Trial Assesses SLNB's Future in Melanoma Management

NEW YORK – Sentinel lymph node biopsy continues to aid the management of about 30% of melanoma patients, though its role in the future will depend on ongoing follow-up of a major trial that started nearly 20 years ago to assess the effect of SLNB on patient survival.

But SLNB’s role could soon be upstaged by molecular profiling and the identification of specific genetic mutations that drive various melanoma subtypes, Dr. Timothy M. Johnson said at the American Academy of Dermatology’s Summer Academy Meeting.

"In the future, I hope we can do molecular profiling on melanoma and [based on that] tell patients who will benefit [from various targeted treatments] and who won’t. We are already doing this [on an investigational basis] with several new molecular profiling tests such as BRAF mutations" and treatment with vemurafenib, said Dr. Johnson, a professor of dermatology at the University of Michigan in Ann Arbor.

For the time being, melanoma patients should be counseled regarding SLNB if their tumors are at least 0.75 mm in Breslow depth and if they meet certain other criteria.

Even patients with thinner tumors should be counseled on the pros and cons of SLNB, because they will likely hear or know about the technique and may have questions. That is the approach taken at the University of Michigan and other centers, he said.

"SLN status is a powerful predictor of survival in the relatively small subset of patients where SLNB is indicated," he said. Reasons not to do SLNB include thin primary melanomas generally less than 0.75 mm with a low probability of a positive SLNB, high comorbidities, and maybe prior wide local excision, certainly in areas of ambiguous lymphatic drainage or following a local flap. This group includes about 70% of all U.S. melanoma patients. Albeit rarely, these thin lesions may be at higher risk when they have greater degrees of adverse features or positive deep margins on shave biopsy.

Melanoma patients with primary tumors that are 0.75-0.99 mm generally need an additional risk factor, such as ulceration, young age – up to about 40 years old, an increased mitotic rate, or angiolymphatic invasion to justify SLNB. When patients have additional risk factors, "we have a discussion with the patient to help them decide," he said. "We tell them the likely rate of positive lymph nodes based on our best information."

A clearer role for SLNB exists for patients with tumors with a Breslow thickness of 1 mm or greater. In these patients, exclusions from SLNB include "highly significant" medical comorbidities, a prior wide excision of the tumor, and tumors in "ambiguous" lymphatic drainage areas, such as the central back or central chest. Even in these cases, exclusion from SLNB "usually occurs but not always," Dr. Johnson noted.

Patients whose tumors have a Breslow thickness of more than 4 mm are also candidates for SLNB. In these cases, SLNB can help refine the patient’s prognosis, and may also aid the choice of adjuvant therapy.

Historically, patients with tumors 4 mm or larger were considered likely to have distant metastatic disease and a poor prognosis, and, hence, no benefit from SLNB. But Dr. Johnson and his colleagues showed a substantial difference in survival rate between patients with positive and negative SLNs even when they had thicker primary tumors.

In a series of 227 patients with melanomas at least 4 mm thick and no clinically or radiologically-apparent distant disease, patients with a positive SLNB had a 5-year overall survival rate of 47%, while patients with negative SLNs had a 5-year survival rate of 80%, a statistically significant difference (P less than .0001). The difference in 5-year distant disease-free survival rates ran slightly larger, 85% in the node-negative patients and 48% in the node-positive patients (P less than .0001) (Cancer 2009;115:5752-60). Following this study, supporting evidence has come from several other research groups.

The ongoing Multicenter Selective Lymphadenectomy Trial (MSLT) should provide more definitive evidence on the survival effects of SLNB. The interim, 5-year follow-up data from 1,327 patients at 18 worldwide centers reported in 2006 included patients with primary-tumor Breslow thicknesses of 1.2-3.5 mm. Although the study’s primary endpoint of the 5-year melanoma-specific survival rate was similar in the patients randomized to SLNB or wide local excision (87%), the prespecified secondary endpoint of 5-year disease-free survival ran 78% in patients who underwent SLNB and 73% in the wide excision group, a statistically-significant difference (P = .009) (N. Engl. J. Med. 2006;355:1307-17).

"The question is, can we identify a subset of patients with occult nodal disease with SLNB, intervene early, and improve outcomes? At face value, the third interim analysis data [the 2006 report] suggests potentially yes. However, this is a subset analysis and its validity can be debated. The data certainly support the potential for a subset benefit in node-positive patients," said Dr. Johnson. Updated survival results from a longer-term, fourth interim analysis of the MSLT survival outcomes are expected within the next year, and will help answer this question.

In addition to the disease-free survival benefit shown in the MSLT, the 30% of melanoma patients who are candidates for SLNB stand to gain useful prognostic information from the procedure. On average, about 20% of patients who are eligible for SLNB have a positive SLN, and this subgroup of patients also stand to benefit from more durable regional control of their disease with better quality of life. The survival benefit most likely occurs in a subset, perhaps 20%, of the node-positive patients, he said.

In summary, Dr. Johnson said the main reasons to consider SLNB are prognosis, durable regional control, and potential survival benefit in a select subset. These factors should be presented in "an honest discussion with the patient and family about the risks and benefits of SLNB, to help them make a best informed decision," he said.

Although many cancer centers currently use SLNB for melanoma in the way outlined by Dr. Johnson, with "not much controversy" among the "mainstream" of physicians and surgeons who treat melanoma, he noted that "there is posturing and emotion with this procedure," with controversy among some clinicians about the proper role.

"Some dermatologists don’t believe that SLNB should be used for anybody, and some surgeons overuse it on everybody. The answer [on when to use SLNB] is somewhere in between," he said in an interview. The forthcoming, longer-term follow-up data from MSLT may help clinicians how best to use SLNB most appropriately, he added.

Dr. Johnson said that he had no disclosures.

NEW YORK – Sentinel lymph node biopsy continues to aid the management of about 30% of melanoma patients, though its role in the future will depend on ongoing follow-up of a major trial that started nearly 20 years ago to assess the effect of SLNB on patient survival.

But SLNB’s role could soon be upstaged by molecular profiling and the identification of specific genetic mutations that drive various melanoma subtypes, Dr. Timothy M. Johnson said at the American Academy of Dermatology’s Summer Academy Meeting.

"In the future, I hope we can do molecular profiling on melanoma and [based on that] tell patients who will benefit [from various targeted treatments] and who won’t. We are already doing this [on an investigational basis] with several new molecular profiling tests such as BRAF mutations" and treatment with vemurafenib, said Dr. Johnson, a professor of dermatology at the University of Michigan in Ann Arbor.

For the time being, melanoma patients should be counseled regarding SLNB if their tumors are at least 0.75 mm in Breslow depth and if they meet certain other criteria.

Even patients with thinner tumors should be counseled on the pros and cons of SLNB, because they will likely hear or know about the technique and may have questions. That is the approach taken at the University of Michigan and other centers, he said.

"SLN status is a powerful predictor of survival in the relatively small subset of patients where SLNB is indicated," he said. Reasons not to do SLNB include thin primary melanomas generally less than 0.75 mm with a low probability of a positive SLNB, high comorbidities, and maybe prior wide local excision, certainly in areas of ambiguous lymphatic drainage or following a local flap. This group includes about 70% of all U.S. melanoma patients. Albeit rarely, these thin lesions may be at higher risk when they have greater degrees of adverse features or positive deep margins on shave biopsy.

Melanoma patients with primary tumors that are 0.75-0.99 mm generally need an additional risk factor, such as ulceration, young age – up to about 40 years old, an increased mitotic rate, or angiolymphatic invasion to justify SLNB. When patients have additional risk factors, "we have a discussion with the patient to help them decide," he said. "We tell them the likely rate of positive lymph nodes based on our best information."

A clearer role for SLNB exists for patients with tumors with a Breslow thickness of 1 mm or greater. In these patients, exclusions from SLNB include "highly significant" medical comorbidities, a prior wide excision of the tumor, and tumors in "ambiguous" lymphatic drainage areas, such as the central back or central chest. Even in these cases, exclusion from SLNB "usually occurs but not always," Dr. Johnson noted.

Patients whose tumors have a Breslow thickness of more than 4 mm are also candidates for SLNB. In these cases, SLNB can help refine the patient’s prognosis, and may also aid the choice of adjuvant therapy.

Historically, patients with tumors 4 mm or larger were considered likely to have distant metastatic disease and a poor prognosis, and, hence, no benefit from SLNB. But Dr. Johnson and his colleagues showed a substantial difference in survival rate between patients with positive and negative SLNs even when they had thicker primary tumors.

In a series of 227 patients with melanomas at least 4 mm thick and no clinically or radiologically-apparent distant disease, patients with a positive SLNB had a 5-year overall survival rate of 47%, while patients with negative SLNs had a 5-year survival rate of 80%, a statistically significant difference (P less than .0001). The difference in 5-year distant disease-free survival rates ran slightly larger, 85% in the node-negative patients and 48% in the node-positive patients (P less than .0001) (Cancer 2009;115:5752-60). Following this study, supporting evidence has come from several other research groups.

The ongoing Multicenter Selective Lymphadenectomy Trial (MSLT) should provide more definitive evidence on the survival effects of SLNB. The interim, 5-year follow-up data from 1,327 patients at 18 worldwide centers reported in 2006 included patients with primary-tumor Breslow thicknesses of 1.2-3.5 mm. Although the study’s primary endpoint of the 5-year melanoma-specific survival rate was similar in the patients randomized to SLNB or wide local excision (87%), the prespecified secondary endpoint of 5-year disease-free survival ran 78% in patients who underwent SLNB and 73% in the wide excision group, a statistically-significant difference (P = .009) (N. Engl. J. Med. 2006;355:1307-17).

"The question is, can we identify a subset of patients with occult nodal disease with SLNB, intervene early, and improve outcomes? At face value, the third interim analysis data [the 2006 report] suggests potentially yes. However, this is a subset analysis and its validity can be debated. The data certainly support the potential for a subset benefit in node-positive patients," said Dr. Johnson. Updated survival results from a longer-term, fourth interim analysis of the MSLT survival outcomes are expected within the next year, and will help answer this question.

In addition to the disease-free survival benefit shown in the MSLT, the 30% of melanoma patients who are candidates for SLNB stand to gain useful prognostic information from the procedure. On average, about 20% of patients who are eligible for SLNB have a positive SLN, and this subgroup of patients also stand to benefit from more durable regional control of their disease with better quality of life. The survival benefit most likely occurs in a subset, perhaps 20%, of the node-positive patients, he said.

In summary, Dr. Johnson said the main reasons to consider SLNB are prognosis, durable regional control, and potential survival benefit in a select subset. These factors should be presented in "an honest discussion with the patient and family about the risks and benefits of SLNB, to help them make a best informed decision," he said.

Although many cancer centers currently use SLNB for melanoma in the way outlined by Dr. Johnson, with "not much controversy" among the "mainstream" of physicians and surgeons who treat melanoma, he noted that "there is posturing and emotion with this procedure," with controversy among some clinicians about the proper role.

"Some dermatologists don’t believe that SLNB should be used for anybody, and some surgeons overuse it on everybody. The answer [on when to use SLNB] is somewhere in between," he said in an interview. The forthcoming, longer-term follow-up data from MSLT may help clinicians how best to use SLNB most appropriately, he added.

Dr. Johnson said that he had no disclosures.

NEW YORK – Sentinel lymph node biopsy continues to aid the management of about 30% of melanoma patients, though its role in the future will depend on ongoing follow-up of a major trial that started nearly 20 years ago to assess the effect of SLNB on patient survival.

But SLNB’s role could soon be upstaged by molecular profiling and the identification of specific genetic mutations that drive various melanoma subtypes, Dr. Timothy M. Johnson said at the American Academy of Dermatology’s Summer Academy Meeting.

"In the future, I hope we can do molecular profiling on melanoma and [based on that] tell patients who will benefit [from various targeted treatments] and who won’t. We are already doing this [on an investigational basis] with several new molecular profiling tests such as BRAF mutations" and treatment with vemurafenib, said Dr. Johnson, a professor of dermatology at the University of Michigan in Ann Arbor.

For the time being, melanoma patients should be counseled regarding SLNB if their tumors are at least 0.75 mm in Breslow depth and if they meet certain other criteria.

Even patients with thinner tumors should be counseled on the pros and cons of SLNB, because they will likely hear or know about the technique and may have questions. That is the approach taken at the University of Michigan and other centers, he said.

"SLN status is a powerful predictor of survival in the relatively small subset of patients where SLNB is indicated," he said. Reasons not to do SLNB include thin primary melanomas generally less than 0.75 mm with a low probability of a positive SLNB, high comorbidities, and maybe prior wide local excision, certainly in areas of ambiguous lymphatic drainage or following a local flap. This group includes about 70% of all U.S. melanoma patients. Albeit rarely, these thin lesions may be at higher risk when they have greater degrees of adverse features or positive deep margins on shave biopsy.

Melanoma patients with primary tumors that are 0.75-0.99 mm generally need an additional risk factor, such as ulceration, young age – up to about 40 years old, an increased mitotic rate, or angiolymphatic invasion to justify SLNB. When patients have additional risk factors, "we have a discussion with the patient to help them decide," he said. "We tell them the likely rate of positive lymph nodes based on our best information."

A clearer role for SLNB exists for patients with tumors with a Breslow thickness of 1 mm or greater. In these patients, exclusions from SLNB include "highly significant" medical comorbidities, a prior wide excision of the tumor, and tumors in "ambiguous" lymphatic drainage areas, such as the central back or central chest. Even in these cases, exclusion from SLNB "usually occurs but not always," Dr. Johnson noted.

Patients whose tumors have a Breslow thickness of more than 4 mm are also candidates for SLNB. In these cases, SLNB can help refine the patient’s prognosis, and may also aid the choice of adjuvant therapy.

Historically, patients with tumors 4 mm or larger were considered likely to have distant metastatic disease and a poor prognosis, and, hence, no benefit from SLNB. But Dr. Johnson and his colleagues showed a substantial difference in survival rate between patients with positive and negative SLNs even when they had thicker primary tumors.

In a series of 227 patients with melanomas at least 4 mm thick and no clinically or radiologically-apparent distant disease, patients with a positive SLNB had a 5-year overall survival rate of 47%, while patients with negative SLNs had a 5-year survival rate of 80%, a statistically significant difference (P less than .0001). The difference in 5-year distant disease-free survival rates ran slightly larger, 85% in the node-negative patients and 48% in the node-positive patients (P less than .0001) (Cancer 2009;115:5752-60). Following this study, supporting evidence has come from several other research groups.

The ongoing Multicenter Selective Lymphadenectomy Trial (MSLT) should provide more definitive evidence on the survival effects of SLNB. The interim, 5-year follow-up data from 1,327 patients at 18 worldwide centers reported in 2006 included patients with primary-tumor Breslow thicknesses of 1.2-3.5 mm. Although the study’s primary endpoint of the 5-year melanoma-specific survival rate was similar in the patients randomized to SLNB or wide local excision (87%), the prespecified secondary endpoint of 5-year disease-free survival ran 78% in patients who underwent SLNB and 73% in the wide excision group, a statistically-significant difference (P = .009) (N. Engl. J. Med. 2006;355:1307-17).

"The question is, can we identify a subset of patients with occult nodal disease with SLNB, intervene early, and improve outcomes? At face value, the third interim analysis data [the 2006 report] suggests potentially yes. However, this is a subset analysis and its validity can be debated. The data certainly support the potential for a subset benefit in node-positive patients," said Dr. Johnson. Updated survival results from a longer-term, fourth interim analysis of the MSLT survival outcomes are expected within the next year, and will help answer this question.

In addition to the disease-free survival benefit shown in the MSLT, the 30% of melanoma patients who are candidates for SLNB stand to gain useful prognostic information from the procedure. On average, about 20% of patients who are eligible for SLNB have a positive SLN, and this subgroup of patients also stand to benefit from more durable regional control of their disease with better quality of life. The survival benefit most likely occurs in a subset, perhaps 20%, of the node-positive patients, he said.

In summary, Dr. Johnson said the main reasons to consider SLNB are prognosis, durable regional control, and potential survival benefit in a select subset. These factors should be presented in "an honest discussion with the patient and family about the risks and benefits of SLNB, to help them make a best informed decision," he said.

Although many cancer centers currently use SLNB for melanoma in the way outlined by Dr. Johnson, with "not much controversy" among the "mainstream" of physicians and surgeons who treat melanoma, he noted that "there is posturing and emotion with this procedure," with controversy among some clinicians about the proper role.

"Some dermatologists don’t believe that SLNB should be used for anybody, and some surgeons overuse it on everybody. The answer [on when to use SLNB] is somewhere in between," he said in an interview. The forthcoming, longer-term follow-up data from MSLT may help clinicians how best to use SLNB most appropriately, he added.

Dr. Johnson said that he had no disclosures.