a positive SLNB in the setting of a thin melanoma.

At present, the decision regarding whether to recommend SLNB in a patient with a thin melanoma is based upon a general gestalt, said Dr. Johnson. He and his colleagues have received a grant to study more than 2,000 cases of thin melanoma in an effort to develop a system for weighting the individual risk factors.

“As dermatologists – you, me, we – should be one of the lead dogs with respect to melanoma advancement, knowledge, management, and guidance. To do that most effectively, you must learn from and work closely with other specialists – collegially, collaboratively, and humbly,” he concluded.

Dr. Johnson reported having no financial conflicts of interest regarding his talk.

[email protected]

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

Sonidegib, a hedgehog pathway inhibitor, has been approved for treating patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy, the Food and Drug Administration announced on July 24. The drug is taken once a day, at a recommended dose of 200 mg on an empty stomach and will be marketed as Odomzo by Novartis Pharmaceuticals. Approval was based on a study that found the objective response rate to be 58% among patients treated with the 200-mg dose; an effect that lasted for about 2-19 months, according to the FDA.

“Our increasing understanding of molecular pathways involved in cancer has led to approvals of many oncology drugs in difficult-to-treat diseases for which few therapeutic options previously existed,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. “Thanks to a better understanding of the hedgehog pathway, the FDA has now approved two drugs for the treatment of basal cell carcinoma just in the last 3 years,” he added.

The first drug to treat locally advanced and metastatic basal cell carcinoma was vismodegib, marketed as Erivedge by Genentech in 2012.

The most common adverse events associated with the 200-mg dose include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (itching). It has also been associated “with rare reports” of rhabdomyolysis, muscle spasms, and myalgia, according to the FDA.

The prescribing information includes a boxed warning about the risk of embryo-fetal toxicity, and includes recommendations to verify that women of reproductive potential are not pregnant before starting treatment and to use effective contraception during treatment and for at least 20 months after the last dose. Men on this treatment should also be advised about “the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment,” and for at least 8 months after stopping treatment.

More information on the approval is available on the FDA website at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455865.htm.

Exposed pregnancies should be reported to Novartis at 888-669-6682. Serious adverse events associated with sonidegib should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch.

[email protected]

Sonidegib, a hedgehog pathway inhibitor, has been approved for treating patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy, the Food and Drug Administration announced on July 24. The drug is taken once a day, at a recommended dose of 200 mg on an empty stomach and will be marketed as Odomzo by Novartis Pharmaceuticals. Approval was based on a study that found the objective response rate to be 58% among patients treated with the 200-mg dose; an effect that lasted for about 2-19 months, according to the FDA.

“Our increasing understanding of molecular pathways involved in cancer has led to approvals of many oncology drugs in difficult-to-treat diseases for which few therapeutic options previously existed,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. “Thanks to a better understanding of the hedgehog pathway, the FDA has now approved two drugs for the treatment of basal cell carcinoma just in the last 3 years,” he added.

The first drug to treat locally advanced and metastatic basal cell carcinoma was vismodegib, marketed as Erivedge by Genentech in 2012.

The most common adverse events associated with the 200-mg dose include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (itching). It has also been associated “with rare reports” of rhabdomyolysis, muscle spasms, and myalgia, according to the FDA.

The prescribing information includes a boxed warning about the risk of embryo-fetal toxicity, and includes recommendations to verify that women of reproductive potential are not pregnant before starting treatment and to use effective contraception during treatment and for at least 20 months after the last dose. Men on this treatment should also be advised about “the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment,” and for at least 8 months after stopping treatment.

More information on the approval is available on the FDA website at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455865.htm.

Exposed pregnancies should be reported to Novartis at 888-669-6682. Serious adverse events associated with sonidegib should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch.

[email protected]

Sonidegib, a hedgehog pathway inhibitor, has been approved for treating patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy, the Food and Drug Administration announced on July 24. The drug is taken once a day, at a recommended dose of 200 mg on an empty stomach and will be marketed as Odomzo by Novartis Pharmaceuticals. Approval was based on a study that found the objective response rate to be 58% among patients treated with the 200-mg dose; an effect that lasted for about 2-19 months, according to the FDA.

“Our increasing understanding of molecular pathways involved in cancer has led to approvals of many oncology drugs in difficult-to-treat diseases for which few therapeutic options previously existed,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. “Thanks to a better understanding of the hedgehog pathway, the FDA has now approved two drugs for the treatment of basal cell carcinoma just in the last 3 years,” he added.

The first drug to treat locally advanced and metastatic basal cell carcinoma was vismodegib, marketed as Erivedge by Genentech in 2012.

The most common adverse events associated with the 200-mg dose include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (itching). It has also been associated “with rare reports” of rhabdomyolysis, muscle spasms, and myalgia, according to the FDA.

The prescribing information includes a boxed warning about the risk of embryo-fetal toxicity, and includes recommendations to verify that women of reproductive potential are not pregnant before starting treatment and to use effective contraception during treatment and for at least 20 months after the last dose. Men on this treatment should also be advised about “the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment,” and for at least 8 months after stopping treatment.

More information on the approval is available on the FDA website at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm455865.htm.

Exposed pregnancies should be reported to Novartis at 888-669-6682. Serious adverse events associated with sonidegib should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch.

[email protected]

The calcium channel blocker amlodipine besylate was effective in reducing the number of muscle cramps caused by vismodegib, a basal cell carcinoma drug, according to a research letter from Dr. Mina Ally and her associates.

Patients who took amlodipine had the number of muscle cramps halved after 2 weeks of treatment, and this level was maintained for the 8-week medication regimen. No significant change in cramp severity, duration, or frequency of nighttime awakenings was seen. Side effects only appeared in too patients, with one reporting mild intermittent dizziness and another reporting grade 1 peripheral edema.

The control group saw a nonsignificant increase in cramp frequency, compared with the significant decrease in the amlodipine group. No change was seen in cramp severity, duration, or number of nighttime awakenings in the control group.

“Amlodipine may be effective in vismodegib-induced muscle cramps because it blocks voltage-gated calcium channels and inhibits the transport of extracellular calcium into muscle that is required for contraction,” the investigators noted.

Find the full research letter in JAMA Dermatology (doi:10.1001/jamadermatol.2015.1937).

[email protected]

The calcium channel blocker amlodipine besylate was effective in reducing the number of muscle cramps caused by vismodegib, a basal cell carcinoma drug, according to a research letter from Dr. Mina Ally and her associates.

Patients who took amlodipine had the number of muscle cramps halved after 2 weeks of treatment, and this level was maintained for the 8-week medication regimen. No significant change in cramp severity, duration, or frequency of nighttime awakenings was seen. Side effects only appeared in too patients, with one reporting mild intermittent dizziness and another reporting grade 1 peripheral edema.

The control group saw a nonsignificant increase in cramp frequency, compared with the significant decrease in the amlodipine group. No change was seen in cramp severity, duration, or number of nighttime awakenings in the control group.

“Amlodipine may be effective in vismodegib-induced muscle cramps because it blocks voltage-gated calcium channels and inhibits the transport of extracellular calcium into muscle that is required for contraction,” the investigators noted.

Find the full research letter in JAMA Dermatology (doi:10.1001/jamadermatol.2015.1937).

[email protected]

The calcium channel blocker amlodipine besylate was effective in reducing the number of muscle cramps caused by vismodegib, a basal cell carcinoma drug, according to a research letter from Dr. Mina Ally and her associates.

Patients who took amlodipine had the number of muscle cramps halved after 2 weeks of treatment, and this level was maintained for the 8-week medication regimen. No significant change in cramp severity, duration, or frequency of nighttime awakenings was seen. Side effects only appeared in too patients, with one reporting mild intermittent dizziness and another reporting grade 1 peripheral edema.

The control group saw a nonsignificant increase in cramp frequency, compared with the significant decrease in the amlodipine group. No change was seen in cramp severity, duration, or number of nighttime awakenings in the control group.

“Amlodipine may be effective in vismodegib-induced muscle cramps because it blocks voltage-gated calcium channels and inhibits the transport of extracellular calcium into muscle that is required for contraction,” the investigators noted.

Find the full research letter in JAMA Dermatology (doi:10.1001/jamadermatol.2015.1937).

[email protected]