Melanoma

CHICAGO — An ultrasound technique that measures tissue elasticity could dramatically alter the way in which skin cancer is diagnosed.

In a prospective study of 56 patients with proliferative malignant neoplasms or benign skin lesions, the use of ultrasound elastography analysis prior to biopsy correctly differentiated benign from malignant lesions in 100% of cases (P value equal .0007), Dr. Eliot Siegel reported at the annual meeting of the Radiological Society of North America.

“We believe that ultrasound has tremendous potential that is completely untapped now to characterize and delineate the extent of skin lesions currently evaluated visually,” he said.

“We believe it has tremendous promise to reduce unnecessary biopsies,” he added.

Elastography noninvasively estimates the axial tissue strain, or elastic properties of tissue. Cystic lesions demonstrate high levels of elasticity, while malignant lesions are relatively “hard” with a very low level of elasticity.

Ultrasound with elastography, more so than optical or light images, is unique in its ability to provide the proper depth at which to analyze lesions—around 5 mm below the surface, said Dr. Siegel, vice chair of radiology and a professor at the University of Maryland in Baltimore. This may be useful in the early detection of melanoma before the classic signs such as asymmetry or changes in border are present on the skin's surface. In addition, elastography could have a role during surgery.

“This also could guide the surgeon as the surgeon is doing an excision or biopsy to not just look at the tip of the iceberg that they can see at the skin surface, but actually to be able to look deeper, so they can see exactly which areas they can cut out safely and still remove the entire tumor without unnecessarily removing more than that,” he said.

Elastography software is available on most new ultrasound machines, and has been used with promising results for breast, thyroid, and liver cancer. It has not been used to explore skin lesions, except for one prior study from 2007.

That study used absolute strain values, whereas Dr. Siegel and associates also calculated strain ratios. Malignant lesions had higher strain ratios (minimum 5.3; maximum 32.2), compared with benign lesions (min. 0.01; max. 3). None of the malignant lesions violated a strain-ratio cutoff of 3-5, Dr. Siegel said. He presented a few examples, including a squamous cell carcinoma with a ratio of 13.27 and a benign keloid with a ratio of 1.25.

Although preliminary, the data suggest that strain ratios may also be useful in distinguishing between malignant lesions. Squamous cell carcinomas had a higher ratio overall, said coauthor Dr. Bahar Dasgeb, a radiologist and second-year dermatology resident at Wayne State University in Detroit. Moreover, the strain ratio was higher, even within squamous cell or basal cell cancers, when more invasive cells were present.

If strain ratios are combined with higher ultrasound frequencies, it's possible that the anatomic information gleaned from elastography “could rival the information that a pathologist would see after the lesion was excised,” Dr. Siegel said. “That's really the direction that we'd like to head into for research and development, as we look at much higher ultrasound frequencies.”

The current study used a clinically available 14- to 16-mHz ultrasound unit.

The findings were enthusiastically received when presented by Dr. Dasgeb at the Michigan Dermatological Society meeting in November.

“The feedback from Mohs' surgeons was amazing,” she said in an interview. “A couple of clinical dermatologists said, 'there is no other way.'”

She suggested transitioning this technology from radiology to clinical dermatology would not be difficult nor take long because of need and the rising incidence and economic impact of skin cancer. It is estimated that one in five Americans will develop skin cancer at some point in their lives.

Disclosures: Dr. Siegel disclosed receiving research grants from several imaging companies. Dr. Dasgeb had no disclosures.

An elastogram (left) and ultrasound (right) show squamous cell carcinoma of the skin. The technique could eliminate unnecessary biopsies of benign skin lesions.

Source Courtesy Radiological Society of North America

The information gleaned could rival 'information that a pathologist would see after the lesion was excised.'

Source DR. SIEGEL

'A couple of clinical dermatologists said, “there is no other way.”'

Source DR. DASGEB

CHICAGO — An ultrasound technique that measures tissue elasticity could dramatically alter the way in which skin cancer is diagnosed.

In a prospective study of 56 patients with proliferative malignant neoplasms or benign skin lesions, the use of ultrasound elastography analysis prior to biopsy correctly differentiated benign from malignant lesions in 100% of cases (P value equal .0007), Dr. Eliot Siegel reported at the annual meeting of the Radiological Society of North America.

“We believe that ultrasound has tremendous potential that is completely untapped now to characterize and delineate the extent of skin lesions currently evaluated visually,” he said.

“We believe it has tremendous promise to reduce unnecessary biopsies,” he added.

Elastography noninvasively estimates the axial tissue strain, or elastic properties of tissue. Cystic lesions demonstrate high levels of elasticity, while malignant lesions are relatively “hard” with a very low level of elasticity.

Ultrasound with elastography, more so than optical or light images, is unique in its ability to provide the proper depth at which to analyze lesions—around 5 mm below the surface, said Dr. Siegel, vice chair of radiology and a professor at the University of Maryland in Baltimore. This may be useful in the early detection of melanoma before the classic signs such as asymmetry or changes in border are present on the skin's surface. In addition, elastography could have a role during surgery.

“This also could guide the surgeon as the surgeon is doing an excision or biopsy to not just look at the tip of the iceberg that they can see at the skin surface, but actually to be able to look deeper, so they can see exactly which areas they can cut out safely and still remove the entire tumor without unnecessarily removing more than that,” he said.

Elastography software is available on most new ultrasound machines, and has been used with promising results for breast, thyroid, and liver cancer. It has not been used to explore skin lesions, except for one prior study from 2007.

That study used absolute strain values, whereas Dr. Siegel and associates also calculated strain ratios. Malignant lesions had higher strain ratios (minimum 5.3; maximum 32.2), compared with benign lesions (min. 0.01; max. 3). None of the malignant lesions violated a strain-ratio cutoff of 3-5, Dr. Siegel said. He presented a few examples, including a squamous cell carcinoma with a ratio of 13.27 and a benign keloid with a ratio of 1.25.

Although preliminary, the data suggest that strain ratios may also be useful in distinguishing between malignant lesions. Squamous cell carcinomas had a higher ratio overall, said coauthor Dr. Bahar Dasgeb, a radiologist and second-year dermatology resident at Wayne State University in Detroit. Moreover, the strain ratio was higher, even within squamous cell or basal cell cancers, when more invasive cells were present.

If strain ratios are combined with higher ultrasound frequencies, it's possible that the anatomic information gleaned from elastography “could rival the information that a pathologist would see after the lesion was excised,” Dr. Siegel said. “That's really the direction that we'd like to head into for research and development, as we look at much higher ultrasound frequencies.”

The current study used a clinically available 14- to 16-mHz ultrasound unit.

The findings were enthusiastically received when presented by Dr. Dasgeb at the Michigan Dermatological Society meeting in November.

“The feedback from Mohs' surgeons was amazing,” she said in an interview. “A couple of clinical dermatologists said, 'there is no other way.'”

She suggested transitioning this technology from radiology to clinical dermatology would not be difficult nor take long because of need and the rising incidence and economic impact of skin cancer. It is estimated that one in five Americans will develop skin cancer at some point in their lives.

Disclosures: Dr. Siegel disclosed receiving research grants from several imaging companies. Dr. Dasgeb had no disclosures.

An elastogram (left) and ultrasound (right) show squamous cell carcinoma of the skin. The technique could eliminate unnecessary biopsies of benign skin lesions.

Source Courtesy Radiological Society of North America

The information gleaned could rival 'information that a pathologist would see after the lesion was excised.'

Source DR. SIEGEL

'A couple of clinical dermatologists said, “there is no other way.”'

Source DR. DASGEB

CHICAGO — An ultrasound technique that measures tissue elasticity could dramatically alter the way in which skin cancer is diagnosed.

In a prospective study of 56 patients with proliferative malignant neoplasms or benign skin lesions, the use of ultrasound elastography analysis prior to biopsy correctly differentiated benign from malignant lesions in 100% of cases (P value equal .0007), Dr. Eliot Siegel reported at the annual meeting of the Radiological Society of North America.

“We believe that ultrasound has tremendous potential that is completely untapped now to characterize and delineate the extent of skin lesions currently evaluated visually,” he said.

“We believe it has tremendous promise to reduce unnecessary biopsies,” he added.

Elastography noninvasively estimates the axial tissue strain, or elastic properties of tissue. Cystic lesions demonstrate high levels of elasticity, while malignant lesions are relatively “hard” with a very low level of elasticity.

Ultrasound with elastography, more so than optical or light images, is unique in its ability to provide the proper depth at which to analyze lesions—around 5 mm below the surface, said Dr. Siegel, vice chair of radiology and a professor at the University of Maryland in Baltimore. This may be useful in the early detection of melanoma before the classic signs such as asymmetry or changes in border are present on the skin's surface. In addition, elastography could have a role during surgery.

“This also could guide the surgeon as the surgeon is doing an excision or biopsy to not just look at the tip of the iceberg that they can see at the skin surface, but actually to be able to look deeper, so they can see exactly which areas they can cut out safely and still remove the entire tumor without unnecessarily removing more than that,” he said.

Elastography software is available on most new ultrasound machines, and has been used with promising results for breast, thyroid, and liver cancer. It has not been used to explore skin lesions, except for one prior study from 2007.

That study used absolute strain values, whereas Dr. Siegel and associates also calculated strain ratios. Malignant lesions had higher strain ratios (minimum 5.3; maximum 32.2), compared with benign lesions (min. 0.01; max. 3). None of the malignant lesions violated a strain-ratio cutoff of 3-5, Dr. Siegel said. He presented a few examples, including a squamous cell carcinoma with a ratio of 13.27 and a benign keloid with a ratio of 1.25.

Although preliminary, the data suggest that strain ratios may also be useful in distinguishing between malignant lesions. Squamous cell carcinomas had a higher ratio overall, said coauthor Dr. Bahar Dasgeb, a radiologist and second-year dermatology resident at Wayne State University in Detroit. Moreover, the strain ratio was higher, even within squamous cell or basal cell cancers, when more invasive cells were present.

If strain ratios are combined with higher ultrasound frequencies, it's possible that the anatomic information gleaned from elastography “could rival the information that a pathologist would see after the lesion was excised,” Dr. Siegel said. “That's really the direction that we'd like to head into for research and development, as we look at much higher ultrasound frequencies.”

The current study used a clinically available 14- to 16-mHz ultrasound unit.

The findings were enthusiastically received when presented by Dr. Dasgeb at the Michigan Dermatological Society meeting in November.

“The feedback from Mohs' surgeons was amazing,” she said in an interview. “A couple of clinical dermatologists said, 'there is no other way.'”

She suggested transitioning this technology from radiology to clinical dermatology would not be difficult nor take long because of need and the rising incidence and economic impact of skin cancer. It is estimated that one in five Americans will develop skin cancer at some point in their lives.

Disclosures: Dr. Siegel disclosed receiving research grants from several imaging companies. Dr. Dasgeb had no disclosures.

An elastogram (left) and ultrasound (right) show squamous cell carcinoma of the skin. The technique could eliminate unnecessary biopsies of benign skin lesions.

Source Courtesy Radiological Society of North America

The information gleaned could rival 'information that a pathologist would see after the lesion was excised.'

Source DR. SIEGEL

'A couple of clinical dermatologists said, “there is no other way.”'

Source DR. DASGEB

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

PHILADELPHIA — Two studies showed an increased risk for nonmelanoma skin cancer in patients who take anti–tumor necrosis factor therapies, and should prompt physicians to evaluate the use of these drugs in patients who are at risk for skin cancer, according to the researchers.

Previous studies have been too small to show a definitive link between biologic therapy for rheumatoid arthritis (RA) and skin malignancy, although RA previously has been well established as a risk factor for skin cancer, according to Dr. Prahba Ranganathan.

She presented the results of her retrospective cohort study of RA patients in the Department of Veterans Affairs national database at the annual meeting of the American College of Rheumatology.

According to Dr. Ranganathan, among 16,829 patients with RA, 3,096 were treated with anti-TNFs at the VA between Oct. 1, 1998, and Sept. 30, 2006. The incidence of nonmelanoma skin cancer was 25.9 per 1,000 patient-years in this cohort, compared with 19.6 per 1,000 patient-years in the biologic-naive cohort, a 34% increased risk.

The incidence of melanoma also was increased by about 50%, with about 3.7 cases per 1,000 patient-years seen in the anti-TNF-treated group, vs. 2.6 cases per 1,000 patient-years in the biologic-naive cohort. Both results were significant.

A second study presented at the press conference confirmed these findings. Dr. Kimme Hyrich of the University of Manchester (England) looked at RA patients from the British Society for Rheumatology's biologics register, a prospective cohort study begun in 2001 to monitor the long-term safety of anti-TNFs.

Dr. Hyrich found that among 11,598 RA patients who were treated with anti-TNFs and had no prior nonmelanoma skin cancer, the incidence of a malignancy was 3.5 per 1,000 patient-years. In contrast, among 8,975 similar patients who were treated with nonbiologic therapies, the incidence of new nonmelanoma skin cancers was 2.4.

That was a 70% increased risk for the anti-TNF–treated patients, although the data were not significant, Dr. Hyrich reported.

Dr. Hyrich pointed out that patients treated with anti-TNF drugs typically have more contact with their physicians, which could have introduced a surveillance bias.

Dr. Ranganathan cautioned that even in patients with multiple skin cancer risks anti-TNFs are still a good choice for patients who've failed other treatments. “People with risk factors should be watched more closely and maybe have periodic skin exams,” she said.

Dr. Ranganathan, Dr. Hyrich, and their respective research teams did not report having any financial conflicts relative to their studies.

BERLIN — The addition of bevacizumab to chemotherapy failed to significantly improve progression-free or overall survival in previously untreated advanced melanoma in the phase II BEAM trial.

Median progression-free survival was 5.6 months for bevacizumab (Avastin) plus carboplatin and paclitaxel-based chemotherapy, and 4.2 months for chemotherapy alone. Despite a hazard ratio of 0.78, the difference was not statistically significant (P = .14), Dr. Steven O'Day reported at a joint congress of the European Cancer Organization and the European Society for Medical Oncology.

Overall survival was widely reported before the congress as having been significantly increased by 4 months with bevacizumab, but an unplanned post hoc analysis performed just before the formal data presentation showed that the survival benefit had narrowed and had taken the statistical advantage with it.

Median overall survival went from 12.3 months in the bevacizumab arm and 8.6 months in the chemotherapy arm at a median follow-up of 13 months in the initial analysis (HR, 0.67; P = .04) to 12.3 months and 9.2 months, respectively, at a median follow-up of 18 months in the post hoc analysis (HR, 0.79; P = .19).

Response rates also favored bevacizumab over chemotherapy (25.5% vs. 16.4%), but were not significantly different (P =.16) in the Roche Pharmaceuticals–sponsored study.

Although the revised data sent stock analysts and journalists scrambling, the findings are still cause for optimism in a disease with few treatment options and a 5-year survival of less than 5%, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

“I am optimistic because strong trends of improvement were seen across all efficacy parameters” (progression-free survival, overall survival, and response), he said in an interview. “This was a randomized, phase II with 2:1 randomization, so it wasn't powered for overall survival to be significantly different. I'm also optimistic because even the worse prognosis patients with M1c disease and elevated [lactate dehydrogenase] seemed to benefit from this treatment.”

Based on the current data, Roche plans to go forward with a larger, randomized phase III trial that is adequately powered to detect a significant survival benefit, he said.

BEAM (A Study of Bevacizumab With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma) included 214 patients (mean age, 60 years) with stage IV M1a/b, M1c disease, of which 73% was M1c disease and 54% of M1c patients had abnormal lactate dehydrogenase levels. Patients received chemotherapy with or without bevacizumab 15 mg/kg administered intravenously on day 1 every 3 weeks.

Bevacizumab, an anti–vascular endothelial growth factor (VEGF)–specific inhibitor, was evaluated because melanoma is a very vascular tumor, and elevated VEGF levels correlate with tumor progression and worse prognosis. The addition of bevacizumab to chemotherapy has improved outcomes in other cancers, including metastatic colorectal cancer and non–small cell lung cancer.

No new safety events were observed in the trial. Grade 3/4 treatment-related adverse events that occurred with 2% or more increased incidence in the bevacizumab arm included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia, and musculoskeletal pain. There were two deaths in the bevacizumab arm and none in the chemotherapy arm, Dr. O'Day said.

He has served an advisory/consultant role and received research funds from Genentech Inc. and Roche for clinical trials.

BERLIN — The addition of bevacizumab to chemotherapy failed to significantly improve progression-free or overall survival in previously untreated advanced melanoma in the phase II BEAM trial.

Median progression-free survival was 5.6 months for bevacizumab (Avastin) plus carboplatin and paclitaxel-based chemotherapy, and 4.2 months for chemotherapy alone. Despite a hazard ratio of 0.78, the difference was not statistically significant (P = .14), Dr. Steven O'Day reported at a joint congress of the European Cancer Organization and the European Society for Medical Oncology.

Overall survival was widely reported before the congress as having been significantly increased by 4 months with bevacizumab, but an unplanned post hoc analysis performed just before the formal data presentation showed that the survival benefit had narrowed and had taken the statistical advantage with it.

Median overall survival went from 12.3 months in the bevacizumab arm and 8.6 months in the chemotherapy arm at a median follow-up of 13 months in the initial analysis (HR, 0.67; P = .04) to 12.3 months and 9.2 months, respectively, at a median follow-up of 18 months in the post hoc analysis (HR, 0.79; P = .19).

Response rates also favored bevacizumab over chemotherapy (25.5% vs. 16.4%), but were not significantly different (P =.16) in the Roche Pharmaceuticals–sponsored study.

Although the revised data sent stock analysts and journalists scrambling, the findings are still cause for optimism in a disease with few treatment options and a 5-year survival of less than 5%, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

“I am optimistic because strong trends of improvement were seen across all efficacy parameters” (progression-free survival, overall survival, and response), he said in an interview. “This was a randomized, phase II with 2:1 randomization, so it wasn't powered for overall survival to be significantly different. I'm also optimistic because even the worse prognosis patients with M1c disease and elevated [lactate dehydrogenase] seemed to benefit from this treatment.”

Based on the current data, Roche plans to go forward with a larger, randomized phase III trial that is adequately powered to detect a significant survival benefit, he said.

BEAM (A Study of Bevacizumab With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma) included 214 patients (mean age, 60 years) with stage IV M1a/b, M1c disease, of which 73% was M1c disease and 54% of M1c patients had abnormal lactate dehydrogenase levels. Patients received chemotherapy with or without bevacizumab 15 mg/kg administered intravenously on day 1 every 3 weeks.

Bevacizumab, an anti–vascular endothelial growth factor (VEGF)–specific inhibitor, was evaluated because melanoma is a very vascular tumor, and elevated VEGF levels correlate with tumor progression and worse prognosis. The addition of bevacizumab to chemotherapy has improved outcomes in other cancers, including metastatic colorectal cancer and non–small cell lung cancer.

No new safety events were observed in the trial. Grade 3/4 treatment-related adverse events that occurred with 2% or more increased incidence in the bevacizumab arm included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia, and musculoskeletal pain. There were two deaths in the bevacizumab arm and none in the chemotherapy arm, Dr. O'Day said.

He has served an advisory/consultant role and received research funds from Genentech Inc. and Roche for clinical trials.

BERLIN — The addition of bevacizumab to chemotherapy failed to significantly improve progression-free or overall survival in previously untreated advanced melanoma in the phase II BEAM trial.

Median progression-free survival was 5.6 months for bevacizumab (Avastin) plus carboplatin and paclitaxel-based chemotherapy, and 4.2 months for chemotherapy alone. Despite a hazard ratio of 0.78, the difference was not statistically significant (P = .14), Dr. Steven O'Day reported at a joint congress of the European Cancer Organization and the European Society for Medical Oncology.

Overall survival was widely reported before the congress as having been significantly increased by 4 months with bevacizumab, but an unplanned post hoc analysis performed just before the formal data presentation showed that the survival benefit had narrowed and had taken the statistical advantage with it.

Median overall survival went from 12.3 months in the bevacizumab arm and 8.6 months in the chemotherapy arm at a median follow-up of 13 months in the initial analysis (HR, 0.67; P = .04) to 12.3 months and 9.2 months, respectively, at a median follow-up of 18 months in the post hoc analysis (HR, 0.79; P = .19).

Response rates also favored bevacizumab over chemotherapy (25.5% vs. 16.4%), but were not significantly different (P =.16) in the Roche Pharmaceuticals–sponsored study.

Although the revised data sent stock analysts and journalists scrambling, the findings are still cause for optimism in a disease with few treatment options and a 5-year survival of less than 5%, according to Dr. O'Day, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

“I am optimistic because strong trends of improvement were seen across all efficacy parameters” (progression-free survival, overall survival, and response), he said in an interview. “This was a randomized, phase II with 2:1 randomization, so it wasn't powered for overall survival to be significantly different. I'm also optimistic because even the worse prognosis patients with M1c disease and elevated [lactate dehydrogenase] seemed to benefit from this treatment.”

Based on the current data, Roche plans to go forward with a larger, randomized phase III trial that is adequately powered to detect a significant survival benefit, he said.

BEAM (A Study of Bevacizumab With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma) included 214 patients (mean age, 60 years) with stage IV M1a/b, M1c disease, of which 73% was M1c disease and 54% of M1c patients had abnormal lactate dehydrogenase levels. Patients received chemotherapy with or without bevacizumab 15 mg/kg administered intravenously on day 1 every 3 weeks.

Bevacizumab, an anti–vascular endothelial growth factor (VEGF)–specific inhibitor, was evaluated because melanoma is a very vascular tumor, and elevated VEGF levels correlate with tumor progression and worse prognosis. The addition of bevacizumab to chemotherapy has improved outcomes in other cancers, including metastatic colorectal cancer and non–small cell lung cancer.

No new safety events were observed in the trial. Grade 3/4 treatment-related adverse events that occurred with 2% or more increased incidence in the bevacizumab arm included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia, and musculoskeletal pain. There were two deaths in the bevacizumab arm and none in the chemotherapy arm, Dr. O'Day said.

He has served an advisory/consultant role and received research funds from Genentech Inc. and Roche for clinical trials.

SEATTLE — Evidence from recent and ongoing trials is helping to clarify the best strategies for managing cutaneous melanoma.

A hurdle to better melanoma management has been the high variability of the disease, exemplified in part by its wide-ranging presentations, said Dr. William Dzwierzynski, professor of plastic and reconstructive surgery at the Medical College of Wisconsin in Milwaukee. In fact, accumulating evidence suggests that melanoma may encompass several different diseases with differing biology.

When initially evaluating a suspicious skin lesion, the type of biopsy is critical. "Excisional biopsy is probably the most key thing. You really try not to do an incisional or a shave biopsy," he said, unless the latter is deep and removes the whole lesion. Reassuringly, though, the type of biopsy does not affect survival (Am. J. Surg. 2005;190:913–7)."But we'll never know the depth of the lesion" with an incisional or shave biopsy, he pointed out, "so we'll never have the right prognosis."

Accurate diagnosis of melanoma requires permanent sections. "Melanoma is not accurately diagnosed on frozen sections. Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives," Dr. Dzwierzynski said at the annual meeting of the American Society of Plastic Surgeons.

Positron emission tomography (PET) imaging is unreliable for staging in patients with melanoma, yielding a false-negative rate of 79% when used preoperatively to identify occult nodal metastases (Cancer 2005;104:570–9). "There is not any conclusive data that PET scan is any more accurate than a chest x-ray or lab tests," he added. On the flip side, patients should not be assumed to have metastases solely based on a positive PET scan.

"I send everybody who has a melanoma that is 1 mm or greater to an oncologist," he added. "I tell them that the oncologist probably won't have anything to offer you, and that's a good thing. But they are the ones who are going to know if there are any investigational studies or treatment trials."

Whenever possible, patients with advanced disease should be referred for clinical trials. "Investigational therapies—I think this is where the promise is," Dr. Dzwierzynski commented.

When it comes to resecting the tumor, contemporary margins are 1–3 cm for most invasive melanomas. Prospective studies have found no difference in survival between margins of 1–2 cm and larger margins of 3–5 cm, but methodologic limitations leave the issue unresolved, he said.

Mohs surgery for invasive melanoma remains controversial. "There is a lot of distortion when you do Mohs," he noted. "It's really easy to get false-negatives and false-positives." To date, controlled survival data and randomized trials are lacking.

Sentinel node biopsy (SNB) is recommended for patients whose tumors have a Breslow thickness of greater than 1 mm and for those whose tumors are thinner but have adverse features, such as ulceration or a Clark level of IV or V. Currently, it is done to obtain prognostic information and identify the roughly 20% of patients who may benefit from a complete lymph node dissection, Dr. Dzwierzynski noted.

The results of the first Multicenter Selective Lymphadenectomy Trial (MSLT-1) raised the possibility that SNB also may be curing disease in some patients and improving survival (N. Engl. J. Med. 2006;355;1307–17). An ongoing follow-up trial, MSLT-2, is looking more closely at the issue and the possibility that patients with only microscopic disease in the sentinel node may be spared further surgery.

Importantly, there is a learning curve to the SNB procedure. In MSLT-1, the false-negative rate was 10% in a physician's first 25 cases, but fell to 5% thereafter (Ann. Surg. 2005;242:302–13). "So right now, the recommendation is that it does take probably 30 cases for that learning curve," he said.

For pathologic evaluation of sentinel nodes, the combination of step sectioning (at less than 1-mm intervals) and hematoxylin and eosin staining with HMB-45 and S-100 immunohistochemistry has sensitivity approaching 98%, according to Dr. Dzwierzynski. A triple stain used at his institution—the MCW melanoma cocktail (Melan-A, MART-1, and tyrosinase)—has high accuracy (BMC Cancer 2003;3:15), albeit at a fairly high cost. In contrast, polymerase chain reaction has proven to be of limited use because it can be falsely positive in patients with subcapsular nevi.

The National Comprehensive Cancer Network recommends complete lymph node dissection for patients with a positive SNB, but a recent analysis of national data found that only half of such patients underwent the procedure (Ann. Surg. Oncol. 2008;15:1566–76).

"Complete lymph node dissection is a curative procedure," he commented. As such, it is extensive, more so than the lymph node sampling done for, say, breast cancer. "In most of my axillary dissections, I will remove 35–40 lymph nodes," Dr. Dzwierzynski said. "For a superficial inguinal dissection, you should have at least 10 nodes, and for a deep dissection, you have at least 5 nodes."

Complication rates of complete lymph node dissection are generally high, and they tend to be higher after inguinal procedures (48%–84%) than after axillary ones (47%–53%), he noted.

Several trials have shown that adjuvant high-dose interferon therapy modestly improves outcomes among patients with melanoma at high risk for recurrence, but with the tradeoff of substantial toxicity. The benefits are lost when the dose is reduced and therapy is shortened. "But there may be a subgroup in which interferon is useful," he added, so an individualized approach, with discussion of risks and benefits, is needed. It should not be given automatically "because it's the only thing that's available," he said.

The optimal approach to follow-up of patients with treated melanoma has not been established, but follow-up is typically lifelong and multidisciplinary, according to Dr. Dzwierzynski. Importantly, all patients must have lymph node palpation for detection of recurrences, and full-body skin checks for detection of second primaries.

Dr. Dzwierzynski reported that he had no conflicts of interest in association with his presentation.

'Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives.'

Source Dr. Dzwierzynski

SEATTLE — Evidence from recent and ongoing trials is helping to clarify the best strategies for managing cutaneous melanoma.

A hurdle to better melanoma management has been the high variability of the disease, exemplified in part by its wide-ranging presentations, said Dr. William Dzwierzynski, professor of plastic and reconstructive surgery at the Medical College of Wisconsin in Milwaukee. In fact, accumulating evidence suggests that melanoma may encompass several different diseases with differing biology.

When initially evaluating a suspicious skin lesion, the type of biopsy is critical. "Excisional biopsy is probably the most key thing. You really try not to do an incisional or a shave biopsy," he said, unless the latter is deep and removes the whole lesion. Reassuringly, though, the type of biopsy does not affect survival (Am. J. Surg. 2005;190:913–7)."But we'll never know the depth of the lesion" with an incisional or shave biopsy, he pointed out, "so we'll never have the right prognosis."

Accurate diagnosis of melanoma requires permanent sections. "Melanoma is not accurately diagnosed on frozen sections. Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives," Dr. Dzwierzynski said at the annual meeting of the American Society of Plastic Surgeons.

Positron emission tomography (PET) imaging is unreliable for staging in patients with melanoma, yielding a false-negative rate of 79% when used preoperatively to identify occult nodal metastases (Cancer 2005;104:570–9). "There is not any conclusive data that PET scan is any more accurate than a chest x-ray or lab tests," he added. On the flip side, patients should not be assumed to have metastases solely based on a positive PET scan.

"I send everybody who has a melanoma that is 1 mm or greater to an oncologist," he added. "I tell them that the oncologist probably won't have anything to offer you, and that's a good thing. But they are the ones who are going to know if there are any investigational studies or treatment trials."

Whenever possible, patients with advanced disease should be referred for clinical trials. "Investigational therapies—I think this is where the promise is," Dr. Dzwierzynski commented.

When it comes to resecting the tumor, contemporary margins are 1–3 cm for most invasive melanomas. Prospective studies have found no difference in survival between margins of 1–2 cm and larger margins of 3–5 cm, but methodologic limitations leave the issue unresolved, he said.

Mohs surgery for invasive melanoma remains controversial. "There is a lot of distortion when you do Mohs," he noted. "It's really easy to get false-negatives and false-positives." To date, controlled survival data and randomized trials are lacking.

Sentinel node biopsy (SNB) is recommended for patients whose tumors have a Breslow thickness of greater than 1 mm and for those whose tumors are thinner but have adverse features, such as ulceration or a Clark level of IV or V. Currently, it is done to obtain prognostic information and identify the roughly 20% of patients who may benefit from a complete lymph node dissection, Dr. Dzwierzynski noted.

The results of the first Multicenter Selective Lymphadenectomy Trial (MSLT-1) raised the possibility that SNB also may be curing disease in some patients and improving survival (N. Engl. J. Med. 2006;355;1307–17). An ongoing follow-up trial, MSLT-2, is looking more closely at the issue and the possibility that patients with only microscopic disease in the sentinel node may be spared further surgery.

Importantly, there is a learning curve to the SNB procedure. In MSLT-1, the false-negative rate was 10% in a physician's first 25 cases, but fell to 5% thereafter (Ann. Surg. 2005;242:302–13). "So right now, the recommendation is that it does take probably 30 cases for that learning curve," he said.

For pathologic evaluation of sentinel nodes, the combination of step sectioning (at less than 1-mm intervals) and hematoxylin and eosin staining with HMB-45 and S-100 immunohistochemistry has sensitivity approaching 98%, according to Dr. Dzwierzynski. A triple stain used at his institution—the MCW melanoma cocktail (Melan-A, MART-1, and tyrosinase)—has high accuracy (BMC Cancer 2003;3:15), albeit at a fairly high cost. In contrast, polymerase chain reaction has proven to be of limited use because it can be falsely positive in patients with subcapsular nevi.

The National Comprehensive Cancer Network recommends complete lymph node dissection for patients with a positive SNB, but a recent analysis of national data found that only half of such patients underwent the procedure (Ann. Surg. Oncol. 2008;15:1566–76).

"Complete lymph node dissection is a curative procedure," he commented. As such, it is extensive, more so than the lymph node sampling done for, say, breast cancer. "In most of my axillary dissections, I will remove 35–40 lymph nodes," Dr. Dzwierzynski said. "For a superficial inguinal dissection, you should have at least 10 nodes, and for a deep dissection, you have at least 5 nodes."

Complication rates of complete lymph node dissection are generally high, and they tend to be higher after inguinal procedures (48%–84%) than after axillary ones (47%–53%), he noted.

Several trials have shown that adjuvant high-dose interferon therapy modestly improves outcomes among patients with melanoma at high risk for recurrence, but with the tradeoff of substantial toxicity. The benefits are lost when the dose is reduced and therapy is shortened. "But there may be a subgroup in which interferon is useful," he added, so an individualized approach, with discussion of risks and benefits, is needed. It should not be given automatically "because it's the only thing that's available," he said.

The optimal approach to follow-up of patients with treated melanoma has not been established, but follow-up is typically lifelong and multidisciplinary, according to Dr. Dzwierzynski. Importantly, all patients must have lymph node palpation for detection of recurrences, and full-body skin checks for detection of second primaries.

Dr. Dzwierzynski reported that he had no conflicts of interest in association with his presentation.

'Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives.'

Source Dr. Dzwierzynski

SEATTLE — Evidence from recent and ongoing trials is helping to clarify the best strategies for managing cutaneous melanoma.

A hurdle to better melanoma management has been the high variability of the disease, exemplified in part by its wide-ranging presentations, said Dr. William Dzwierzynski, professor of plastic and reconstructive surgery at the Medical College of Wisconsin in Milwaukee. In fact, accumulating evidence suggests that melanoma may encompass several different diseases with differing biology.

When initially evaluating a suspicious skin lesion, the type of biopsy is critical. "Excisional biopsy is probably the most key thing. You really try not to do an incisional or a shave biopsy," he said, unless the latter is deep and removes the whole lesion. Reassuringly, though, the type of biopsy does not affect survival (Am. J. Surg. 2005;190:913–7)."But we'll never know the depth of the lesion" with an incisional or shave biopsy, he pointed out, "so we'll never have the right prognosis."

Accurate diagnosis of melanoma requires permanent sections. "Melanoma is not accurately diagnosed on frozen sections. Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives," Dr. Dzwierzynski said at the annual meeting of the American Society of Plastic Surgeons.

Positron emission tomography (PET) imaging is unreliable for staging in patients with melanoma, yielding a false-negative rate of 79% when used preoperatively to identify occult nodal metastases (Cancer 2005;104:570–9). "There is not any conclusive data that PET scan is any more accurate than a chest x-ray or lab tests," he added. On the flip side, patients should not be assumed to have metastases solely based on a positive PET scan.

"I send everybody who has a melanoma that is 1 mm or greater to an oncologist," he added. "I tell them that the oncologist probably won't have anything to offer you, and that's a good thing. But they are the ones who are going to know if there are any investigational studies or treatment trials."

Whenever possible, patients with advanced disease should be referred for clinical trials. "Investigational therapies—I think this is where the promise is," Dr. Dzwierzynski commented.

When it comes to resecting the tumor, contemporary margins are 1–3 cm for most invasive melanomas. Prospective studies have found no difference in survival between margins of 1–2 cm and larger margins of 3–5 cm, but methodologic limitations leave the issue unresolved, he said.

Mohs surgery for invasive melanoma remains controversial. "There is a lot of distortion when you do Mohs," he noted. "It's really easy to get false-negatives and false-positives." To date, controlled survival data and randomized trials are lacking.

Sentinel node biopsy (SNB) is recommended for patients whose tumors have a Breslow thickness of greater than 1 mm and for those whose tumors are thinner but have adverse features, such as ulceration or a Clark level of IV or V. Currently, it is done to obtain prognostic information and identify the roughly 20% of patients who may benefit from a complete lymph node dissection, Dr. Dzwierzynski noted.

The results of the first Multicenter Selective Lymphadenectomy Trial (MSLT-1) raised the possibility that SNB also may be curing disease in some patients and improving survival (N. Engl. J. Med. 2006;355;1307–17). An ongoing follow-up trial, MSLT-2, is looking more closely at the issue and the possibility that patients with only microscopic disease in the sentinel node may be spared further surgery.

Importantly, there is a learning curve to the SNB procedure. In MSLT-1, the false-negative rate was 10% in a physician's first 25 cases, but fell to 5% thereafter (Ann. Surg. 2005;242:302–13). "So right now, the recommendation is that it does take probably 30 cases for that learning curve," he said.

For pathologic evaluation of sentinel nodes, the combination of step sectioning (at less than 1-mm intervals) and hematoxylin and eosin staining with HMB-45 and S-100 immunohistochemistry has sensitivity approaching 98%, according to Dr. Dzwierzynski. A triple stain used at his institution—the MCW melanoma cocktail (Melan-A, MART-1, and tyrosinase)—has high accuracy (BMC Cancer 2003;3:15), albeit at a fairly high cost. In contrast, polymerase chain reaction has proven to be of limited use because it can be falsely positive in patients with subcapsular nevi.

The National Comprehensive Cancer Network recommends complete lymph node dissection for patients with a positive SNB, but a recent analysis of national data found that only half of such patients underwent the procedure (Ann. Surg. Oncol. 2008;15:1566–76).

"Complete lymph node dissection is a curative procedure," he commented. As such, it is extensive, more so than the lymph node sampling done for, say, breast cancer. "In most of my axillary dissections, I will remove 35–40 lymph nodes," Dr. Dzwierzynski said. "For a superficial inguinal dissection, you should have at least 10 nodes, and for a deep dissection, you have at least 5 nodes."

Complication rates of complete lymph node dissection are generally high, and they tend to be higher after inguinal procedures (48%–84%) than after axillary ones (47%–53%), he noted.

Several trials have shown that adjuvant high-dose interferon therapy modestly improves outcomes among patients with melanoma at high risk for recurrence, but with the tradeoff of substantial toxicity. The benefits are lost when the dose is reduced and therapy is shortened. "But there may be a subgroup in which interferon is useful," he added, so an individualized approach, with discussion of risks and benefits, is needed. It should not be given automatically "because it's the only thing that's available," he said.

The optimal approach to follow-up of patients with treated melanoma has not been established, but follow-up is typically lifelong and multidisciplinary, according to Dr. Dzwierzynski. Importantly, all patients must have lymph node palpation for detection of recurrences, and full-body skin checks for detection of second primaries.

Dr. Dzwierzynski reported that he had no conflicts of interest in association with his presentation.

'Don't do frozen sections on melanoma—you get a lot of false-negatives and a lot of false-positives.'

Source Dr. Dzwierzynski

GAITHERSBURG, MD. — Peginterferon alfa-2b has a favorable risk-benefit ratio as an adjuvant treatment for stage III melanoma, a Food and Drug Administration advisory panel said

The FDA's Oncologic Drugs Advisory Committee voted 6-4 after reviewing the data on the adjuvant use of peginterferon alfa-2b after complete lymphadenectomy, the indication up for approval. The panel did not vote specifically on whether to recommend approval of peginterferon for the indication.

Peginterferon alfa-2b (Peg-IFN), a long-acting formulation of interferon alfa-2b, is marketed by Schering-Plough Corp. as Pegintron and was approved as a treatment for chronic hepatitis C in 2001. Interferon alfa-2b (Intron A), also manufactured by Schering-Plough, was approved as an adjuvant treatment for melanoma in 1995, on the basis of a study that found it had a significant impact on overall survival, the primary end point.

Those voting positively generally agreed that although the substantial toxicity and the modest effect on relapse-free survival were concerns, the toxicity did not appear to be worse than that associated with high-dose interferon, and that it would be a reasonable alternative treatment option. Several said that the pegylated formulation would be more convenient, since it is administered subcutaneously once a week.

Peg IFN is administered subcutaneously once a week, with a higher dose during the 8-week induction period, and is recommended for 5 years.

The results of a multicenter, phase III study, of 1,256 patients (median age 50 years) with stage III melanoma were submitted for approval.

Subjects had either microscopic or palpable nodal involvement, and were randomized to either treatment with Peg-IFN or observation after undergoing regional lymph node dissection. Most of the patients were in Europe, but none was in the United States.

The primary endpoint was relapse-free survival (defined as the earliest detection of locoregional relapse, distant metastasis, or death). The rate of these events was 52.3% among those on Peg-IFN, compared with 58.5% in the observation group. The median relapse-free survival was 34.8 months, compared with 25.5 months among those in the observation arm, an 18% reduction in the risk of relapse or death associated with treatment, which was statistically significant. However, there were no significant differences in overall survival or distant metastasis-free survival between the two arms.

Fatigue was the most common serious adverse event associated with treatment. Depression was more than twice as high among patients on Peg-IFN, and severe depression was also higher among treated patients (7% vs. 0.5%). Of those on Peg-IFN, 44% stopped treatment because of adverse events. Only 13% of patients completed 5 years of treatment.

There were three deaths considered possibly related to peginterferon, which were cardiovascular related.

The FDA usually follows the recommendations of its advisory panels.

GAITHERSBURG, MD. — Peginterferon alfa-2b has a favorable risk-benefit ratio as an adjuvant treatment for stage III melanoma, a Food and Drug Administration advisory panel said

The FDA's Oncologic Drugs Advisory Committee voted 6-4 after reviewing the data on the adjuvant use of peginterferon alfa-2b after complete lymphadenectomy, the indication up for approval. The panel did not vote specifically on whether to recommend approval of peginterferon for the indication.

Peginterferon alfa-2b (Peg-IFN), a long-acting formulation of interferon alfa-2b, is marketed by Schering-Plough Corp. as Pegintron and was approved as a treatment for chronic hepatitis C in 2001. Interferon alfa-2b (Intron A), also manufactured by Schering-Plough, was approved as an adjuvant treatment for melanoma in 1995, on the basis of a study that found it had a significant impact on overall survival, the primary end point.

Those voting positively generally agreed that although the substantial toxicity and the modest effect on relapse-free survival were concerns, the toxicity did not appear to be worse than that associated with high-dose interferon, and that it would be a reasonable alternative treatment option. Several said that the pegylated formulation would be more convenient, since it is administered subcutaneously once a week.

Peg IFN is administered subcutaneously once a week, with a higher dose during the 8-week induction period, and is recommended for 5 years.

The results of a multicenter, phase III study, of 1,256 patients (median age 50 years) with stage III melanoma were submitted for approval.

Subjects had either microscopic or palpable nodal involvement, and were randomized to either treatment with Peg-IFN or observation after undergoing regional lymph node dissection. Most of the patients were in Europe, but none was in the United States.

The primary endpoint was relapse-free survival (defined as the earliest detection of locoregional relapse, distant metastasis, or death). The rate of these events was 52.3% among those on Peg-IFN, compared with 58.5% in the observation group. The median relapse-free survival was 34.8 months, compared with 25.5 months among those in the observation arm, an 18% reduction in the risk of relapse or death associated with treatment, which was statistically significant. However, there were no significant differences in overall survival or distant metastasis-free survival between the two arms.

Fatigue was the most common serious adverse event associated with treatment. Depression was more than twice as high among patients on Peg-IFN, and severe depression was also higher among treated patients (7% vs. 0.5%). Of those on Peg-IFN, 44% stopped treatment because of adverse events. Only 13% of patients completed 5 years of treatment.

There were three deaths considered possibly related to peginterferon, which were cardiovascular related.

The FDA usually follows the recommendations of its advisory panels.

GAITHERSBURG, MD. — Peginterferon alfa-2b has a favorable risk-benefit ratio as an adjuvant treatment for stage III melanoma, a Food and Drug Administration advisory panel said

The FDA's Oncologic Drugs Advisory Committee voted 6-4 after reviewing the data on the adjuvant use of peginterferon alfa-2b after complete lymphadenectomy, the indication up for approval. The panel did not vote specifically on whether to recommend approval of peginterferon for the indication.

Peginterferon alfa-2b (Peg-IFN), a long-acting formulation of interferon alfa-2b, is marketed by Schering-Plough Corp. as Pegintron and was approved as a treatment for chronic hepatitis C in 2001. Interferon alfa-2b (Intron A), also manufactured by Schering-Plough, was approved as an adjuvant treatment for melanoma in 1995, on the basis of a study that found it had a significant impact on overall survival, the primary end point.

Those voting positively generally agreed that although the substantial toxicity and the modest effect on relapse-free survival were concerns, the toxicity did not appear to be worse than that associated with high-dose interferon, and that it would be a reasonable alternative treatment option. Several said that the pegylated formulation would be more convenient, since it is administered subcutaneously once a week.

Peg IFN is administered subcutaneously once a week, with a higher dose during the 8-week induction period, and is recommended for 5 years.

The results of a multicenter, phase III study, of 1,256 patients (median age 50 years) with stage III melanoma were submitted for approval.

Subjects had either microscopic or palpable nodal involvement, and were randomized to either treatment with Peg-IFN or observation after undergoing regional lymph node dissection. Most of the patients were in Europe, but none was in the United States.

The primary endpoint was relapse-free survival (defined as the earliest detection of locoregional relapse, distant metastasis, or death). The rate of these events was 52.3% among those on Peg-IFN, compared with 58.5% in the observation group. The median relapse-free survival was 34.8 months, compared with 25.5 months among those in the observation arm, an 18% reduction in the risk of relapse or death associated with treatment, which was statistically significant. However, there were no significant differences in overall survival or distant metastasis-free survival between the two arms.

Fatigue was the most common serious adverse event associated with treatment. Depression was more than twice as high among patients on Peg-IFN, and severe depression was also higher among treated patients (7% vs. 0.5%). Of those on Peg-IFN, 44% stopped treatment because of adverse events. Only 13% of patients completed 5 years of treatment.

There were three deaths considered possibly related to peginterferon, which were cardiovascular related.

The FDA usually follows the recommendations of its advisory panels.

Berlin — An investigational agent that targets the BRAF mutation and is present in at least half of melanoma patients has shown impressive results in a second phase I trial.

Response rates with the oral agent PLX4032 reached an unprecedented 70% in metastatic melanoma, signaling a fundamental shift in the way this deadly disease will be treated.

“What's very encouraging is actually that the response rate in nonmutated melanoma is 0%; so we know exactly what we're doing,” European Cancer Organization (ECCO) president Dr. Alexander Eggermont told reporters at the joint congress of ECCO and the European Society for Medical Oncology, where the latest data were presented.

The ability to target therapy based on genetic mutation status is expected to transform the once-bleak field of melanoma, which has seen no improvement in overall survival in the last 30 randomized trials using various chemotherapeutic agents and vaccines. The 5-year survival rate for stage IV melanoma remains at just 18%.

“If I have a young, talented medical oncologist at a cancer center, now I would have no reservations to recommend him to become a melanoma specialist because it's going to become a very exciting field instead of a graveyard,” Dr. Eggermont of Erasmus University in Rotterdam, the Netherlands, said at a press briefing. “One of the fellows here said, 'Wow, this is fantastic; now I will get time to get to know my metastatic melanoma patients.' That's how bad the field was. So this is simply fantastic.”

The phase I extension trial included 31 metastatic melanoma patients who had a BRAF mutation known as V600E and who were treated twice daily with 960 mg of PLX4032. Among 27 evaluable patients, the response rate was 70% by RECIST, including 18 partial responses and 1 complete response. One partial responder subsequently became a complete responder after the data analysis cutoff date.

Progression-free survival is about 8.5 months, although the median has not yet been reached, lead author Dr. Paul Chapman said. Overall survival was not measured. Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG (

Enthusiasm for the study, which was supported by Plexxicon Inc., was not diminished by the preliminary nature of the data or a string of disappointing late-phase results from other promising melanoma agents.

“My take—and I think it's pretty representative of many in the melanoma academic world—is that this is cataclysmic; this is hugely important,” Dr. David E. Fisher, chief of the dermatology service and director of the cutaneous biology research center at Massachusetts General Hospital, Boston, said in an interview.

Clinicians can predict which patients will respond and which won't, based on the presence of the BRAF

In a previous phase I dose-escalation trial in 55 patients with a variety of cancers, partial responses were reported in 9 of 16 metastatic melanoma patients with the BRAF

Because of the selectivity of the molecule, adverse events have tended to be mild, said Dr. Chapman, an attending physician on the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center in New York. Common grade 3 events in the current trial were arthralgia (3%), rash (3%), photosensitivity (3%), and fatigue (7%).

A Disease of Subtypes

Dr. Chapman told reporters that genetic screening will have to become universal in melanoma, just as KRAS testing is essential in treating colorectal cancer. Screening can be completed in 1–2 weeks at active, participating centers.

The BRAF mutation is not the first example of a genetic subtype targeted in metastatic melanoma; Dr. Fisher and his colleagues reported dramatic results last year after targeting the c-KIT mutation with imatinib (Gleevec). Although the armamentarium is not deep for drugs that block BRAF, there are several available agents that target c-KIT, including nilotinib (Tasigna) and sunitinib (Sutent).

Although the signal from the PLX4032 trials is strong, the early data suggest that the single agent is not going to be enough, Dr. Fisher said. Future strategies will likely include combination therapy and the use of agents prior to the development of metastatic disease.

“We need complete remission. We need these tumors to melt away,” he said.

Reporters questioned whether PLX4032 could be used with the monoclonal antibody bevacizumab (Avastin), which increased overall survival by more than 40% when combined with the chemotherapeutic agents carboplatin and paclitaxel in a phase II metastatic melanoma trial that was also presented at the congress.

Dr. Chapman responded, “If you shrink the tumor too much with PLX4032, it may not be as sensitive to VEGF [vascular endothelial growth factor] inhibition, but from a toxicity point of view, I don't think there's any reason why we couldn't combine them.”

Further Trials

A phase II single arm trial (BRIM2) is evaluating 960 mg twice daily of PLX4032 in about 100 BRAF

The randomized, phase III BRIM3 trial is expected to start by the end of 2009 in first-line patients. Plexxicon is codeveloping PLX4032 with Roche.

Dr. Chapman said he had no conflicts of interest.

Melanoma is 'going to become a very exciting field instead of a graveyard.'

Source DR. EGGERMONT

Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG uptake was essentially shut down.

Source DR. CHAPMAN

Berlin — An investigational agent that targets the BRAF mutation and is present in at least half of melanoma patients has shown impressive results in a second phase I trial.

Response rates with the oral agent PLX4032 reached an unprecedented 70% in metastatic melanoma, signaling a fundamental shift in the way this deadly disease will be treated.

“What's very encouraging is actually that the response rate in nonmutated melanoma is 0%; so we know exactly what we're doing,” European Cancer Organization (ECCO) president Dr. Alexander Eggermont told reporters at the joint congress of ECCO and the European Society for Medical Oncology, where the latest data were presented.

The ability to target therapy based on genetic mutation status is expected to transform the once-bleak field of melanoma, which has seen no improvement in overall survival in the last 30 randomized trials using various chemotherapeutic agents and vaccines. The 5-year survival rate for stage IV melanoma remains at just 18%.

“If I have a young, talented medical oncologist at a cancer center, now I would have no reservations to recommend him to become a melanoma specialist because it's going to become a very exciting field instead of a graveyard,” Dr. Eggermont of Erasmus University in Rotterdam, the Netherlands, said at a press briefing. “One of the fellows here said, 'Wow, this is fantastic; now I will get time to get to know my metastatic melanoma patients.' That's how bad the field was. So this is simply fantastic.”

The phase I extension trial included 31 metastatic melanoma patients who had a BRAF mutation known as V600E and who were treated twice daily with 960 mg of PLX4032. Among 27 evaluable patients, the response rate was 70% by RECIST, including 18 partial responses and 1 complete response. One partial responder subsequently became a complete responder after the data analysis cutoff date.

Progression-free survival is about 8.5 months, although the median has not yet been reached, lead author Dr. Paul Chapman said. Overall survival was not measured. Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG (

Enthusiasm for the study, which was supported by Plexxicon Inc., was not diminished by the preliminary nature of the data or a string of disappointing late-phase results from other promising melanoma agents.

“My take—and I think it's pretty representative of many in the melanoma academic world—is that this is cataclysmic; this is hugely important,” Dr. David E. Fisher, chief of the dermatology service and director of the cutaneous biology research center at Massachusetts General Hospital, Boston, said in an interview.

Clinicians can predict which patients will respond and which won't, based on the presence of the BRAF

In a previous phase I dose-escalation trial in 55 patients with a variety of cancers, partial responses were reported in 9 of 16 metastatic melanoma patients with the BRAF

Because of the selectivity of the molecule, adverse events have tended to be mild, said Dr. Chapman, an attending physician on the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center in New York. Common grade 3 events in the current trial were arthralgia (3%), rash (3%), photosensitivity (3%), and fatigue (7%).

A Disease of Subtypes

Dr. Chapman told reporters that genetic screening will have to become universal in melanoma, just as KRAS testing is essential in treating colorectal cancer. Screening can be completed in 1–2 weeks at active, participating centers.

The BRAF mutation is not the first example of a genetic subtype targeted in metastatic melanoma; Dr. Fisher and his colleagues reported dramatic results last year after targeting the c-KIT mutation with imatinib (Gleevec). Although the armamentarium is not deep for drugs that block BRAF, there are several available agents that target c-KIT, including nilotinib (Tasigna) and sunitinib (Sutent).

Although the signal from the PLX4032 trials is strong, the early data suggest that the single agent is not going to be enough, Dr. Fisher said. Future strategies will likely include combination therapy and the use of agents prior to the development of metastatic disease.

“We need complete remission. We need these tumors to melt away,” he said.

Reporters questioned whether PLX4032 could be used with the monoclonal antibody bevacizumab (Avastin), which increased overall survival by more than 40% when combined with the chemotherapeutic agents carboplatin and paclitaxel in a phase II metastatic melanoma trial that was also presented at the congress.

Dr. Chapman responded, “If you shrink the tumor too much with PLX4032, it may not be as sensitive to VEGF [vascular endothelial growth factor] inhibition, but from a toxicity point of view, I don't think there's any reason why we couldn't combine them.”

Further Trials

A phase II single arm trial (BRIM2) is evaluating 960 mg twice daily of PLX4032 in about 100 BRAF

The randomized, phase III BRIM3 trial is expected to start by the end of 2009 in first-line patients. Plexxicon is codeveloping PLX4032 with Roche.

Dr. Chapman said he had no conflicts of interest.

Melanoma is 'going to become a very exciting field instead of a graveyard.'

Source DR. EGGERMONT

Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG uptake was essentially shut down.

Source DR. CHAPMAN

Berlin — An investigational agent that targets the BRAF mutation and is present in at least half of melanoma patients has shown impressive results in a second phase I trial.

Response rates with the oral agent PLX4032 reached an unprecedented 70% in metastatic melanoma, signaling a fundamental shift in the way this deadly disease will be treated.

“What's very encouraging is actually that the response rate in nonmutated melanoma is 0%; so we know exactly what we're doing,” European Cancer Organization (ECCO) president Dr. Alexander Eggermont told reporters at the joint congress of ECCO and the European Society for Medical Oncology, where the latest data were presented.

The ability to target therapy based on genetic mutation status is expected to transform the once-bleak field of melanoma, which has seen no improvement in overall survival in the last 30 randomized trials using various chemotherapeutic agents and vaccines. The 5-year survival rate for stage IV melanoma remains at just 18%.

“If I have a young, talented medical oncologist at a cancer center, now I would have no reservations to recommend him to become a melanoma specialist because it's going to become a very exciting field instead of a graveyard,” Dr. Eggermont of Erasmus University in Rotterdam, the Netherlands, said at a press briefing. “One of the fellows here said, 'Wow, this is fantastic; now I will get time to get to know my metastatic melanoma patients.' That's how bad the field was. So this is simply fantastic.”

The phase I extension trial included 31 metastatic melanoma patients who had a BRAF mutation known as V600E and who were treated twice daily with 960 mg of PLX4032. Among 27 evaluable patients, the response rate was 70% by RECIST, including 18 partial responses and 1 complete response. One partial responder subsequently became a complete responder after the data analysis cutoff date.

Progression-free survival is about 8.5 months, although the median has not yet been reached, lead author Dr. Paul Chapman said. Overall survival was not measured. Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG (

Enthusiasm for the study, which was supported by Plexxicon Inc., was not diminished by the preliminary nature of the data or a string of disappointing late-phase results from other promising melanoma agents.

“My take—and I think it's pretty representative of many in the melanoma academic world—is that this is cataclysmic; this is hugely important,” Dr. David E. Fisher, chief of the dermatology service and director of the cutaneous biology research center at Massachusetts General Hospital, Boston, said in an interview.

Clinicians can predict which patients will respond and which won't, based on the presence of the BRAF

In a previous phase I dose-escalation trial in 55 patients with a variety of cancers, partial responses were reported in 9 of 16 metastatic melanoma patients with the BRAF

Because of the selectivity of the molecule, adverse events have tended to be mild, said Dr. Chapman, an attending physician on the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center in New York. Common grade 3 events in the current trial were arthralgia (3%), rash (3%), photosensitivity (3%), and fatigue (7%).

A Disease of Subtypes

Dr. Chapman told reporters that genetic screening will have to become universal in melanoma, just as KRAS testing is essential in treating colorectal cancer. Screening can be completed in 1–2 weeks at active, participating centers.

The BRAF mutation is not the first example of a genetic subtype targeted in metastatic melanoma; Dr. Fisher and his colleagues reported dramatic results last year after targeting the c-KIT mutation with imatinib (Gleevec). Although the armamentarium is not deep for drugs that block BRAF, there are several available agents that target c-KIT, including nilotinib (Tasigna) and sunitinib (Sutent).

Although the signal from the PLX4032 trials is strong, the early data suggest that the single agent is not going to be enough, Dr. Fisher said. Future strategies will likely include combination therapy and the use of agents prior to the development of metastatic disease.

“We need complete remission. We need these tumors to melt away,” he said.

Reporters questioned whether PLX4032 could be used with the monoclonal antibody bevacizumab (Avastin), which increased overall survival by more than 40% when combined with the chemotherapeutic agents carboplatin and paclitaxel in a phase II metastatic melanoma trial that was also presented at the congress.

Dr. Chapman responded, “If you shrink the tumor too much with PLX4032, it may not be as sensitive to VEGF [vascular endothelial growth factor] inhibition, but from a toxicity point of view, I don't think there's any reason why we couldn't combine them.”

Further Trials

A phase II single arm trial (BRIM2) is evaluating 960 mg twice daily of PLX4032 in about 100 BRAF

The randomized, phase III BRIM3 trial is expected to start by the end of 2009 in first-line patients. Plexxicon is codeveloping PLX4032 with Roche.

Dr. Chapman said he had no conflicts of interest.

Melanoma is 'going to become a very exciting field instead of a graveyard.'

Source DR. EGGERMONT

Tumor shrinkage on MRI showed that, after just 15 days of treatment, FDG uptake was essentially shut down.

Source DR. CHAPMAN

Budapest, Hungary — Switching renal transplant recipients from azathioprine to mycophenolate mofetil for long-term immunosuppression significantly reduced UVA photosensitivity in a crossover study.

This is likely to decrease the extraordinarily high rate of cutaneous squamous cell carcinoma (SCC) that renal transplant patients experience, Dr. Günther Hofbauer said at the annual congress of the European Society for Dermatological Research.

The medication switch did not affect glomerular filtration rate, urine protein-to-creatinine ratio, or other measures of allograft function, added Dr. Hofbauer of the University of Zurich.

SCC is the most common cancer in solid organ transplant recipients, with a 65- to 250-fold greater incidence than in the general population.

In response to the observation by other investigators that direct DNA damage occurs in response to azathioprine, Dr. Hofbauer and his coworkers measured photosensitivity to UVA and UVB in 16 kidney transplant recipients on long-term azathioprine and 17 on mycophenolate mofetil (CellCept).

They found that the mean minimal erythema dose for UVA in the azathioprine group was 21 J/cm

To follow up on this finding, the investigators conducted a switch from azathioprine to mycophenolate mofetil in 23 stable patients who had received a donor kidney a mean of 14.5 years earlier. Their minimal erythema dose for UVA on azathioprine was 16 J/m

Azathioprine is a mainstay immunosuppressant given to prevent graft rejection in many types of transplant recipients. It is now known to cause selective UVA photosensitivity in the 320- to 400-nm wavelengths, with resultant incorporation of 6-thioguanine (6-TG)—the drug's active metabolite—into the DNA of all cells in the body. The 6-TG absorbs UVA, with the resultant production of reactive oxygen species capable of damaging DNA, Dr. Hofbauer explained.

The mean 6-TG level contained in the patients' peripheral white blood cells dropped from 99 pmol/mg of total DNA while on azathioprine to 43 pmol/mg after 3 months on mycophenolate mofetil. A particularly striking finding, he said, was that the steeper the decline in DNA 6-TG, the greater the increase in the minimal erythema dose for UVA.

“The 6-TG levels didn't drop to 0, so we have reason to believe that 6-TG stays in the system for much longer than our 3-month washout period,” he continued.

Study participants were typically on about 50 mg/day of azathioprine and were switched to 500 mg of mycophenolate mofetil twice daily.

“Our nephrologists say that dose of mycophenolate mofetil actually provides slightly greater immunosuppression, which should, if anything, decrease the rejection rate,” said Dr. Hofbauer, who had no conflicts of interest relevant to his presentation.

This drug is likely to decrease the high rate of cutaneous SCC that renal transplant patients experience.

Source DR. HOFBAUER

Budapest, Hungary — Switching renal transplant recipients from azathioprine to mycophenolate mofetil for long-term immunosuppression significantly reduced UVA photosensitivity in a crossover study.

This is likely to decrease the extraordinarily high rate of cutaneous squamous cell carcinoma (SCC) that renal transplant patients experience, Dr. Günther Hofbauer said at the annual congress of the European Society for Dermatological Research.

The medication switch did not affect glomerular filtration rate, urine protein-to-creatinine ratio, or other measures of allograft function, added Dr. Hofbauer of the University of Zurich.

SCC is the most common cancer in solid organ transplant recipients, with a 65- to 250-fold greater incidence than in the general population.

In response to the observation by other investigators that direct DNA damage occurs in response to azathioprine, Dr. Hofbauer and his coworkers measured photosensitivity to UVA and UVB in 16 kidney transplant recipients on long-term azathioprine and 17 on mycophenolate mofetil (CellCept).

They found that the mean minimal erythema dose for UVA in the azathioprine group was 21 J/cm

To follow up on this finding, the investigators conducted a switch from azathioprine to mycophenolate mofetil in 23 stable patients who had received a donor kidney a mean of 14.5 years earlier. Their minimal erythema dose for UVA on azathioprine was 16 J/m

Azathioprine is a mainstay immunosuppressant given to prevent graft rejection in many types of transplant recipients. It is now known to cause selective UVA photosensitivity in the 320- to 400-nm wavelengths, with resultant incorporation of 6-thioguanine (6-TG)—the drug's active metabolite—into the DNA of all cells in the body. The 6-TG absorbs UVA, with the resultant production of reactive oxygen species capable of damaging DNA, Dr. Hofbauer explained.

The mean 6-TG level contained in the patients' peripheral white blood cells dropped from 99 pmol/mg of total DNA while on azathioprine to 43 pmol/mg after 3 months on mycophenolate mofetil. A particularly striking finding, he said, was that the steeper the decline in DNA 6-TG, the greater the increase in the minimal erythema dose for UVA.

“The 6-TG levels didn't drop to 0, so we have reason to believe that 6-TG stays in the system for much longer than our 3-month washout period,” he continued.

Study participants were typically on about 50 mg/day of azathioprine and were switched to 500 mg of mycophenolate mofetil twice daily.

“Our nephrologists say that dose of mycophenolate mofetil actually provides slightly greater immunosuppression, which should, if anything, decrease the rejection rate,” said Dr. Hofbauer, who had no conflicts of interest relevant to his presentation.

This drug is likely to decrease the high rate of cutaneous SCC that renal transplant patients experience.

Source DR. HOFBAUER

Budapest, Hungary — Switching renal transplant recipients from azathioprine to mycophenolate mofetil for long-term immunosuppression significantly reduced UVA photosensitivity in a crossover study.

This is likely to decrease the extraordinarily high rate of cutaneous squamous cell carcinoma (SCC) that renal transplant patients experience, Dr. Günther Hofbauer said at the annual congress of the European Society for Dermatological Research.

The medication switch did not affect glomerular filtration rate, urine protein-to-creatinine ratio, or other measures of allograft function, added Dr. Hofbauer of the University of Zurich.

SCC is the most common cancer in solid organ transplant recipients, with a 65- to 250-fold greater incidence than in the general population.

In response to the observation by other investigators that direct DNA damage occurs in response to azathioprine, Dr. Hofbauer and his coworkers measured photosensitivity to UVA and UVB in 16 kidney transplant recipients on long-term azathioprine and 17 on mycophenolate mofetil (CellCept).

They found that the mean minimal erythema dose for UVA in the azathioprine group was 21 J/cm

To follow up on this finding, the investigators conducted a switch from azathioprine to mycophenolate mofetil in 23 stable patients who had received a donor kidney a mean of 14.5 years earlier. Their minimal erythema dose for UVA on azathioprine was 16 J/m

Azathioprine is a mainstay immunosuppressant given to prevent graft rejection in many types of transplant recipients. It is now known to cause selective UVA photosensitivity in the 320- to 400-nm wavelengths, with resultant incorporation of 6-thioguanine (6-TG)—the drug's active metabolite—into the DNA of all cells in the body. The 6-TG absorbs UVA, with the resultant production of reactive oxygen species capable of damaging DNA, Dr. Hofbauer explained.

The mean 6-TG level contained in the patients' peripheral white blood cells dropped from 99 pmol/mg of total DNA while on azathioprine to 43 pmol/mg after 3 months on mycophenolate mofetil. A particularly striking finding, he said, was that the steeper the decline in DNA 6-TG, the greater the increase in the minimal erythema dose for UVA.

“The 6-TG levels didn't drop to 0, so we have reason to believe that 6-TG stays in the system for much longer than our 3-month washout period,” he continued.

Study participants were typically on about 50 mg/day of azathioprine and were switched to 500 mg of mycophenolate mofetil twice daily.

“Our nephrologists say that dose of mycophenolate mofetil actually provides slightly greater immunosuppression, which should, if anything, decrease the rejection rate,” said Dr. Hofbauer, who had no conflicts of interest relevant to his presentation.

This drug is likely to decrease the high rate of cutaneous SCC that renal transplant patients experience.

Source DR. HOFBAUER

BERLIN — Look for a big jump in the number of melanoma patients diagnosed with stage III disease beginning early next year, when the new American Joint Committee on Cancer classification system takes effect.

The new AJCC system endorses immunohistochemical detection of nodal metastases, and there will no longer be a lower limit for the definition of nodal disease, Dr. Claus Garbe explained at the annual congress of the European Academy of Dermatology and Venereology.

“In allowing micrometastases to be defined through immunohistochemistry, it means isolated tumor cells which weren't previously considered to be stage III are now considered to be N+. So even one metastatic cell is now enough,” said Dr. Garbe, professor of dermatology at the University of Tübingen (Germany).

The clinical implication of this revision is that a lot more radical lymphadenectomies will be performed, since that is a recommended part of the management of stage III disease. Likewise, patients who have immunohistochemically defined micrometastatic stage III disease will need to be offered an adjuvant therapy, as it is also standard in stage III melanoma, he continued.

From the audience reaction in Berlin, this redefinition of what constitutes stage III melanoma is likely to be the most controversial change coming in the melanoma section of AJCC 2010 (“AJCC to Institute New Melanoma Staging System,” March 2009, p. 1).

“It worries me enormously that one positive cell on immunohistochemistry will be stage III melanoma. And it worries me enormously that we're going to be doing more nodal dissections in the absence of any supporting evidence,” commented Dr. J.M. Thomas, who is professor of surgery at Royal Marsden Hospital in London.

Dr. Jean-Jacques Grob, president of the European Association of Dermato-Oncology, said he is troubled by the prospect of considerable difficulties in comparing data from studies using the new criteria for stage III disease with historical data.

“And applying the same therapeutic principles used in the old stage III patients to the new ones is perhaps not a good idea,” added Dr. Grob, professor of dermatology at the University of Marseille (France).

Other audience members complained that the AJCC change is premature in light of recent evidence from the Rotterdam melanoma study group that micrometastases less than 0.1 mm in diameter carry essentially as good a prognosis as no micrometastases at all.

“My guess is that this is not the end of the story,” Dr. Garbe replied to the critics.

For example, he and his coworkers will soon publish a study showing a near-linear inverse relationship between the number of metastatic cells found upon immunostaining of a completely dissected lymph node and prognosis.

Also, there are two highly pertinent ongoing clinical trials—one in Germany, and the U.S.-based Multicenter Selective Lymphadenopathy Trial-2—that have randomized patients after a positive sentinel lymph node biopsy to radical lymph node dissection or observation, he noted.

“I think these trials will help us to determine whether it's really useful to do radical lymphadenectomy for micrometastases. Currently we don't have a basis in evidence, we just have consensus surgical recommendations,” Dr. Garbe continued.

In addition to the hot-button issue of the broadened criteria for stage III melanoma, other coming changes in the 2010 AJCC melanoma classification system include:

▸ Mitotic rate will make its debut as an independent prognostic factor. It is to be routinely determined histopathologically. A finding of one or more mitoses/mm

This new criterion is based upon a multivariate regression analysis that involved more than 10,000 melanoma patients in which mitotic rate ran a close second to tumor thickness as a predictor of 10-year mortality, with ulceration a distant third.

The old nomenclature, expressed as mitoses per 10 high-power fields, is out. The new terminology is mitoses/mm

▸ Clark's level of invasion is being eliminated from the new classification scheme based upon insufficient prognostic value.

▸ Isolated metastases arising in skin, subcutaneous tissue, or lymph nodes from an unknown primary site are to be classified as stage III, not stage IV as often occurred before. These soft-tissue metastases from a melanoma of unknown primary, or MUP, have been shown to carry a prognosis akin to regional metastases, not the distant metastases which define stage IV disease.

The 655-page seventh edition of the AJCC Staging Manual, which was recently published by Springer, goes into effect next year.

BERLIN — Look for a big jump in the number of melanoma patients diagnosed with stage III disease beginning early next year, when the new American Joint Committee on Cancer classification system takes effect.

The new AJCC system endorses immunohistochemical detection of nodal metastases, and there will no longer be a lower limit for the definition of nodal disease, Dr. Claus Garbe explained at the annual congress of the European Academy of Dermatology and Venereology.

“In allowing micrometastases to be defined through immunohistochemistry, it means isolated tumor cells which weren't previously considered to be stage III are now considered to be N+. So even one metastatic cell is now enough,” said Dr. Garbe, professor of dermatology at the University of Tübingen (Germany).

The clinical implication of this revision is that a lot more radical lymphadenectomies will be performed, since that is a recommended part of the management of stage III disease. Likewise, patients who have immunohistochemically defined micrometastatic stage III disease will need to be offered an adjuvant therapy, as it is also standard in stage III melanoma, he continued.

From the audience reaction in Berlin, this redefinition of what constitutes stage III melanoma is likely to be the most controversial change coming in the melanoma section of AJCC 2010 (“AJCC to Institute New Melanoma Staging System,” March 2009, p. 1).

“It worries me enormously that one positive cell on immunohistochemistry will be stage III melanoma. And it worries me enormously that we're going to be doing more nodal dissections in the absence of any supporting evidence,” commented Dr. J.M. Thomas, who is professor of surgery at Royal Marsden Hospital in London.

Dr. Jean-Jacques Grob, president of the European Association of Dermato-Oncology, said he is troubled by the prospect of considerable difficulties in comparing data from studies using the new criteria for stage III disease with historical data.

“And applying the same therapeutic principles used in the old stage III patients to the new ones is perhaps not a good idea,” added Dr. Grob, professor of dermatology at the University of Marseille (France).

Other audience members complained that the AJCC change is premature in light of recent evidence from the Rotterdam melanoma study group that micrometastases less than 0.1 mm in diameter carry essentially as good a prognosis as no micrometastases at all.

“My guess is that this is not the end of the story,” Dr. Garbe replied to the critics.

For example, he and his coworkers will soon publish a study showing a near-linear inverse relationship between the number of metastatic cells found upon immunostaining of a completely dissected lymph node and prognosis.

Also, there are two highly pertinent ongoing clinical trials—one in Germany, and the U.S.-based Multicenter Selective Lymphadenopathy Trial-2—that have randomized patients after a positive sentinel lymph node biopsy to radical lymph node dissection or observation, he noted.

“I think these trials will help us to determine whether it's really useful to do radical lymphadenectomy for micrometastases. Currently we don't have a basis in evidence, we just have consensus surgical recommendations,” Dr. Garbe continued.

In addition to the hot-button issue of the broadened criteria for stage III melanoma, other coming changes in the 2010 AJCC melanoma classification system include:

▸ Mitotic rate will make its debut as an independent prognostic factor. It is to be routinely determined histopathologically. A finding of one or more mitoses/mm

This new criterion is based upon a multivariate regression analysis that involved more than 10,000 melanoma patients in which mitotic rate ran a close second to tumor thickness as a predictor of 10-year mortality, with ulceration a distant third.

The old nomenclature, expressed as mitoses per 10 high-power fields, is out. The new terminology is mitoses/mm

▸ Clark's level of invasion is being eliminated from the new classification scheme based upon insufficient prognostic value.

▸ Isolated metastases arising in skin, subcutaneous tissue, or lymph nodes from an unknown primary site are to be classified as stage III, not stage IV as often occurred before. These soft-tissue metastases from a melanoma of unknown primary, or MUP, have been shown to carry a prognosis akin to regional metastases, not the distant metastases which define stage IV disease.

The 655-page seventh edition of the AJCC Staging Manual, which was recently published by Springer, goes into effect next year.

BERLIN — Look for a big jump in the number of melanoma patients diagnosed with stage III disease beginning early next year, when the new American Joint Committee on Cancer classification system takes effect.

The new AJCC system endorses immunohistochemical detection of nodal metastases, and there will no longer be a lower limit for the definition of nodal disease, Dr. Claus Garbe explained at the annual congress of the European Academy of Dermatology and Venereology.

“In allowing micrometastases to be defined through immunohistochemistry, it means isolated tumor cells which weren't previously considered to be stage III are now considered to be N+. So even one metastatic cell is now enough,” said Dr. Garbe, professor of dermatology at the University of Tübingen (Germany).

The clinical implication of this revision is that a lot more radical lymphadenectomies will be performed, since that is a recommended part of the management of stage III disease. Likewise, patients who have immunohistochemically defined micrometastatic stage III disease will need to be offered an adjuvant therapy, as it is also standard in stage III melanoma, he continued.

From the audience reaction in Berlin, this redefinition of what constitutes stage III melanoma is likely to be the most controversial change coming in the melanoma section of AJCC 2010 (“AJCC to Institute New Melanoma Staging System,” March 2009, p. 1).

“It worries me enormously that one positive cell on immunohistochemistry will be stage III melanoma. And it worries me enormously that we're going to be doing more nodal dissections in the absence of any supporting evidence,” commented Dr. J.M. Thomas, who is professor of surgery at Royal Marsden Hospital in London.

Dr. Jean-Jacques Grob, president of the European Association of Dermato-Oncology, said he is troubled by the prospect of considerable difficulties in comparing data from studies using the new criteria for stage III disease with historical data.

“And applying the same therapeutic principles used in the old stage III patients to the new ones is perhaps not a good idea,” added Dr. Grob, professor of dermatology at the University of Marseille (France).

Other audience members complained that the AJCC change is premature in light of recent evidence from the Rotterdam melanoma study group that micrometastases less than 0.1 mm in diameter carry essentially as good a prognosis as no micrometastases at all.

“My guess is that this is not the end of the story,” Dr. Garbe replied to the critics.

For example, he and his coworkers will soon publish a study showing a near-linear inverse relationship between the number of metastatic cells found upon immunostaining of a completely dissected lymph node and prognosis.

Also, there are two highly pertinent ongoing clinical trials—one in Germany, and the U.S.-based Multicenter Selective Lymphadenopathy Trial-2—that have randomized patients after a positive sentinel lymph node biopsy to radical lymph node dissection or observation, he noted.

“I think these trials will help us to determine whether it's really useful to do radical lymphadenectomy for micrometastases. Currently we don't have a basis in evidence, we just have consensus surgical recommendations,” Dr. Garbe continued.

In addition to the hot-button issue of the broadened criteria for stage III melanoma, other coming changes in the 2010 AJCC melanoma classification system include:

▸ Mitotic rate will make its debut as an independent prognostic factor. It is to be routinely determined histopathologically. A finding of one or more mitoses/mm

This new criterion is based upon a multivariate regression analysis that involved more than 10,000 melanoma patients in which mitotic rate ran a close second to tumor thickness as a predictor of 10-year mortality, with ulceration a distant third.

The old nomenclature, expressed as mitoses per 10 high-power fields, is out. The new terminology is mitoses/mm

▸ Clark's level of invasion is being eliminated from the new classification scheme based upon insufficient prognostic value.

▸ Isolated metastases arising in skin, subcutaneous tissue, or lymph nodes from an unknown primary site are to be classified as stage III, not stage IV as often occurred before. These soft-tissue metastases from a melanoma of unknown primary, or MUP, have been shown to carry a prognosis akin to regional metastases, not the distant metastases which define stage IV disease.

The 655-page seventh edition of the AJCC Staging Manual, which was recently published by Springer, goes into effect next year.