Melanoma

Melanoma continues to be a devastating disease unless diagnosed and treated early. According to the National Cancer Institute, there will be more than 76,000 new cases of invasive melanoma and nearly 10,000 melanoma-related deaths in 2014 in the United States.¹ If diagnosed early, more than 93% of melanoma patients can expect to be cured, but later diagnosis of thicker melanoma is associated with a worse prognosis. Surgery remains the mainstay of therapy for cutaneous melanoma, including wide excision and sentinel lymph node (SLN) biopsy for staging of the regional nodal basins in appropriate patients. Although novel targeted therapies and immunotherapies have been associated with improved survival in metastatic melanoma, detection of cutaneous melanoma in its early phases remains the best chance for cure.

Tumor thickness, or Breslow depth, is the most important histologic determinant of prognosis in melanoma patients and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of the tumor involvement. Increased tumor thickness confers a higher metastatic potential and poorer prognosis.² Other histologic prognostic factors that have been incorporated into the American Joint Committee on Cancer melanoma staging system include the presence or absence of ulceration and mitotic index (measured per square millimeter), particularly for T1 melanomas (<1 mm thick), though Breslow depth greater than 0.75 mm appears to be the most reliable predictor of SLN metastasis in thin (T1) melanomas (≤1 mm).³

Tumor volume assessment may be a helpful adjunct to Breslow depth as a prognostic indicator for melanoma, particularly for predicting SLN metastasis.⁴ This retrospective study was designed to assess the improvement in the accuracy of Breslow depth as a prognostic factor by utilizing tumor volume combined with mitotic index, presence or absence of ulceration, and inflammatory host reaction (eg, tumor-infiltrating lymphocytes).

Methods

The study was approved by the Stanford University (Stanford, California) institutional review board. A retrospective review of invasive primary melanomas recorded in Stanford University’s pathology/dermatopathology database from January 2007 through December 2010 was conducted. Because cases included both Stanford Health Care (formerly Stanford Hospital & Clinics) and outside pathology consultations, clinical assessment of patient outcome was not possible for all cases and thus was not performed.

Assessment

Information extracted from the pathology reports included Breslow depth; estimated surface area of the primary tumor (measured by the longest vertical and horizontal dimensions recorded by the clinician prior to diagnostic biopsy and reported on the biopsy requisition form [>90% of cases] or reported by the pathologist on gross measurement of the pigmented lesion in formalin [<10% of cases]); mitotic index (measured per square millimeter); presence or absence of ulceration; and inflammatory host reaction (as noted by tumor-infiltrating response). Our method of estimating the tumor volume (lesion surface area • Breslow depth) did not take into account border irregularities in the primary tumor. This method also was limited because prebiopsy clinical measurement could differ from gross pathologic measurement of the tumor due to shrinkage of the latter ex vivo and following formalin fixation. However, when both measurements were documented, the pathological measurement was only slightly less than the clinical measurement. Metastases were defined as those in lymph nodes (microscopic or macroscopic), skin, or in distant organs, as identified through review of subsequent pathology reports.

Statistical Analysis

Statistical analyses were conducted using SAS version 9.3. Test statistics were preset at a significance level of α=.05. Using metastasis status as the outcome, univariate regression models were first fitted to assess the predictive ability of each prognostic indicator. In univariate analyses, continuous prognostic indicators (Breslow depth, tumor volume, and surface area) were included in the model while seeking the best functional form by means of fractional polynomials modeling.^5,6 Predictive ability of prognostic indicators was determined by the area under the receiver operating characteristic curve (AUC).⁷ Using best functional form for Breslow depth, all other prognostic indicators were added to the model to assess their individual contributions to improve the predictive ability for tumor metastasis. The functional forms used for tumor volume and surface area were those determined in the univariate analysis. Multivariable models were compared aiming for an improvement of the best Breslow model indices: Schwarz criterion, Hosmer-Lemeshow goodness-of-fit test, generalized R², and AUC.⁵ The added contribution of clinical predictors to the model for Breslow depth was judged by the significance of the coefficient for the added clinical predictor, the significance of the change in AUC, and the change in the model indices listed above. A check on overdispersion was carried out on the final model selected.

Results

There were 108 eligible cases in the 4-year time period in which tumor volume assessment could be determined based on the pathology report in conjunction with Breslow depth, mitotic index, presence or absence of ulceration, and tumor infiltrating response. Breslow depth ranged from 0.20 to 10.00 mm, with a median depth of 1.37 mm. Surface area ranged from 12.00 to 1720.00 mm² (median, 100.00 mm²). Tumor volume was calculated by multiplying Breslow depth by surface area and ranged from 2.76 to 11,180.00 mm³ (median, 113.05 mm³)(Table 1). Ulceration was present in 18.69% of the tumors, 20.37% exhibited a brisk inflammatory host reaction, and 53.27% had a mitotic index of 1/mm² or more. Tumor metastasis was noted in 40.74% (44/108) of patients (Table 2), all of whom had a primary melanoma with a Breslow depth greater than 1 mm. Only one T1 melanoma had a tumor volume greater than 250 mm³. Metastasis in patients with T2 (1- to 2-mm thick) and T3 (2- to 4-mm thick) melanoma was associated with a tumor volume greater than 250 mm³ in 16 of 26 patients (61.54%), and all 18 patients with T4 melanomas (>4-mm thick) had tumor volume greater than 250 mm³.

Univariate analysis demonstrated that Breslow depth was the best prognostic indicator of metastasis (AUC=0.946) but that tumor volume (as a continuous variable) was nearly equally predictive (AUC=0.940)(Table 3). Tumor volume alone (categorized as <250 mm³ vs >250 mm³) had lower prognostic value (AUC=0.855). Mitotic index, presence or absence of ulceration, inflammatory host reaction, and surface area also had lower prognostic values, though all were significant factors (P values ranging from <.0001 to .0077)(Table 3).

Importantly, the addition of surface area, mitotic index, presence or absence of ulceration, and inflammatory host reaction to the model to Breslow depth did not improve predictive ability for metastasis, and AUC values did not increase significantly after adding these factors (Table 4). In particular, the change in AUC for adding surface area to the model with Breslow depth was 0.023 (P=.1095). Models in Table 4 were checked for interaction of these 2 predictors, and the interaction term for thickness and surface area was not statistically significant (P=.0932)(data not shown).

Comment

Decades after the concept of measuring tumor thickness in cutaneous melanomas was proposed by Dr. Alexander Breslow, it remains the most reliable predictor of prognosis in melanoma patients.² Our study demonstrated that tumor volume may be contributory to thickness, despite our relatively imprecise assessment of tumor volume based on clinical or pathological reporting of primary tumor area. Because more than 90% of our tumor volume measurements were based on clinician reports of the lesion size before diagnostic biopsy rather than gross measurement of the tumor by the pathologist after biopsy, we believe that measurement and assessment of tumor volume could be readily incorporated into the clinical practice setting. Although we could not demonstrate a correlation between SLN positivity and tumor volume in T1 melanomas because none of the T1 tumors exhibited microscopic nodal metastasis, assessment of tumor volume may assist the clinician in patient management, using a 250-mm³ cutoff point. Gross tumor measurement is important to allow for accurate assessment of volume and would preferably be recorded by the clinician prior to biopsy with notation of clinical lesion size on the pathology requisition form, as is recommended in the American Academy of Dermatology’s melanoma practice guidelines.⁸

A prior assessment of 123 patients with invasive primary melanomas demonstrated that greater tumor volume (>250 mm³) was associated with metastasis across all tumor thicknesses.⁴ In T1 melanoma, no patients with a tumor volume less than 250 mm³ demonstrated SLN metastasis,⁴ suggesting that volume assessment may aid in consideration of staging with SLN biopsy in conjunction with tumor thickness and other established prognostic factors for SLN positivity in thin melanomas (eg, high mitotic index [particularly in tumors >0.75-mm thick]), histologic ulceration, and/or lymphovascular invasion).^2,8

It should be noted, however, that lentigo maligna melanoma, which often is predominantly in situ with only focal papillary dermal invasion, may have an erroneously high tumor volume due to its larger total surface area. However, tumor volume would not be expected to correlate with tumor metastasis given the thin invasive component. The current study was limited by not accounting for melanoma subtype in the overall analysis.

A practical estimation of tumor volume based on clinical measurement of tumor size (ie, surface area of the suspicious lesion prior to biopsy) in combination with the pathologist’s assessment of Breslow depth may be a helpful adjunct to predicting likelihood of development of metastasis. We suggest that the concept of tumor volume should be subjected to more rigorous investigation with standardized clinical/prebiopsy measurement of the lesion; correlation with known histologic prognostic factors, SLN positivity, and/or development of additional nodal or visceral metastasis; and most importantly long-term patient outcome in terms of survival. Our preliminary data suggest the value of this enterprise.

Melanoma continues to be a devastating disease unless diagnosed and treated early. According to the National Cancer Institute, there will be more than 76,000 new cases of invasive melanoma and nearly 10,000 melanoma-related deaths in 2014 in the United States.¹ If diagnosed early, more than 93% of melanoma patients can expect to be cured, but later diagnosis of thicker melanoma is associated with a worse prognosis. Surgery remains the mainstay of therapy for cutaneous melanoma, including wide excision and sentinel lymph node (SLN) biopsy for staging of the regional nodal basins in appropriate patients. Although novel targeted therapies and immunotherapies have been associated with improved survival in metastatic melanoma, detection of cutaneous melanoma in its early phases remains the best chance for cure.

Tumor thickness, or Breslow depth, is the most important histologic determinant of prognosis in melanoma patients and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of the tumor involvement. Increased tumor thickness confers a higher metastatic potential and poorer prognosis.² Other histologic prognostic factors that have been incorporated into the American Joint Committee on Cancer melanoma staging system include the presence or absence of ulceration and mitotic index (measured per square millimeter), particularly for T1 melanomas (<1 mm thick), though Breslow depth greater than 0.75 mm appears to be the most reliable predictor of SLN metastasis in thin (T1) melanomas (≤1 mm).³

Tumor volume assessment may be a helpful adjunct to Breslow depth as a prognostic indicator for melanoma, particularly for predicting SLN metastasis.⁴ This retrospective study was designed to assess the improvement in the accuracy of Breslow depth as a prognostic factor by utilizing tumor volume combined with mitotic index, presence or absence of ulceration, and inflammatory host reaction (eg, tumor-infiltrating lymphocytes).

Methods

The study was approved by the Stanford University (Stanford, California) institutional review board. A retrospective review of invasive primary melanomas recorded in Stanford University’s pathology/dermatopathology database from January 2007 through December 2010 was conducted. Because cases included both Stanford Health Care (formerly Stanford Hospital & Clinics) and outside pathology consultations, clinical assessment of patient outcome was not possible for all cases and thus was not performed.

Assessment

Information extracted from the pathology reports included Breslow depth; estimated surface area of the primary tumor (measured by the longest vertical and horizontal dimensions recorded by the clinician prior to diagnostic biopsy and reported on the biopsy requisition form [>90% of cases] or reported by the pathologist on gross measurement of the pigmented lesion in formalin [<10% of cases]); mitotic index (measured per square millimeter); presence or absence of ulceration; and inflammatory host reaction (as noted by tumor-infiltrating response). Our method of estimating the tumor volume (lesion surface area • Breslow depth) did not take into account border irregularities in the primary tumor. This method also was limited because prebiopsy clinical measurement could differ from gross pathologic measurement of the tumor due to shrinkage of the latter ex vivo and following formalin fixation. However, when both measurements were documented, the pathological measurement was only slightly less than the clinical measurement. Metastases were defined as those in lymph nodes (microscopic or macroscopic), skin, or in distant organs, as identified through review of subsequent pathology reports.

Statistical Analysis

Statistical analyses were conducted using SAS version 9.3. Test statistics were preset at a significance level of α=.05. Using metastasis status as the outcome, univariate regression models were first fitted to assess the predictive ability of each prognostic indicator. In univariate analyses, continuous prognostic indicators (Breslow depth, tumor volume, and surface area) were included in the model while seeking the best functional form by means of fractional polynomials modeling.^5,6 Predictive ability of prognostic indicators was determined by the area under the receiver operating characteristic curve (AUC).⁷ Using best functional form for Breslow depth, all other prognostic indicators were added to the model to assess their individual contributions to improve the predictive ability for tumor metastasis. The functional forms used for tumor volume and surface area were those determined in the univariate analysis. Multivariable models were compared aiming for an improvement of the best Breslow model indices: Schwarz criterion, Hosmer-Lemeshow goodness-of-fit test, generalized R², and AUC.⁵ The added contribution of clinical predictors to the model for Breslow depth was judged by the significance of the coefficient for the added clinical predictor, the significance of the change in AUC, and the change in the model indices listed above. A check on overdispersion was carried out on the final model selected.

Results

There were 108 eligible cases in the 4-year time period in which tumor volume assessment could be determined based on the pathology report in conjunction with Breslow depth, mitotic index, presence or absence of ulceration, and tumor infiltrating response. Breslow depth ranged from 0.20 to 10.00 mm, with a median depth of 1.37 mm. Surface area ranged from 12.00 to 1720.00 mm² (median, 100.00 mm²). Tumor volume was calculated by multiplying Breslow depth by surface area and ranged from 2.76 to 11,180.00 mm³ (median, 113.05 mm³)(Table 1). Ulceration was present in 18.69% of the tumors, 20.37% exhibited a brisk inflammatory host reaction, and 53.27% had a mitotic index of 1/mm² or more. Tumor metastasis was noted in 40.74% (44/108) of patients (Table 2), all of whom had a primary melanoma with a Breslow depth greater than 1 mm. Only one T1 melanoma had a tumor volume greater than 250 mm³. Metastasis in patients with T2 (1- to 2-mm thick) and T3 (2- to 4-mm thick) melanoma was associated with a tumor volume greater than 250 mm³ in 16 of 26 patients (61.54%), and all 18 patients with T4 melanomas (>4-mm thick) had tumor volume greater than 250 mm³.

Univariate analysis demonstrated that Breslow depth was the best prognostic indicator of metastasis (AUC=0.946) but that tumor volume (as a continuous variable) was nearly equally predictive (AUC=0.940)(Table 3). Tumor volume alone (categorized as <250 mm³ vs >250 mm³) had lower prognostic value (AUC=0.855). Mitotic index, presence or absence of ulceration, inflammatory host reaction, and surface area also had lower prognostic values, though all were significant factors (P values ranging from <.0001 to .0077)(Table 3).

Importantly, the addition of surface area, mitotic index, presence or absence of ulceration, and inflammatory host reaction to the model to Breslow depth did not improve predictive ability for metastasis, and AUC values did not increase significantly after adding these factors (Table 4). In particular, the change in AUC for adding surface area to the model with Breslow depth was 0.023 (P=.1095). Models in Table 4 were checked for interaction of these 2 predictors, and the interaction term for thickness and surface area was not statistically significant (P=.0932)(data not shown).

Comment

Decades after the concept of measuring tumor thickness in cutaneous melanomas was proposed by Dr. Alexander Breslow, it remains the most reliable predictor of prognosis in melanoma patients.² Our study demonstrated that tumor volume may be contributory to thickness, despite our relatively imprecise assessment of tumor volume based on clinical or pathological reporting of primary tumor area. Because more than 90% of our tumor volume measurements were based on clinician reports of the lesion size before diagnostic biopsy rather than gross measurement of the tumor by the pathologist after biopsy, we believe that measurement and assessment of tumor volume could be readily incorporated into the clinical practice setting. Although we could not demonstrate a correlation between SLN positivity and tumor volume in T1 melanomas because none of the T1 tumors exhibited microscopic nodal metastasis, assessment of tumor volume may assist the clinician in patient management, using a 250-mm³ cutoff point. Gross tumor measurement is important to allow for accurate assessment of volume and would preferably be recorded by the clinician prior to biopsy with notation of clinical lesion size on the pathology requisition form, as is recommended in the American Academy of Dermatology’s melanoma practice guidelines.⁸

A prior assessment of 123 patients with invasive primary melanomas demonstrated that greater tumor volume (>250 mm³) was associated with metastasis across all tumor thicknesses.⁴ In T1 melanoma, no patients with a tumor volume less than 250 mm³ demonstrated SLN metastasis,⁴ suggesting that volume assessment may aid in consideration of staging with SLN biopsy in conjunction with tumor thickness and other established prognostic factors for SLN positivity in thin melanomas (eg, high mitotic index [particularly in tumors >0.75-mm thick]), histologic ulceration, and/or lymphovascular invasion).^2,8

It should be noted, however, that lentigo maligna melanoma, which often is predominantly in situ with only focal papillary dermal invasion, may have an erroneously high tumor volume due to its larger total surface area. However, tumor volume would not be expected to correlate with tumor metastasis given the thin invasive component. The current study was limited by not accounting for melanoma subtype in the overall analysis.

A practical estimation of tumor volume based on clinical measurement of tumor size (ie, surface area of the suspicious lesion prior to biopsy) in combination with the pathologist’s assessment of Breslow depth may be a helpful adjunct to predicting likelihood of development of metastasis. We suggest that the concept of tumor volume should be subjected to more rigorous investigation with standardized clinical/prebiopsy measurement of the lesion; correlation with known histologic prognostic factors, SLN positivity, and/or development of additional nodal or visceral metastasis; and most importantly long-term patient outcome in terms of survival. Our preliminary data suggest the value of this enterprise.

Melanoma continues to be a devastating disease unless diagnosed and treated early. According to the National Cancer Institute, there will be more than 76,000 new cases of invasive melanoma and nearly 10,000 melanoma-related deaths in 2014 in the United States.¹ If diagnosed early, more than 93% of melanoma patients can expect to be cured, but later diagnosis of thicker melanoma is associated with a worse prognosis. Surgery remains the mainstay of therapy for cutaneous melanoma, including wide excision and sentinel lymph node (SLN) biopsy for staging of the regional nodal basins in appropriate patients. Although novel targeted therapies and immunotherapies have been associated with improved survival in metastatic melanoma, detection of cutaneous melanoma in its early phases remains the best chance for cure.

Tumor thickness, or Breslow depth, is the most important histologic determinant of prognosis in melanoma patients and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of the tumor involvement. Increased tumor thickness confers a higher metastatic potential and poorer prognosis.² Other histologic prognostic factors that have been incorporated into the American Joint Committee on Cancer melanoma staging system include the presence or absence of ulceration and mitotic index (measured per square millimeter), particularly for T1 melanomas (<1 mm thick), though Breslow depth greater than 0.75 mm appears to be the most reliable predictor of SLN metastasis in thin (T1) melanomas (≤1 mm).³

Tumor volume assessment may be a helpful adjunct to Breslow depth as a prognostic indicator for melanoma, particularly for predicting SLN metastasis.⁴ This retrospective study was designed to assess the improvement in the accuracy of Breslow depth as a prognostic factor by utilizing tumor volume combined with mitotic index, presence or absence of ulceration, and inflammatory host reaction (eg, tumor-infiltrating lymphocytes).

Methods

The study was approved by the Stanford University (Stanford, California) institutional review board. A retrospective review of invasive primary melanomas recorded in Stanford University’s pathology/dermatopathology database from January 2007 through December 2010 was conducted. Because cases included both Stanford Health Care (formerly Stanford Hospital & Clinics) and outside pathology consultations, clinical assessment of patient outcome was not possible for all cases and thus was not performed.

Assessment

Information extracted from the pathology reports included Breslow depth; estimated surface area of the primary tumor (measured by the longest vertical and horizontal dimensions recorded by the clinician prior to diagnostic biopsy and reported on the biopsy requisition form [>90% of cases] or reported by the pathologist on gross measurement of the pigmented lesion in formalin [<10% of cases]); mitotic index (measured per square millimeter); presence or absence of ulceration; and inflammatory host reaction (as noted by tumor-infiltrating response). Our method of estimating the tumor volume (lesion surface area • Breslow depth) did not take into account border irregularities in the primary tumor. This method also was limited because prebiopsy clinical measurement could differ from gross pathologic measurement of the tumor due to shrinkage of the latter ex vivo and following formalin fixation. However, when both measurements were documented, the pathological measurement was only slightly less than the clinical measurement. Metastases were defined as those in lymph nodes (microscopic or macroscopic), skin, or in distant organs, as identified through review of subsequent pathology reports.

Statistical Analysis

Statistical analyses were conducted using SAS version 9.3. Test statistics were preset at a significance level of α=.05. Using metastasis status as the outcome, univariate regression models were first fitted to assess the predictive ability of each prognostic indicator. In univariate analyses, continuous prognostic indicators (Breslow depth, tumor volume, and surface area) were included in the model while seeking the best functional form by means of fractional polynomials modeling.^5,6 Predictive ability of prognostic indicators was determined by the area under the receiver operating characteristic curve (AUC).⁷ Using best functional form for Breslow depth, all other prognostic indicators were added to the model to assess their individual contributions to improve the predictive ability for tumor metastasis. The functional forms used for tumor volume and surface area were those determined in the univariate analysis. Multivariable models were compared aiming for an improvement of the best Breslow model indices: Schwarz criterion, Hosmer-Lemeshow goodness-of-fit test, generalized R², and AUC.⁵ The added contribution of clinical predictors to the model for Breslow depth was judged by the significance of the coefficient for the added clinical predictor, the significance of the change in AUC, and the change in the model indices listed above. A check on overdispersion was carried out on the final model selected.

Results

There were 108 eligible cases in the 4-year time period in which tumor volume assessment could be determined based on the pathology report in conjunction with Breslow depth, mitotic index, presence or absence of ulceration, and tumor infiltrating response. Breslow depth ranged from 0.20 to 10.00 mm, with a median depth of 1.37 mm. Surface area ranged from 12.00 to 1720.00 mm² (median, 100.00 mm²). Tumor volume was calculated by multiplying Breslow depth by surface area and ranged from 2.76 to 11,180.00 mm³ (median, 113.05 mm³)(Table 1). Ulceration was present in 18.69% of the tumors, 20.37% exhibited a brisk inflammatory host reaction, and 53.27% had a mitotic index of 1/mm² or more. Tumor metastasis was noted in 40.74% (44/108) of patients (Table 2), all of whom had a primary melanoma with a Breslow depth greater than 1 mm. Only one T1 melanoma had a tumor volume greater than 250 mm³. Metastasis in patients with T2 (1- to 2-mm thick) and T3 (2- to 4-mm thick) melanoma was associated with a tumor volume greater than 250 mm³ in 16 of 26 patients (61.54%), and all 18 patients with T4 melanomas (>4-mm thick) had tumor volume greater than 250 mm³.

Univariate analysis demonstrated that Breslow depth was the best prognostic indicator of metastasis (AUC=0.946) but that tumor volume (as a continuous variable) was nearly equally predictive (AUC=0.940)(Table 3). Tumor volume alone (categorized as <250 mm³ vs >250 mm³) had lower prognostic value (AUC=0.855). Mitotic index, presence or absence of ulceration, inflammatory host reaction, and surface area also had lower prognostic values, though all were significant factors (P values ranging from <.0001 to .0077)(Table 3).

Importantly, the addition of surface area, mitotic index, presence or absence of ulceration, and inflammatory host reaction to the model to Breslow depth did not improve predictive ability for metastasis, and AUC values did not increase significantly after adding these factors (Table 4). In particular, the change in AUC for adding surface area to the model with Breslow depth was 0.023 (P=.1095). Models in Table 4 were checked for interaction of these 2 predictors, and the interaction term for thickness and surface area was not statistically significant (P=.0932)(data not shown).

Comment

Decades after the concept of measuring tumor thickness in cutaneous melanomas was proposed by Dr. Alexander Breslow, it remains the most reliable predictor of prognosis in melanoma patients.² Our study demonstrated that tumor volume may be contributory to thickness, despite our relatively imprecise assessment of tumor volume based on clinical or pathological reporting of primary tumor area. Because more than 90% of our tumor volume measurements were based on clinician reports of the lesion size before diagnostic biopsy rather than gross measurement of the tumor by the pathologist after biopsy, we believe that measurement and assessment of tumor volume could be readily incorporated into the clinical practice setting. Although we could not demonstrate a correlation between SLN positivity and tumor volume in T1 melanomas because none of the T1 tumors exhibited microscopic nodal metastasis, assessment of tumor volume may assist the clinician in patient management, using a 250-mm³ cutoff point. Gross tumor measurement is important to allow for accurate assessment of volume and would preferably be recorded by the clinician prior to biopsy with notation of clinical lesion size on the pathology requisition form, as is recommended in the American Academy of Dermatology’s melanoma practice guidelines.⁸

A prior assessment of 123 patients with invasive primary melanomas demonstrated that greater tumor volume (>250 mm³) was associated with metastasis across all tumor thicknesses.⁴ In T1 melanoma, no patients with a tumor volume less than 250 mm³ demonstrated SLN metastasis,⁴ suggesting that volume assessment may aid in consideration of staging with SLN biopsy in conjunction with tumor thickness and other established prognostic factors for SLN positivity in thin melanomas (eg, high mitotic index [particularly in tumors >0.75-mm thick]), histologic ulceration, and/or lymphovascular invasion).^2,8

It should be noted, however, that lentigo maligna melanoma, which often is predominantly in situ with only focal papillary dermal invasion, may have an erroneously high tumor volume due to its larger total surface area. However, tumor volume would not be expected to correlate with tumor metastasis given the thin invasive component. The current study was limited by not accounting for melanoma subtype in the overall analysis.

A practical estimation of tumor volume based on clinical measurement of tumor size (ie, surface area of the suspicious lesion prior to biopsy) in combination with the pathologist’s assessment of Breslow depth may be a helpful adjunct to predicting likelihood of development of metastasis. We suggest that the concept of tumor volume should be subjected to more rigorous investigation with standardized clinical/prebiopsy measurement of the lesion; correlation with known histologic prognostic factors, SLN positivity, and/or development of additional nodal or visceral metastasis; and most importantly long-term patient outcome in terms of survival. Our preliminary data suggest the value of this enterprise.

The addition of sargramostim to ipilimumab therapy for unresectable stage III or IV melanoma may improve overall survival and toxicity, but it does not appear to affect progression-free survival, results from a phase II randomized trial suggest.

Patients randomized to receive ipilimumab plus sargramostim showed significantly lower mortality at 1 year, compared with those treated with ipilimumab alone (hazard ratio, 0.64), and they experienced significantly fewer grade 3 or above treatment-related toxicities, particularly gastrointestinal toxicities such as colonic perforation.

“The improved toxicity profile must be considered as contributing to the improved survival even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded,” wrote Dr. F. Stephen Hodi of the Dana-Farber Cancer Institute, Boston, and colleagues.

Researchers stressed that the study, which enrolled a total of 245 patients, is ongoing, and that the findings need to be confirmed in larger studies with longer follow-up, according to a paper published online Nov. 4 (JAMA 2014 [doi:10.1001/jama.2014.13943].

The study was supported by Public Health Service grants, the Eastern Cooperative Oncology Group, the U.S. National Cancer Institute, the U.S. National Institutes of Health, the U.S. Department of Health & Human Services, Bristol-Myers Squibb, and Genzyme. Some authors reported grants, personal fees, and support from pharmaceutical companies, including Bristol-Myers Squibb and Genzyme.

The addition of sargramostim to ipilimumab therapy for unresectable stage III or IV melanoma may improve overall survival and toxicity, but it does not appear to affect progression-free survival, results from a phase II randomized trial suggest.

Patients randomized to receive ipilimumab plus sargramostim showed significantly lower mortality at 1 year, compared with those treated with ipilimumab alone (hazard ratio, 0.64), and they experienced significantly fewer grade 3 or above treatment-related toxicities, particularly gastrointestinal toxicities such as colonic perforation.

“The improved toxicity profile must be considered as contributing to the improved survival even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded,” wrote Dr. F. Stephen Hodi of the Dana-Farber Cancer Institute, Boston, and colleagues.

Researchers stressed that the study, which enrolled a total of 245 patients, is ongoing, and that the findings need to be confirmed in larger studies with longer follow-up, according to a paper published online Nov. 4 (JAMA 2014 [doi:10.1001/jama.2014.13943].

The study was supported by Public Health Service grants, the Eastern Cooperative Oncology Group, the U.S. National Cancer Institute, the U.S. National Institutes of Health, the U.S. Department of Health & Human Services, Bristol-Myers Squibb, and Genzyme. Some authors reported grants, personal fees, and support from pharmaceutical companies, including Bristol-Myers Squibb and Genzyme.

The addition of sargramostim to ipilimumab therapy for unresectable stage III or IV melanoma may improve overall survival and toxicity, but it does not appear to affect progression-free survival, results from a phase II randomized trial suggest.

Patients randomized to receive ipilimumab plus sargramostim showed significantly lower mortality at 1 year, compared with those treated with ipilimumab alone (hazard ratio, 0.64), and they experienced significantly fewer grade 3 or above treatment-related toxicities, particularly gastrointestinal toxicities such as colonic perforation.

“The improved toxicity profile must be considered as contributing to the improved survival even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded,” wrote Dr. F. Stephen Hodi of the Dana-Farber Cancer Institute, Boston, and colleagues.

Researchers stressed that the study, which enrolled a total of 245 patients, is ongoing, and that the findings need to be confirmed in larger studies with longer follow-up, according to a paper published online Nov. 4 (JAMA 2014 [doi:10.1001/jama.2014.13943].

The study was supported by Public Health Service grants, the Eastern Cooperative Oncology Group, the U.S. National Cancer Institute, the U.S. National Institutes of Health, the U.S. Department of Health & Human Services, Bristol-Myers Squibb, and Genzyme. Some authors reported grants, personal fees, and support from pharmaceutical companies, including Bristol-Myers Squibb and Genzyme.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

MADRID – More complete blockade of the MAP kinase pathway with both a BRAF and MEK inhibitor decreased the risk of death by one-third among patients with advanced BRAF mutation–positive melanoma in the phase III COMBI-v study.

After a median follow-up of 10-11 months, the primary endpoint of overall survival was 17.2 months with the BRAF inhibitor vemurafenib (Zelboraf) alone, but had not been reached with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) (hazard ratio, 0.69; P = .005).

Patrice Wendling/Frontline Medical News

“This combination has met all the endpoints that were looked for, and I’d like to remind you that we compared this combination to an already very active drug,” study author Dr. Caroline Robert, head of dermatology at the Institut Gustave Roussy in Paris, said during a presidential session at the European Society for Medical Oncology Congress.

Patients in the combination arm had significantly better median progression-free survival than those given vemurafenib monotherapy (11.4 vs. 7.3 months; HR, 0.56; P < .001), as well as higher response rates (64% vs. 51%; P < .001), more complete responses (13% vs. 8%), and a longer duration of response (13.8 vs. 7.5 months).

COMBI-v was stopped early for efficacy at the interim analysis, which de facto became the final overall survival analysis presented by Dr. Robert.

The study evenly randomized 704 patients with stage IIIC or IV BRAF V600E or V600K mutation–positive melanoma to first-line therapy with twice-daily dabrafenib 150 mg plus daily trametinib 2 mg or twice-daily vemurafenib 960 mg.

The study sponsor, GlaxoSmithKline, gained accelerated approval in the United States in January 2014 for use of combination dabrafenib and trametinib in unresectable BRAF V600E or V600K mutation–positive melanoma based on positive response data.

The strategy of up-front BRAF and MEK inhibition in BRAF-mutant unresectable disease was supported by data presented in the same session from the coBRIM study, where treatment with vemurafenib and the investigational MEK inhibitor cobimetinib improved progression-free survival, response rates, and overall survival, although the overall survival data are immature. Listen to our interview with coBRIM study author Dr. Grant McArthur.

Dr. Christian Blank, from the Netherlands Cancer Institute in Amsterdam, who was invited to discuss both studies, commented that the combinations used in COMBI-v and coBRIM had similar toxicity to that of single-agent treatment, and that if mature data confirm the presented observations, combined BRAF and MEK inhibition is the new standard therapy for patients with BRAF V600 melanoma.

In COMBI-v, patients receiving dabrafenib plus trametinib, as compared with vemurafenib alone, had more pyrexia (53% vs. 21%), chills (31% vs. 8%), and decreases in ejection fraction (8% vs. 0%), although the latter was easily reversible without sequelae, Dr. Robert stressed. The addition of a MEK inhibitor, however, reduced BRAF inhibitor–related adverse skin events such as cutaneous squamous cell carcinoma and keratoacanthoma (1% vs. 18%), as well as photosensitivity (4% vs. 36%).

GlaxoSmithKline funded the study. Dr. Robert reported serving as a consultant to GlaxoSmithKline, Roche, Bristol-Myers Squibb, Amgen, Novartis, and Merck. Dr. Blank disclosed an advisory role with GSK, Roche, BMS, MSD, and Novartis, honoraria from GSK, Roche, BMS, and MSD, and a research grant from Novartis.

[email protected]

MADRID – More complete blockade of the MAP kinase pathway with both a BRAF and MEK inhibitor decreased the risk of death by one-third among patients with advanced BRAF mutation–positive melanoma in the phase III COMBI-v study.

After a median follow-up of 10-11 months, the primary endpoint of overall survival was 17.2 months with the BRAF inhibitor vemurafenib (Zelboraf) alone, but had not been reached with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) (hazard ratio, 0.69; P = .005).

Patrice Wendling/Frontline Medical News

“This combination has met all the endpoints that were looked for, and I’d like to remind you that we compared this combination to an already very active drug,” study author Dr. Caroline Robert, head of dermatology at the Institut Gustave Roussy in Paris, said during a presidential session at the European Society for Medical Oncology Congress.

Patients in the combination arm had significantly better median progression-free survival than those given vemurafenib monotherapy (11.4 vs. 7.3 months; HR, 0.56; P < .001), as well as higher response rates (64% vs. 51%; P < .001), more complete responses (13% vs. 8%), and a longer duration of response (13.8 vs. 7.5 months).

COMBI-v was stopped early for efficacy at the interim analysis, which de facto became the final overall survival analysis presented by Dr. Robert.

The study evenly randomized 704 patients with stage IIIC or IV BRAF V600E or V600K mutation–positive melanoma to first-line therapy with twice-daily dabrafenib 150 mg plus daily trametinib 2 mg or twice-daily vemurafenib 960 mg.

The study sponsor, GlaxoSmithKline, gained accelerated approval in the United States in January 2014 for use of combination dabrafenib and trametinib in unresectable BRAF V600E or V600K mutation–positive melanoma based on positive response data.

The strategy of up-front BRAF and MEK inhibition in BRAF-mutant unresectable disease was supported by data presented in the same session from the coBRIM study, where treatment with vemurafenib and the investigational MEK inhibitor cobimetinib improved progression-free survival, response rates, and overall survival, although the overall survival data are immature. Listen to our interview with coBRIM study author Dr. Grant McArthur.

Dr. Christian Blank, from the Netherlands Cancer Institute in Amsterdam, who was invited to discuss both studies, commented that the combinations used in COMBI-v and coBRIM had similar toxicity to that of single-agent treatment, and that if mature data confirm the presented observations, combined BRAF and MEK inhibition is the new standard therapy for patients with BRAF V600 melanoma.

In COMBI-v, patients receiving dabrafenib plus trametinib, as compared with vemurafenib alone, had more pyrexia (53% vs. 21%), chills (31% vs. 8%), and decreases in ejection fraction (8% vs. 0%), although the latter was easily reversible without sequelae, Dr. Robert stressed. The addition of a MEK inhibitor, however, reduced BRAF inhibitor–related adverse skin events such as cutaneous squamous cell carcinoma and keratoacanthoma (1% vs. 18%), as well as photosensitivity (4% vs. 36%).

GlaxoSmithKline funded the study. Dr. Robert reported serving as a consultant to GlaxoSmithKline, Roche, Bristol-Myers Squibb, Amgen, Novartis, and Merck. Dr. Blank disclosed an advisory role with GSK, Roche, BMS, MSD, and Novartis, honoraria from GSK, Roche, BMS, and MSD, and a research grant from Novartis.

[email protected]

MADRID – More complete blockade of the MAP kinase pathway with both a BRAF and MEK inhibitor decreased the risk of death by one-third among patients with advanced BRAF mutation–positive melanoma in the phase III COMBI-v study.

After a median follow-up of 10-11 months, the primary endpoint of overall survival was 17.2 months with the BRAF inhibitor vemurafenib (Zelboraf) alone, but had not been reached with the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) (hazard ratio, 0.69; P = .005).

Patrice Wendling/Frontline Medical News

“This combination has met all the endpoints that were looked for, and I’d like to remind you that we compared this combination to an already very active drug,” study author Dr. Caroline Robert, head of dermatology at the Institut Gustave Roussy in Paris, said during a presidential session at the European Society for Medical Oncology Congress.

Patients in the combination arm had significantly better median progression-free survival than those given vemurafenib monotherapy (11.4 vs. 7.3 months; HR, 0.56; P < .001), as well as higher response rates (64% vs. 51%; P < .001), more complete responses (13% vs. 8%), and a longer duration of response (13.8 vs. 7.5 months).

COMBI-v was stopped early for efficacy at the interim analysis, which de facto became the final overall survival analysis presented by Dr. Robert.

The study evenly randomized 704 patients with stage IIIC or IV BRAF V600E or V600K mutation–positive melanoma to first-line therapy with twice-daily dabrafenib 150 mg plus daily trametinib 2 mg or twice-daily vemurafenib 960 mg.

The study sponsor, GlaxoSmithKline, gained accelerated approval in the United States in January 2014 for use of combination dabrafenib and trametinib in unresectable BRAF V600E or V600K mutation–positive melanoma based on positive response data.

The strategy of up-front BRAF and MEK inhibition in BRAF-mutant unresectable disease was supported by data presented in the same session from the coBRIM study, where treatment with vemurafenib and the investigational MEK inhibitor cobimetinib improved progression-free survival, response rates, and overall survival, although the overall survival data are immature. Listen to our interview with coBRIM study author Dr. Grant McArthur.

Dr. Christian Blank, from the Netherlands Cancer Institute in Amsterdam, who was invited to discuss both studies, commented that the combinations used in COMBI-v and coBRIM had similar toxicity to that of single-agent treatment, and that if mature data confirm the presented observations, combined BRAF and MEK inhibition is the new standard therapy for patients with BRAF V600 melanoma.

In COMBI-v, patients receiving dabrafenib plus trametinib, as compared with vemurafenib alone, had more pyrexia (53% vs. 21%), chills (31% vs. 8%), and decreases in ejection fraction (8% vs. 0%), although the latter was easily reversible without sequelae, Dr. Robert stressed. The addition of a MEK inhibitor, however, reduced BRAF inhibitor–related adverse skin events such as cutaneous squamous cell carcinoma and keratoacanthoma (1% vs. 18%), as well as photosensitivity (4% vs. 36%).

GlaxoSmithKline funded the study. Dr. Robert reported serving as a consultant to GlaxoSmithKline, Roche, Bristol-Myers Squibb, Amgen, Novartis, and Merck. Dr. Blank disclosed an advisory role with GSK, Roche, BMS, MSD, and Novartis, honoraria from GSK, Roche, BMS, and MSD, and a research grant from Novartis.

[email protected]

MADRID – The investigational anti-PD-1 drug nivolumab bested investigator’s choice of chemotherapy in pretreated advanced melanoma in the phase III CheckMate-037 trial.

The coprimary end point of objective response rate by central review was 32% with nivolumab vs. 11% with investigator’s choice chemotherapy among patients with unresectable metastatic melanoma that progressed despite prior ipilimumab or a BRAF inhibitor, if BRAF mutation-positive.

The median duration of response for chemotherapy was 3.6 months, but has not been reached with nivolumab. Five patients on chemotherapy continue to respond, whereas 95% of nivolumab responders (36/38) continue in remission with a minimum follow-up of 24 weeks, Dr. Jeffrey Weber reported during a presidential symposium at the European Society for Medical Oncology Congress.

Patrice Wendling/Frontline Medical News

Grade 3-4 treatment-related adverse events also were significantly lower with nivolumab than with chemotherapy (9% vs. 31%), as were toxicity-related treatment discontinuations (2% vs. 8%).

“Overall nivolumab was superior to chemotherapy in terms of toxicity and response rate in patients that fail prior ipilimumab and in my view should replace chemotherapy in practice for second-line or even third-line melanoma,” said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, Fla.

Survival data are pending, but the impressive data on duration of response suggest there will be significant prolongation of progression-free and overall survival with the programmed death (PD)-1 blocking antibody when the analysis of those data is mature, Dr. Weber said in a statement.

Nivolumab is under priority review with the Food and Drug Administration and accelerated assessment with the European Medicines Agency based on these data. The drug is already approved for unresectable melanoma in Japan, where it is sold under the trade name Opdivo.

Dr. Weber told reporters in a press briefing that he rarely uses chemotherapy in his practice for patients with melanoma. This sentiment was echoed by invited discussant Ignacio Melero of the University of Navarra, Pamplona, Spain. “The trends that one can foresee are that we will be moving PD-1 blockade up front in treatment and will probably get rid of chemotherapy or save it as a last-ditch effort,” said Dr. Melero.

Patrice Wendling/Frontline Medical News

He added that the “best is yet to come,” and that this is particularly true about immunotherapy combinations. Dr. Melero highlighted recent phase I data for pembrolizumab (Keytruda), which just gained approval in September as the first PD-1 checkpoint inhibitor in the United States in advanced melanoma. The overall response rate with pembrolizumab was in the same range as nivolumab at 26% and overall survival was “impressive,” with the median not yet reached after 14 months in patients who also had ipilimumab-refractory advanced melanoma (Lancet 2014;384:1109-17).

CheckMate-037 randomized 405 patients in a 2:1 fashion to intravenous nivolumab 3 mg/kg or investigator’s choice of chemotherapy regimens: dacarbazine 1,000 mg/m2 or carboplatin AUC 6 plus paclitaxel 175 mg/m2 . Response data were based on 120 patients in the nivolumab and 47 in the chemotherapy arm, and safety data were based on the entire population. The best overall response in the nivolumab arm was complete response in 3%, partial response in 28%, and stable disease in 23%, compared with 0%, 11%, and 34%, respectively, in the chemotherapy arm.

Subgroup analysis revealed consistently higher clinical activity with nivolumab regardless of pretreatment PD-ligand 1 expression status, BRAF mutation status, or prior ipilimumab benefit, Dr. Weber said.

Ten patients (8%) given nivolumab had an immune-related response pattern involving 30% or more reduction in target lesion tumor burden.

Dr. Weber reported serving on the advisory board for Genentech, Merck, and the study sponsor, Bristol-Myers Squibb. His institution also receives research funding from BMS and Genentech.

[email protected]

MADRID – The investigational anti-PD-1 drug nivolumab bested investigator’s choice of chemotherapy in pretreated advanced melanoma in the phase III CheckMate-037 trial.

The coprimary end point of objective response rate by central review was 32% with nivolumab vs. 11% with investigator’s choice chemotherapy among patients with unresectable metastatic melanoma that progressed despite prior ipilimumab or a BRAF inhibitor, if BRAF mutation-positive.

The median duration of response for chemotherapy was 3.6 months, but has not been reached with nivolumab. Five patients on chemotherapy continue to respond, whereas 95% of nivolumab responders (36/38) continue in remission with a minimum follow-up of 24 weeks, Dr. Jeffrey Weber reported during a presidential symposium at the European Society for Medical Oncology Congress.

Patrice Wendling/Frontline Medical News

Grade 3-4 treatment-related adverse events also were significantly lower with nivolumab than with chemotherapy (9% vs. 31%), as were toxicity-related treatment discontinuations (2% vs. 8%).

“Overall nivolumab was superior to chemotherapy in terms of toxicity and response rate in patients that fail prior ipilimumab and in my view should replace chemotherapy in practice for second-line or even third-line melanoma,” said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, Fla.

Survival data are pending, but the impressive data on duration of response suggest there will be significant prolongation of progression-free and overall survival with the programmed death (PD)-1 blocking antibody when the analysis of those data is mature, Dr. Weber said in a statement.

Nivolumab is under priority review with the Food and Drug Administration and accelerated assessment with the European Medicines Agency based on these data. The drug is already approved for unresectable melanoma in Japan, where it is sold under the trade name Opdivo.

Dr. Weber told reporters in a press briefing that he rarely uses chemotherapy in his practice for patients with melanoma. This sentiment was echoed by invited discussant Ignacio Melero of the University of Navarra, Pamplona, Spain. “The trends that one can foresee are that we will be moving PD-1 blockade up front in treatment and will probably get rid of chemotherapy or save it as a last-ditch effort,” said Dr. Melero.

Patrice Wendling/Frontline Medical News

He added that the “best is yet to come,” and that this is particularly true about immunotherapy combinations. Dr. Melero highlighted recent phase I data for pembrolizumab (Keytruda), which just gained approval in September as the first PD-1 checkpoint inhibitor in the United States in advanced melanoma. The overall response rate with pembrolizumab was in the same range as nivolumab at 26% and overall survival was “impressive,” with the median not yet reached after 14 months in patients who also had ipilimumab-refractory advanced melanoma (Lancet 2014;384:1109-17).

CheckMate-037 randomized 405 patients in a 2:1 fashion to intravenous nivolumab 3 mg/kg or investigator’s choice of chemotherapy regimens: dacarbazine 1,000 mg/m2 or carboplatin AUC 6 plus paclitaxel 175 mg/m2 . Response data were based on 120 patients in the nivolumab and 47 in the chemotherapy arm, and safety data were based on the entire population. The best overall response in the nivolumab arm was complete response in 3%, partial response in 28%, and stable disease in 23%, compared with 0%, 11%, and 34%, respectively, in the chemotherapy arm.

Subgroup analysis revealed consistently higher clinical activity with nivolumab regardless of pretreatment PD-ligand 1 expression status, BRAF mutation status, or prior ipilimumab benefit, Dr. Weber said.

Ten patients (8%) given nivolumab had an immune-related response pattern involving 30% or more reduction in target lesion tumor burden.

Dr. Weber reported serving on the advisory board for Genentech, Merck, and the study sponsor, Bristol-Myers Squibb. His institution also receives research funding from BMS and Genentech.

[email protected]

MADRID – The investigational anti-PD-1 drug nivolumab bested investigator’s choice of chemotherapy in pretreated advanced melanoma in the phase III CheckMate-037 trial.

The coprimary end point of objective response rate by central review was 32% with nivolumab vs. 11% with investigator’s choice chemotherapy among patients with unresectable metastatic melanoma that progressed despite prior ipilimumab or a BRAF inhibitor, if BRAF mutation-positive.

The median duration of response for chemotherapy was 3.6 months, but has not been reached with nivolumab. Five patients on chemotherapy continue to respond, whereas 95% of nivolumab responders (36/38) continue in remission with a minimum follow-up of 24 weeks, Dr. Jeffrey Weber reported during a presidential symposium at the European Society for Medical Oncology Congress.

Patrice Wendling/Frontline Medical News

Grade 3-4 treatment-related adverse events also were significantly lower with nivolumab than with chemotherapy (9% vs. 31%), as were toxicity-related treatment discontinuations (2% vs. 8%).

“Overall nivolumab was superior to chemotherapy in terms of toxicity and response rate in patients that fail prior ipilimumab and in my view should replace chemotherapy in practice for second-line or even third-line melanoma,” said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, Fla.

Survival data are pending, but the impressive data on duration of response suggest there will be significant prolongation of progression-free and overall survival with the programmed death (PD)-1 blocking antibody when the analysis of those data is mature, Dr. Weber said in a statement.

Nivolumab is under priority review with the Food and Drug Administration and accelerated assessment with the European Medicines Agency based on these data. The drug is already approved for unresectable melanoma in Japan, where it is sold under the trade name Opdivo.

Dr. Weber told reporters in a press briefing that he rarely uses chemotherapy in his practice for patients with melanoma. This sentiment was echoed by invited discussant Ignacio Melero of the University of Navarra, Pamplona, Spain. “The trends that one can foresee are that we will be moving PD-1 blockade up front in treatment and will probably get rid of chemotherapy or save it as a last-ditch effort,” said Dr. Melero.

Patrice Wendling/Frontline Medical News

He added that the “best is yet to come,” and that this is particularly true about immunotherapy combinations. Dr. Melero highlighted recent phase I data for pembrolizumab (Keytruda), which just gained approval in September as the first PD-1 checkpoint inhibitor in the United States in advanced melanoma. The overall response rate with pembrolizumab was in the same range as nivolumab at 26% and overall survival was “impressive,” with the median not yet reached after 14 months in patients who also had ipilimumab-refractory advanced melanoma (Lancet 2014;384:1109-17).

CheckMate-037 randomized 405 patients in a 2:1 fashion to intravenous nivolumab 3 mg/kg or investigator’s choice of chemotherapy regimens: dacarbazine 1,000 mg/m2 or carboplatin AUC 6 plus paclitaxel 175 mg/m2 . Response data were based on 120 patients in the nivolumab and 47 in the chemotherapy arm, and safety data were based on the entire population. The best overall response in the nivolumab arm was complete response in 3%, partial response in 28%, and stable disease in 23%, compared with 0%, 11%, and 34%, respectively, in the chemotherapy arm.

Subgroup analysis revealed consistently higher clinical activity with nivolumab regardless of pretreatment PD-ligand 1 expression status, BRAF mutation status, or prior ipilimumab benefit, Dr. Weber said.

Ten patients (8%) given nivolumab had an immune-related response pattern involving 30% or more reduction in target lesion tumor burden.

Dr. Weber reported serving on the advisory board for Genentech, Merck, and the study sponsor, Bristol-Myers Squibb. His institution also receives research funding from BMS and Genentech.

[email protected]

ORLANDO – Squamous cell carcinoma has a direct cost of nearly $300 million a year. Although squamous cell carcinoma (SCC) is not as deadly as other forms of skin cancer, it is a serious public health issue, according to Dr. Chrysalyne D. Schmults.

Dr. Schmults of Harvard Medical School and the Brigham and Women’s Hospital, Boston, published a study earlier this year introducing a new staging system for SCC, called the Brigham and Women’s Hospital (BWH) tumor staging system.

The BWH system, Dr. Schmults and her colleagues wrote, “offers improved distinctiveness, homogeneity, and monotonicity” over both the American Joint Committee on Cancer and International Union Against Cancer staging systems, although larger studies are needed.

In a video interview at the annual meeting of the Florida Society of Dermatologic Surgeons, Dr. Schmults explained the BWH staging system and shared her clinical advice and recommendations for managing SCC.

[email protected]

On Twitter @naseemmiller

ORLANDO – Squamous cell carcinoma has a direct cost of nearly $300 million a year. Although squamous cell carcinoma (SCC) is not as deadly as other forms of skin cancer, it is a serious public health issue, according to Dr. Chrysalyne D. Schmults.

Dr. Schmults of Harvard Medical School and the Brigham and Women’s Hospital, Boston, published a study earlier this year introducing a new staging system for SCC, called the Brigham and Women’s Hospital (BWH) tumor staging system.

The BWH system, Dr. Schmults and her colleagues wrote, “offers improved distinctiveness, homogeneity, and monotonicity” over both the American Joint Committee on Cancer and International Union Against Cancer staging systems, although larger studies are needed.

In a video interview at the annual meeting of the Florida Society of Dermatologic Surgeons, Dr. Schmults explained the BWH staging system and shared her clinical advice and recommendations for managing SCC.

[email protected]

On Twitter @naseemmiller

ORLANDO – Squamous cell carcinoma has a direct cost of nearly $300 million a year. Although squamous cell carcinoma (SCC) is not as deadly as other forms of skin cancer, it is a serious public health issue, according to Dr. Chrysalyne D. Schmults.

Dr. Schmults of Harvard Medical School and the Brigham and Women’s Hospital, Boston, published a study earlier this year introducing a new staging system for SCC, called the Brigham and Women’s Hospital (BWH) tumor staging system.

The BWH system, Dr. Schmults and her colleagues wrote, “offers improved distinctiveness, homogeneity, and monotonicity” over both the American Joint Committee on Cancer and International Union Against Cancer staging systems, although larger studies are needed.

In a video interview at the annual meeting of the Florida Society of Dermatologic Surgeons, Dr. Schmults explained the BWH staging system and shared her clinical advice and recommendations for managing SCC.

[email protected]

On Twitter @naseemmiller

To the Editor:
Primary malignant melanoma (PMM) of the penis is rare, comprising 1% of melanomas overall and less than 4% of malignancies in the male genitourinary tract.¹ However, regression of PMM is not rare. Melanoma is 6 times more likely to undergo regression compared to other malignancies.² Approximately 10% to 35% of cutaneous PMMs undergo partial regression, but only 42 cases of completely regressed cutaneous PMMs have been reported,^3,4 which may be due to underreporting of completely regressed cutaneous PMMs, as they often are clinically inconspicuous. Additionally, completely regressed cutaneous PMMs may be incorrectly reported as metastatic melanoma of unknown primary.⁵ Clinical characteristics of regression include pink coloration and a lightening or whitening of baseline lesional color. Dermatoscopic features of regression include white areas, blue areas, or vascular structures that translate microscopically to dermal fibrosis, melanophages, and telangiectases.⁵ We report a case of complete clinical regression of a nodular, mucosal, penile PMM with no evidence of metastatic disease.

An 86-year-old man presented with a progressively enlarging, pigmented lesion on the glans penis of 2 years’ duration. His medical history was notable for retinal detachment, macular degeneration, lumbar stenosis, and seizures postneurosurgery for a subdural hematoma. Physical examination revealed a healthy man with a mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis (Figure 1). No other similar skin lesions or lymphadenopathy were detectable. A lesional deep shave biopsy obtained at presentation demonstrated a nodular-type malignant melanoma with a Breslow thickness of approximately 3.5 mm (Figure 2).

Figure 1. Mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis.

Figure 2. Histologic section showed a nodular melanocytic proliferation with a dense sheetlike collection of melanocytes, predominantly in the dermis (H&E, original magnification ×20). Prominent cytologic atypia and multiple mitotic figures were consistent with melanoma (inset)(H&E, original magnification ×400).

Figure 3. High-power view of HMB-45 stain showed strong and diffuse staining, including several pagetoid intraepidermal melanocytes (original magnification ×200).

Figure 4. Skin examination 8 years following the initial primary malignant melanoma diagnosis showed no clinical evidence of recurrent or metastatic melanoma and almost complete loss of pigmentation at the prior melanoma site.

Histologic examination showed nodular nests of malignant melanocytes that were dispersed along the dermal-epidermal junction and coalesced into sheets within the dermis. Numerous dermal mitoses were present. The tumor was strongly and diffusely positive with Melan-A and HMB-45, which also highlighted scattered pagetoid intraepidermal cells (Figure 3). These findings were diagnostic of PMM of the mucocutaneous glans penis. The tumor was nonulcerated and invaded to a Breslow thickness of approximately 3.5 mm, corresponding to American Joint Committee on Cancer stage IIA (T3aN0M0) with an expected 5-year survival rate of 79%.⁶

He was referred to the urology department and was offered cystoscopy, urethrography, and phallectomy, which he refused. He also refused a trial of imiquimod. Computed tomography (CT) scans of his brain, chest, abdomen, and pelvis were negative for metastatic disease. Following the initial melanoma diagnosis, he had yearly dermatologic evaluations consisting of total-body skin and lymph node (LN) examinations. At 87 years of age (1 year following the initial diagnosis), the melanoma became dramatically smaller. At 88 years of age (2 years after diagnosis), the melanoma had near-complete clinical resolution. At 89 years of age, the patient reported asymmetric hearing loss. A cranial magnetic resonance imaging study showed no evidence of metastases.

At 92 years of age (6 years after the initial diagnosis), the patient reported bilateral leg pain. A CT scan of the lumbar spine showed no evidence of metastasis. He also reported abdominal pain. A CT scan of the abdomen and pelvis revealed an ileocecal mass. Biopsy of the ileocecal mass showed moderately differentiated invasive adenocarcinoma and no evidence of metastatic melanoma. The adenocarcinoma was resected and he continues to do well. Skin and LN examination 8 years after the initial diagnosis showed no clinical evidence of recurrent penile mucosal melanoma or metastatic melanoma (Figure 4). The PMM appeared to have clinically regressed spontaneously. He refused repeat skin biopsy and additional imaging studies.

The criteria for complete melanoma regression were initially described in 1965⁷ and revised in 2005.² Although our patient demonstrated complete clinical regression of his PMM, he did not meet the revised criteria for complete regression because there was no histopathologic confirmation of regression or of the absence of melanoma as well as no lymphatic involvement. It is extremely difficult to quantify the percentage of PMMs that completely regress. A case of a completely regressed untreated PMM with no metastatic disease 4 years after diagnosis has been reported. This case involved a nonulcerated melanoma with a Breslow thickness of 0.7 mm (American Joint Committee on Cancer stage IA).⁴ The prognosis of penile mucosal PMM is comparable to that of cutaneous PMM with a similar Breslow thickness.¹

The prognostic significance of melanoma regression is controversial. Regression may be mediated by host immunity, apoptosis, and/or antiangiogenesis. The lymphocytic infiltrate in regressive melanomas consists of cytotoxic T cells with selective antitumor activity, which induces HLA class I–restricted melanoma lysis.⁸ Lymph node migration may result in T-lymphocyte priming and induction of antitumor immunity.⁹ Therefore, regression may indicate risk for sentinel LN metastasis.

It is possible that complete regression of melanoma does not truly exist, and late recurrence due to cancer dormancy is inevitable. Late recurrence is defined as first metastasis 10 years after complete removal of the PMM.¹⁰ Our patient has only been followed for 8 years, so this possibility cannot be entirely excluded.

To the Editor:
Primary malignant melanoma (PMM) of the penis is rare, comprising 1% of melanomas overall and less than 4% of malignancies in the male genitourinary tract.¹ However, regression of PMM is not rare. Melanoma is 6 times more likely to undergo regression compared to other malignancies.² Approximately 10% to 35% of cutaneous PMMs undergo partial regression, but only 42 cases of completely regressed cutaneous PMMs have been reported,^3,4 which may be due to underreporting of completely regressed cutaneous PMMs, as they often are clinically inconspicuous. Additionally, completely regressed cutaneous PMMs may be incorrectly reported as metastatic melanoma of unknown primary.⁵ Clinical characteristics of regression include pink coloration and a lightening or whitening of baseline lesional color. Dermatoscopic features of regression include white areas, blue areas, or vascular structures that translate microscopically to dermal fibrosis, melanophages, and telangiectases.⁵ We report a case of complete clinical regression of a nodular, mucosal, penile PMM with no evidence of metastatic disease.

An 86-year-old man presented with a progressively enlarging, pigmented lesion on the glans penis of 2 years’ duration. His medical history was notable for retinal detachment, macular degeneration, lumbar stenosis, and seizures postneurosurgery for a subdural hematoma. Physical examination revealed a healthy man with a mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis (Figure 1). No other similar skin lesions or lymphadenopathy were detectable. A lesional deep shave biopsy obtained at presentation demonstrated a nodular-type malignant melanoma with a Breslow thickness of approximately 3.5 mm (Figure 2).

Figure 1. Mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis.

Figure 2. Histologic section showed a nodular melanocytic proliferation with a dense sheetlike collection of melanocytes, predominantly in the dermis (H&E, original magnification ×20). Prominent cytologic atypia and multiple mitotic figures were consistent with melanoma (inset)(H&E, original magnification ×400).

Figure 3. High-power view of HMB-45 stain showed strong and diffuse staining, including several pagetoid intraepidermal melanocytes (original magnification ×200).

Figure 4. Skin examination 8 years following the initial primary malignant melanoma diagnosis showed no clinical evidence of recurrent or metastatic melanoma and almost complete loss of pigmentation at the prior melanoma site.

Histologic examination showed nodular nests of malignant melanocytes that were dispersed along the dermal-epidermal junction and coalesced into sheets within the dermis. Numerous dermal mitoses were present. The tumor was strongly and diffusely positive with Melan-A and HMB-45, which also highlighted scattered pagetoid intraepidermal cells (Figure 3). These findings were diagnostic of PMM of the mucocutaneous glans penis. The tumor was nonulcerated and invaded to a Breslow thickness of approximately 3.5 mm, corresponding to American Joint Committee on Cancer stage IIA (T3aN0M0) with an expected 5-year survival rate of 79%.⁶

He was referred to the urology department and was offered cystoscopy, urethrography, and phallectomy, which he refused. He also refused a trial of imiquimod. Computed tomography (CT) scans of his brain, chest, abdomen, and pelvis were negative for metastatic disease. Following the initial melanoma diagnosis, he had yearly dermatologic evaluations consisting of total-body skin and lymph node (LN) examinations. At 87 years of age (1 year following the initial diagnosis), the melanoma became dramatically smaller. At 88 years of age (2 years after diagnosis), the melanoma had near-complete clinical resolution. At 89 years of age, the patient reported asymmetric hearing loss. A cranial magnetic resonance imaging study showed no evidence of metastases.

At 92 years of age (6 years after the initial diagnosis), the patient reported bilateral leg pain. A CT scan of the lumbar spine showed no evidence of metastasis. He also reported abdominal pain. A CT scan of the abdomen and pelvis revealed an ileocecal mass. Biopsy of the ileocecal mass showed moderately differentiated invasive adenocarcinoma and no evidence of metastatic melanoma. The adenocarcinoma was resected and he continues to do well. Skin and LN examination 8 years after the initial diagnosis showed no clinical evidence of recurrent penile mucosal melanoma or metastatic melanoma (Figure 4). The PMM appeared to have clinically regressed spontaneously. He refused repeat skin biopsy and additional imaging studies.

The criteria for complete melanoma regression were initially described in 1965⁷ and revised in 2005.² Although our patient demonstrated complete clinical regression of his PMM, he did not meet the revised criteria for complete regression because there was no histopathologic confirmation of regression or of the absence of melanoma as well as no lymphatic involvement. It is extremely difficult to quantify the percentage of PMMs that completely regress. A case of a completely regressed untreated PMM with no metastatic disease 4 years after diagnosis has been reported. This case involved a nonulcerated melanoma with a Breslow thickness of 0.7 mm (American Joint Committee on Cancer stage IA).⁴ The prognosis of penile mucosal PMM is comparable to that of cutaneous PMM with a similar Breslow thickness.¹

The prognostic significance of melanoma regression is controversial. Regression may be mediated by host immunity, apoptosis, and/or antiangiogenesis. The lymphocytic infiltrate in regressive melanomas consists of cytotoxic T cells with selective antitumor activity, which induces HLA class I–restricted melanoma lysis.⁸ Lymph node migration may result in T-lymphocyte priming and induction of antitumor immunity.⁹ Therefore, regression may indicate risk for sentinel LN metastasis.

It is possible that complete regression of melanoma does not truly exist, and late recurrence due to cancer dormancy is inevitable. Late recurrence is defined as first metastasis 10 years after complete removal of the PMM.¹⁰ Our patient has only been followed for 8 years, so this possibility cannot be entirely excluded.

To the Editor:
Primary malignant melanoma (PMM) of the penis is rare, comprising 1% of melanomas overall and less than 4% of malignancies in the male genitourinary tract.¹ However, regression of PMM is not rare. Melanoma is 6 times more likely to undergo regression compared to other malignancies.² Approximately 10% to 35% of cutaneous PMMs undergo partial regression, but only 42 cases of completely regressed cutaneous PMMs have been reported,^3,4 which may be due to underreporting of completely regressed cutaneous PMMs, as they often are clinically inconspicuous. Additionally, completely regressed cutaneous PMMs may be incorrectly reported as metastatic melanoma of unknown primary.⁵ Clinical characteristics of regression include pink coloration and a lightening or whitening of baseline lesional color. Dermatoscopic features of regression include white areas, blue areas, or vascular structures that translate microscopically to dermal fibrosis, melanophages, and telangiectases.⁵ We report a case of complete clinical regression of a nodular, mucosal, penile PMM with no evidence of metastatic disease.

An 86-year-old man presented with a progressively enlarging, pigmented lesion on the glans penis of 2 years’ duration. His medical history was notable for retinal detachment, macular degeneration, lumbar stenosis, and seizures postneurosurgery for a subdural hematoma. Physical examination revealed a healthy man with a mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis (Figure 1). No other similar skin lesions or lymphadenopathy were detectable. A lesional deep shave biopsy obtained at presentation demonstrated a nodular-type malignant melanoma with a Breslow thickness of approximately 3.5 mm (Figure 2).

Figure 1. Mottled, black-brown, macular, and nodular lesion with irregular margins and irregular shape on the glans penis.

Figure 2. Histologic section showed a nodular melanocytic proliferation with a dense sheetlike collection of melanocytes, predominantly in the dermis (H&E, original magnification ×20). Prominent cytologic atypia and multiple mitotic figures were consistent with melanoma (inset)(H&E, original magnification ×400).

Figure 3. High-power view of HMB-45 stain showed strong and diffuse staining, including several pagetoid intraepidermal melanocytes (original magnification ×200).

Figure 4. Skin examination 8 years following the initial primary malignant melanoma diagnosis showed no clinical evidence of recurrent or metastatic melanoma and almost complete loss of pigmentation at the prior melanoma site.

Histologic examination showed nodular nests of malignant melanocytes that were dispersed along the dermal-epidermal junction and coalesced into sheets within the dermis. Numerous dermal mitoses were present. The tumor was strongly and diffusely positive with Melan-A and HMB-45, which also highlighted scattered pagetoid intraepidermal cells (Figure 3). These findings were diagnostic of PMM of the mucocutaneous glans penis. The tumor was nonulcerated and invaded to a Breslow thickness of approximately 3.5 mm, corresponding to American Joint Committee on Cancer stage IIA (T3aN0M0) with an expected 5-year survival rate of 79%.⁶

He was referred to the urology department and was offered cystoscopy, urethrography, and phallectomy, which he refused. He also refused a trial of imiquimod. Computed tomography (CT) scans of his brain, chest, abdomen, and pelvis were negative for metastatic disease. Following the initial melanoma diagnosis, he had yearly dermatologic evaluations consisting of total-body skin and lymph node (LN) examinations. At 87 years of age (1 year following the initial diagnosis), the melanoma became dramatically smaller. At 88 years of age (2 years after diagnosis), the melanoma had near-complete clinical resolution. At 89 years of age, the patient reported asymmetric hearing loss. A cranial magnetic resonance imaging study showed no evidence of metastases.

At 92 years of age (6 years after the initial diagnosis), the patient reported bilateral leg pain. A CT scan of the lumbar spine showed no evidence of metastasis. He also reported abdominal pain. A CT scan of the abdomen and pelvis revealed an ileocecal mass. Biopsy of the ileocecal mass showed moderately differentiated invasive adenocarcinoma and no evidence of metastatic melanoma. The adenocarcinoma was resected and he continues to do well. Skin and LN examination 8 years after the initial diagnosis showed no clinical evidence of recurrent penile mucosal melanoma or metastatic melanoma (Figure 4). The PMM appeared to have clinically regressed spontaneously. He refused repeat skin biopsy and additional imaging studies.

The criteria for complete melanoma regression were initially described in 1965⁷ and revised in 2005.² Although our patient demonstrated complete clinical regression of his PMM, he did not meet the revised criteria for complete regression because there was no histopathologic confirmation of regression or of the absence of melanoma as well as no lymphatic involvement. It is extremely difficult to quantify the percentage of PMMs that completely regress. A case of a completely regressed untreated PMM with no metastatic disease 4 years after diagnosis has been reported. This case involved a nonulcerated melanoma with a Breslow thickness of 0.7 mm (American Joint Committee on Cancer stage IA).⁴ The prognosis of penile mucosal PMM is comparable to that of cutaneous PMM with a similar Breslow thickness.¹

The prognostic significance of melanoma regression is controversial. Regression may be mediated by host immunity, apoptosis, and/or antiangiogenesis. The lymphocytic infiltrate in regressive melanomas consists of cytotoxic T cells with selective antitumor activity, which induces HLA class I–restricted melanoma lysis.⁸ Lymph node migration may result in T-lymphocyte priming and induction of antitumor immunity.⁹ Therefore, regression may indicate risk for sentinel LN metastasis.

It is possible that complete regression of melanoma does not truly exist, and late recurrence due to cancer dormancy is inevitable. Late recurrence is defined as first metastasis 10 years after complete removal of the PMM.¹⁰ Our patient has only been followed for 8 years, so this possibility cannot be entirely excluded.

MADRID – Combining the investigational MEK inhibitor cobimetinib with the BRAF inhibitor vemurafenib nearly halved the risk of progression in previously untreated patients with BRAF-mutated advanced melanoma in the ongoing, phase III coBRIM study.

Median progression-free survival by investigator was 6.2 months with vemurafenib (Zelboraf) and 9.9 months with the combination (Hazard ratio 0.51; P less than .0001); by independent review, median progression-free survival was 6.0 months versus 11.3 months, respectively (HR, 0.60; P = .0003), study author Dr. Grant McArthur reported in a late-breaking abstract at the European Society for Medical Oncology Congress.

Combination therapy also resulted in a significantly higher objective response rate (68% vs. 45%; P less than .0001) and more complete responses (10% vs. 4%) among the 495 patients with unresectable, locally advanced or metastatic BRAF V600 mutation–positive disease.

Overall survival data are not yet mature, but the interim analysis showed a promising 35% reduction in the risk of death at 9 months (HR, 0.65), said Dr. McArthur of the Peter MacCallum Cancer Centre, Melbourne, Australia. The corresponding P value of .046 is descriptive, as it did not cross the prespecified stopping boundary for the interim analysis.

Grade 3 toxicity, albeit fairly common, was slightly higher with combination therapy vs. vemurafenib alone (65% vs. 59%). Adverse event–related treatment discontinuations were similar between arms (13% vs. 12%), he said.

The data, which were simultaneously published in the New England Journal of Medicine (2014 Sept. 29 [doi:10.1056/NEJMoa1408868]) are expected to be submitted to the U.S. Food and Drug Administration later this year for potential approval of cobimetinib. Vemurafenib was approved in the United States for late-stage or unresectable melanoma in August 2011.

In our video interview, Dr. McArthur discusses coBRIM and his suggestions for how clinicians may incorporate this novel strategy into practice.

coBRIM was funded by F. Hoffmann-LaRoche/Genentech. Dr. McArthur reported grants from Roche, Novartis, Pfizer, Millennium, and Celegene, and consulting for Provectus.

[email protected]

MADRID – Combining the investigational MEK inhibitor cobimetinib with the BRAF inhibitor vemurafenib nearly halved the risk of progression in previously untreated patients with BRAF-mutated advanced melanoma in the ongoing, phase III coBRIM study.

Median progression-free survival by investigator was 6.2 months with vemurafenib (Zelboraf) and 9.9 months with the combination (Hazard ratio 0.51; P less than .0001); by independent review, median progression-free survival was 6.0 months versus 11.3 months, respectively (HR, 0.60; P = .0003), study author Dr. Grant McArthur reported in a late-breaking abstract at the European Society for Medical Oncology Congress.

Combination therapy also resulted in a significantly higher objective response rate (68% vs. 45%; P less than .0001) and more complete responses (10% vs. 4%) among the 495 patients with unresectable, locally advanced or metastatic BRAF V600 mutation–positive disease.

Overall survival data are not yet mature, but the interim analysis showed a promising 35% reduction in the risk of death at 9 months (HR, 0.65), said Dr. McArthur of the Peter MacCallum Cancer Centre, Melbourne, Australia. The corresponding P value of .046 is descriptive, as it did not cross the prespecified stopping boundary for the interim analysis.

Grade 3 toxicity, albeit fairly common, was slightly higher with combination therapy vs. vemurafenib alone (65% vs. 59%). Adverse event–related treatment discontinuations were similar between arms (13% vs. 12%), he said.

The data, which were simultaneously published in the New England Journal of Medicine (2014 Sept. 29 [doi:10.1056/NEJMoa1408868]) are expected to be submitted to the U.S. Food and Drug Administration later this year for potential approval of cobimetinib. Vemurafenib was approved in the United States for late-stage or unresectable melanoma in August 2011.

In our video interview, Dr. McArthur discusses coBRIM and his suggestions for how clinicians may incorporate this novel strategy into practice.

coBRIM was funded by F. Hoffmann-LaRoche/Genentech. Dr. McArthur reported grants from Roche, Novartis, Pfizer, Millennium, and Celegene, and consulting for Provectus.

[email protected]

MADRID – Combining the investigational MEK inhibitor cobimetinib with the BRAF inhibitor vemurafenib nearly halved the risk of progression in previously untreated patients with BRAF-mutated advanced melanoma in the ongoing, phase III coBRIM study.

Median progression-free survival by investigator was 6.2 months with vemurafenib (Zelboraf) and 9.9 months with the combination (Hazard ratio 0.51; P less than .0001); by independent review, median progression-free survival was 6.0 months versus 11.3 months, respectively (HR, 0.60; P = .0003), study author Dr. Grant McArthur reported in a late-breaking abstract at the European Society for Medical Oncology Congress.

Combination therapy also resulted in a significantly higher objective response rate (68% vs. 45%; P less than .0001) and more complete responses (10% vs. 4%) among the 495 patients with unresectable, locally advanced or metastatic BRAF V600 mutation–positive disease.

Overall survival data are not yet mature, but the interim analysis showed a promising 35% reduction in the risk of death at 9 months (HR, 0.65), said Dr. McArthur of the Peter MacCallum Cancer Centre, Melbourne, Australia. The corresponding P value of .046 is descriptive, as it did not cross the prespecified stopping boundary for the interim analysis.

Grade 3 toxicity, albeit fairly common, was slightly higher with combination therapy vs. vemurafenib alone (65% vs. 59%). Adverse event–related treatment discontinuations were similar between arms (13% vs. 12%), he said.

The data, which were simultaneously published in the New England Journal of Medicine (2014 Sept. 29 [doi:10.1056/NEJMoa1408868]) are expected to be submitted to the U.S. Food and Drug Administration later this year for potential approval of cobimetinib. Vemurafenib was approved in the United States for late-stage or unresectable melanoma in August 2011.

In our video interview, Dr. McArthur discusses coBRIM and his suggestions for how clinicians may incorporate this novel strategy into practice.

coBRIM was funded by F. Hoffmann-LaRoche/Genentech. Dr. McArthur reported grants from Roche, Novartis, Pfizer, Millennium, and Celegene, and consulting for Provectus.

[email protected]

EDINBURGH – Contrary to the perception that most melanoma deaths result from thick melanomas, long-term data from Australia show that more people die who initially present with thin melanomas.

Among 4,218 Australians who died from melanoma between 1990 and 2009, thin melanomas (1 mm or less) accounted for 19% of melanoma deaths overall, but increased steadily from 14% of deaths in 1990-1994 to 23% in 2005-2009.

During the most recent time period (2005-2009), more people died from thin melanomas (296 deaths, 23%) than from thick melanomas more than 4 mm in thickness (186 deaths, 14%) or from metastatic presentations (207 deaths, 16%).

The number of deaths in the intermediate thickness categories was also higher for lesions of thickness 1.01-2.0 mm (272 deaths, 21%) than for lesions of thickness 2.01-4.0 mm (267 deaths, 20%).

The patterns of mortality were essentially unchanged when the analyses were restricted to patients with only one primary melanoma, Dr. David Whiteman and Dr. Catherine Olsen of the QIMR Berghofer Medical Research Institute, Brisbane, Australia, reported at the 15th World Congress on Cancers of the Skin.

The melanoma incidence has been rising steadily around the world, mostly because of the greater numbers of thin lesions being diagnosed. The perception that most people who die from melanoma present initially with thick lesions is widespread, but the veracity of this proposition has never been tested because population-based data describing total mortality by the thickness of the primary tumor are scarce, according to the researchers. They used linked histology and death data from the Queensland Cancer Registry, where notification of melanoma has been compulsory since 1982, to calculate age-standardized mortality rates for each year for all melanomas, and by thickness of the first primary lesion. Overall, 67% of patients were male, 68% presented with a single primary lesion, and 68% of all melanomas were thin (1 mm or less).

Deaths from melanoma were most common among those who were in the seventh and eighth decades of life, male, or had a melanoma arising on the trunk. As expected, the intervals from diagnosis to death were significantly shorter for thicker tumors than thinner tumors, Dr. Whiteman and Dr. Olsen noted in the poster presentation.

The average annual rate of change in melanoma mortality increased significantly for men for thin lesions and those of intermediate thickness. Mortality rates from metastatic lesions, however, declined during the observation period.

“From a public health perspective, it can be argued that primary prevention activities aimed at reducing the occurrence of melanoma in the entire population should be accorded the highest priority,” the authors concluded at the meeting, sponsored by the Skin Cancer Foundation.

[email protected]

EDINBURGH – Contrary to the perception that most melanoma deaths result from thick melanomas, long-term data from Australia show that more people die who initially present with thin melanomas.

Among 4,218 Australians who died from melanoma between 1990 and 2009, thin melanomas (1 mm or less) accounted for 19% of melanoma deaths overall, but increased steadily from 14% of deaths in 1990-1994 to 23% in 2005-2009.

During the most recent time period (2005-2009), more people died from thin melanomas (296 deaths, 23%) than from thick melanomas more than 4 mm in thickness (186 deaths, 14%) or from metastatic presentations (207 deaths, 16%).

The number of deaths in the intermediate thickness categories was also higher for lesions of thickness 1.01-2.0 mm (272 deaths, 21%) than for lesions of thickness 2.01-4.0 mm (267 deaths, 20%).

The patterns of mortality were essentially unchanged when the analyses were restricted to patients with only one primary melanoma, Dr. David Whiteman and Dr. Catherine Olsen of the QIMR Berghofer Medical Research Institute, Brisbane, Australia, reported at the 15th World Congress on Cancers of the Skin.

The melanoma incidence has been rising steadily around the world, mostly because of the greater numbers of thin lesions being diagnosed. The perception that most people who die from melanoma present initially with thick lesions is widespread, but the veracity of this proposition has never been tested because population-based data describing total mortality by the thickness of the primary tumor are scarce, according to the researchers. They used linked histology and death data from the Queensland Cancer Registry, where notification of melanoma has been compulsory since 1982, to calculate age-standardized mortality rates for each year for all melanomas, and by thickness of the first primary lesion. Overall, 67% of patients were male, 68% presented with a single primary lesion, and 68% of all melanomas were thin (1 mm or less).

Deaths from melanoma were most common among those who were in the seventh and eighth decades of life, male, or had a melanoma arising on the trunk. As expected, the intervals from diagnosis to death were significantly shorter for thicker tumors than thinner tumors, Dr. Whiteman and Dr. Olsen noted in the poster presentation.

The average annual rate of change in melanoma mortality increased significantly for men for thin lesions and those of intermediate thickness. Mortality rates from metastatic lesions, however, declined during the observation period.

“From a public health perspective, it can be argued that primary prevention activities aimed at reducing the occurrence of melanoma in the entire population should be accorded the highest priority,” the authors concluded at the meeting, sponsored by the Skin Cancer Foundation.

[email protected]

EDINBURGH – Contrary to the perception that most melanoma deaths result from thick melanomas, long-term data from Australia show that more people die who initially present with thin melanomas.

Among 4,218 Australians who died from melanoma between 1990 and 2009, thin melanomas (1 mm or less) accounted for 19% of melanoma deaths overall, but increased steadily from 14% of deaths in 1990-1994 to 23% in 2005-2009.

During the most recent time period (2005-2009), more people died from thin melanomas (296 deaths, 23%) than from thick melanomas more than 4 mm in thickness (186 deaths, 14%) or from metastatic presentations (207 deaths, 16%).

The number of deaths in the intermediate thickness categories was also higher for lesions of thickness 1.01-2.0 mm (272 deaths, 21%) than for lesions of thickness 2.01-4.0 mm (267 deaths, 20%).

The patterns of mortality were essentially unchanged when the analyses were restricted to patients with only one primary melanoma, Dr. David Whiteman and Dr. Catherine Olsen of the QIMR Berghofer Medical Research Institute, Brisbane, Australia, reported at the 15th World Congress on Cancers of the Skin.

The melanoma incidence has been rising steadily around the world, mostly because of the greater numbers of thin lesions being diagnosed. The perception that most people who die from melanoma present initially with thick lesions is widespread, but the veracity of this proposition has never been tested because population-based data describing total mortality by the thickness of the primary tumor are scarce, according to the researchers. They used linked histology and death data from the Queensland Cancer Registry, where notification of melanoma has been compulsory since 1982, to calculate age-standardized mortality rates for each year for all melanomas, and by thickness of the first primary lesion. Overall, 67% of patients were male, 68% presented with a single primary lesion, and 68% of all melanomas were thin (1 mm or less).

Deaths from melanoma were most common among those who were in the seventh and eighth decades of life, male, or had a melanoma arising on the trunk. As expected, the intervals from diagnosis to death were significantly shorter for thicker tumors than thinner tumors, Dr. Whiteman and Dr. Olsen noted in the poster presentation.

The average annual rate of change in melanoma mortality increased significantly for men for thin lesions and those of intermediate thickness. Mortality rates from metastatic lesions, however, declined during the observation period.

“From a public health perspective, it can be argued that primary prevention activities aimed at reducing the occurrence of melanoma in the entire population should be accorded the highest priority,” the authors concluded at the meeting, sponsored by the Skin Cancer Foundation.

[email protected]

EDINBURGH – Patients with moles had more than four times the risk of developing melanoma, compared with those without moles in a large record-linkage study.

The overall rate ratio for melanoma, based on person-years at risk, was 4.68 among patients with moles recorded in their medical record (95% confidence interval, 4.39-4.98), Dr. Eugene Ong reported at the 15th World Congress on Cancers of the Skin.

Rate ratios were also significantly higher for individuals with moles of both sexes and in all age groups, including those aged younger than 25 years (RR, 3.79), 25-59 years (RR, 5.02), and at least 60 years (RR, 4.68).

Prior research has shown that high numbers of melanocytic or dysplastic nevi are strong risk factors for the development of melanoma. The investigators sought to further characterize the risk of melanoma in persons with melanocytic nevus (MN) using linked hospital and mortality records covering the entire population of England from 1999 to 2011.

The analysis included 271,656 patients with a hospital or day-case record of moles and a control cohort of 10,130,417 persons with no moles recorded. Anyone diagnosed with melanoma within 1 year of study entry was excluded.

Patients with a record of moles had a significantly higher risk of developing melanoma both around the site of the mole and elsewhere on their body, and therefore may benefit from increased surveillance, said Dr. Ong of the University of Oxford, England. For patients with a mole on the trunk, the rate ratio for a melanoma on the trunk was 8.99 (95% CI, 7.69-10.46) and 5.66 for a melanoma elsewhere (95% CI, 4.97-6.42).

The investigators were unable to distinguish between different types of moles or to determine the number of moles in each patient. Further, a mole or moles were the principal reason for hospital contact for 91% of patients, so it’s likely they presented with unusual appearing moles in order for them to warrant recording, Dr. Ong acknowledged.

“So while this study does not suggest that everyone with a single mole is far more likely to develop melanoma, it does illustrate the link between moles and skin cancer. This is why it is vital people check their moles regularly and report any changes to their doctor,” he said in a statement released during the meeting, sponsored in part by the Skin Cancer Foundation.

[email protected]

EDINBURGH – Patients with moles had more than four times the risk of developing melanoma, compared with those without moles in a large record-linkage study.

The overall rate ratio for melanoma, based on person-years at risk, was 4.68 among patients with moles recorded in their medical record (95% confidence interval, 4.39-4.98), Dr. Eugene Ong reported at the 15th World Congress on Cancers of the Skin.

Rate ratios were also significantly higher for individuals with moles of both sexes and in all age groups, including those aged younger than 25 years (RR, 3.79), 25-59 years (RR, 5.02), and at least 60 years (RR, 4.68).

Prior research has shown that high numbers of melanocytic or dysplastic nevi are strong risk factors for the development of melanoma. The investigators sought to further characterize the risk of melanoma in persons with melanocytic nevus (MN) using linked hospital and mortality records covering the entire population of England from 1999 to 2011.

The analysis included 271,656 patients with a hospital or day-case record of moles and a control cohort of 10,130,417 persons with no moles recorded. Anyone diagnosed with melanoma within 1 year of study entry was excluded.

Patients with a record of moles had a significantly higher risk of developing melanoma both around the site of the mole and elsewhere on their body, and therefore may benefit from increased surveillance, said Dr. Ong of the University of Oxford, England. For patients with a mole on the trunk, the rate ratio for a melanoma on the trunk was 8.99 (95% CI, 7.69-10.46) and 5.66 for a melanoma elsewhere (95% CI, 4.97-6.42).

The investigators were unable to distinguish between different types of moles or to determine the number of moles in each patient. Further, a mole or moles were the principal reason for hospital contact for 91% of patients, so it’s likely they presented with unusual appearing moles in order for them to warrant recording, Dr. Ong acknowledged.

“So while this study does not suggest that everyone with a single mole is far more likely to develop melanoma, it does illustrate the link between moles and skin cancer. This is why it is vital people check their moles regularly and report any changes to their doctor,” he said in a statement released during the meeting, sponsored in part by the Skin Cancer Foundation.

[email protected]

EDINBURGH – Patients with moles had more than four times the risk of developing melanoma, compared with those without moles in a large record-linkage study.

The overall rate ratio for melanoma, based on person-years at risk, was 4.68 among patients with moles recorded in their medical record (95% confidence interval, 4.39-4.98), Dr. Eugene Ong reported at the 15th World Congress on Cancers of the Skin.

Rate ratios were also significantly higher for individuals with moles of both sexes and in all age groups, including those aged younger than 25 years (RR, 3.79), 25-59 years (RR, 5.02), and at least 60 years (RR, 4.68).

Prior research has shown that high numbers of melanocytic or dysplastic nevi are strong risk factors for the development of melanoma. The investigators sought to further characterize the risk of melanoma in persons with melanocytic nevus (MN) using linked hospital and mortality records covering the entire population of England from 1999 to 2011.

The analysis included 271,656 patients with a hospital or day-case record of moles and a control cohort of 10,130,417 persons with no moles recorded. Anyone diagnosed with melanoma within 1 year of study entry was excluded.

Patients with a record of moles had a significantly higher risk of developing melanoma both around the site of the mole and elsewhere on their body, and therefore may benefit from increased surveillance, said Dr. Ong of the University of Oxford, England. For patients with a mole on the trunk, the rate ratio for a melanoma on the trunk was 8.99 (95% CI, 7.69-10.46) and 5.66 for a melanoma elsewhere (95% CI, 4.97-6.42).

The investigators were unable to distinguish between different types of moles or to determine the number of moles in each patient. Further, a mole or moles were the principal reason for hospital contact for 91% of patients, so it’s likely they presented with unusual appearing moles in order for them to warrant recording, Dr. Ong acknowledged.

“So while this study does not suggest that everyone with a single mole is far more likely to develop melanoma, it does illustrate the link between moles and skin cancer. This is why it is vital people check their moles regularly and report any changes to their doctor,” he said in a statement released during the meeting, sponsored in part by the Skin Cancer Foundation.

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