Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity?

Eggermont, Alexander M.M.; Spatz, Alan; Lazar, Vladimir; Robert, Caroline

doi:10.1097/cco.0b013e32834fcb0d

Cited by 44 publications

(38 citation statements)

References 26 publications

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“…In contrast, in previous EORTC trials of adjuvant therapy in patients with melanoma, 17,19–22 a significant benefit with interferon alfa was observed only in patients with microscopic involvement. Similarly, in contrast to interferon alfa, for which ulceration is the overriding determinant of activity, 13,17,20–23 ipilimumab prolonged survival among patients with nonulcerated melanoma and among those with ulcerated melanoma.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

et al. 2016

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BACKGROUND On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis–free survival, and safety. RESULTS At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P = 0.001). The rate of distant metastasis–free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P = 0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis–free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168, and EudraCT number, 2007-001974-10.)

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Section: Discussionmentioning

confidence: 99%

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

et al. 2016

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“…Ulceration of the primary tumor was first defined as a poor prognostic feature in 1953 by Allen and Spitz [1]. More recently, the classification of ulcerated melanomas as a distinct biological category within melanoma has been advanced [2, 3]. Notably, ulcerated melanomas may respond more favorably to adjuvant interferon [3–5].…”

Section: Introductionmentioning

confidence: 99%

“…Several groups have proposed that ulcerated melanomas have distinct gene profiles, increased vascularity, increased lymphovascular invasion, increased sentinel node positivity, and immunosuppression in primary lymph nodes even in the absence of tumor cells [2, 12]. In addition, it has been advanced that ulcerated melanomas show greater response rates to interferon therapy [3, 5, 13].…”

Section: Introductionmentioning

confidence: 99%

Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas

Moll

Qian

et al. 2015

Cancer Immunol Immunother

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Introduction Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors. Methods Sixty-two stage II–III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers. Results We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count. Conclusion Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

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“…Here, we want to highlight the urgent need for bigger studies comparing the 2 types of IFN, establishing biomarkers 27,28 and subpopulations that benefit most from peg-IFN. 29 Upcoming new technologies such as the doseadjustable peg-IFN injection pen will give physicians and patients more flexibility to adjust to the optimal dose tolerated by patients.…”

Section: Discussionmentioning

confidence: 99%

Real-life Experience With Pegylated Interferon and Conventional Interferon in Adjuvant Melanoma Therapy

Rozati

Naef

Levesque

et al. 2013

Journal of Immunotherapy

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Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.

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Is ulceration in cutaneous melanoma just a prognostic and predictive factor or is ulcerated melanoma a distinct biologic entity?

Cited by 44 publications

References 26 publications

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy

Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas

Real-life Experience With Pegylated Interferon and Conventional Interferon in Adjuvant Melanoma Therapy

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