Ulceration Of Primary Melanoma Research Articles

Impact of adjuvant immunotherapy in resected stage II/III/IV melanoma: A single center experience.

e21565 Background: The incidence of malignant melanoma (MM) in Mediterranean countries is estimated at 3- 5/100.000 inhabitants/year with a predicted rising trend. MM is responsible for over 90% skin cancer deaths due to its tendency to metastasize early. Surgical excision is the treatment of choice for early-stage melanoma, however, 40-60% of patients with high recurrence risk melanoma, thick ulcerated primary melanomas (Stage IIC) and those with lymph node involvement (Stage III), experience a tumor relapse. Adjuvant therapy in resected high-risk melanomas has shown improved Relapse-Free-Survival (RFS), although no Overall Survival (OS) benefit has been observed to date. This retrospective observational study, conducted in one center, aims to evaluate effectiveness and safety of adjuvant therapies for resected high-risk melanoma. Methods: Single center cross-sectional study that included patients with a resected high-risk melanoma candidate for adjuvant treatment, at 2015-2022 period. Convenience sampling 48 patients recruited. Median follow up 55,4 months. Results: Median age was 54y, 52% were male and 93’6 is cutaneous melanoma. 53% were BRAF WT. Median Breslow (mm) was 3’85, median num/mm2 mitosis are 4 and 62’5% had ulceration. 15% presented satelosis or intransit metastasis and 55% had a lymphadenectomy. Melanoma stage: 9%IIB, 11%IIC, 11%IIIA, 25%IIIB, 38%IIIC, 2% IIID and 2% IV. Adjuvant treatment: 22% nivolumab, 20% ipilimumab+nivolumab, 12% ipilimumab, 16% interferon.75% of patients completed adjuvant treatment, 14% stopped for toxicity and 9% presented disease relapse (21% loca, 64% systemic). Best treatment response in relapse was 12% partial response, 37% progression. Toxicity: 18% presented grad ¾ toxicity. Efficacy: median RFS was 78’8m and median OS was NR. Conclusions: Adjuvant treatment is associated with an increased DFI in resected high risk melanoma patients. Adjuvant therapy was generally well tolerated, with manageable adverse events, consistent in type and incidence to those seen in clinical trials that allowed the approval for these compounds in adjuvant and metastatic scenarios. Prospective studies are needed to determine new biomarkers for the selection of those patients who could benefit to a greater extent from adjuvant therapies in resected high-risk melanoma.

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence

BackgroundMost patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human...

Adjuvant therapy with pegylated interferon-alfa2b vs observation in stage II B/C patients with ulcerated primary: Results of the European Organisation for Research and Treatment of Cancer 18081 randomised trial

BackgroundSubgroup analyses of two large EORTC adjuvant interferon-alpha2b (IFNα-2b) vs observation randomised trials demonstrated that a treatment benefit was observed only in patients with an ulcerated melanoma without palpable nodes (hazard ratio [HR] for recurrence-free survival [RFS] was 0.69). This was confirmed by a meta-analysis of 15 adjuvant IFN trials (HR: 0.79). Patients and methodsIn the EORTC 18081 trial, sentinel node-negative stage II patients with an ulcerated primary melanoma were 1:1 randomised between pegylated (PEG)-IFNα-2b at 3 μg/kg/week subcutaneously and observation, for 2 years, or until disease recurrence or unacceptable toxicity in spite of dose adjustments to maintain an Eastern Cooperative Oncology Group performance status of 0 or 1. Main end-point was RFS. Secondary end-points included distant metastasis-free survival (DMFS), overall survival, and safety (EudraCT Number: 2009-010273-20). ResultsBetween February 2013 and January 2017, only 112 patients were randomised, 56 in each arm. The trial was stopped early for lack of recruitment. At a 3.4-year median follow-up, the estimated HR for the PEG-IFNα-2b group compared with the observation group regarding RFS was 0.66 (95% confidence interval [CI]: 0.32–1.37), and the 3-year RFS rate was 80.0% (95% CI: 65.7–88.8%) and 72.9% (95% CI: 58.3–83.0%), respectively. DMFS was prolonged: HR: 0.39 (95% CI: 0.15–0.97), and the 3-year DMFS rate was 90.6% (95% CI: 78.9–96.0%) vs 76.4% (95% CI: 62.1–85.9%). One patient in the PEG-IFNα-2b group died compared with 4 in the observation group. Fifty-four patients started PEG-IFNα-2b treatment, 16 (29%) completed 2 years of treatment, 2 (4%) stopped due to recurrence, 23 (43%) due to toxicity and 14 (25%) due to other reasons. ConclusionsThe EORTC 18081 PEG-IFNα-2b randomised trial, observed a similar HR (0.69) for RFS as the previous EORTC trials (0.69). In countries without access to new drugs, adjuvant (PEG)-IFNα-2b treatment is an option for patients with ulcerated melanomas without palpable nodes.

The value of lymph node ultrasound and whole body PET/CT in stage IIB/C patients prior to SLNB.

e22079 Background: Stage IIB/IIC (pT3b-T4N0) patients are known to have high-risk primary tumors, even higher risk than some stage IIIA/B melanomas (AJCC Staging System 8th edition), however they follow the same routine to sentinel lymph node biopsy (SLNB) as more low-risk tumors. A priori the risk of finding SLNB or other metastases is much higher for these thick and/or ulcerated primary melanomas compared to the thinner ones. Guidelines are not conclusive regarding the use of preoperative imaging in these cases. Recently, a trend to more frequently use cross-sectional imaging has been noticed. However, others have previously shown that preoperative ultrasound was the most sensitive. The aim of this pilot study was to assess the value of ultrasound (US) and Positron Emission Tomography/Computerized Tomography (PET/CT) prior to SLNB for stage IIB/C (pT3b-T4N0) melanoma patients. Methods: Starting 2019-04, all patients with a pT3b melanoma or higher (8th AJCC) were included. All patients underwent US and PET/CT before their planned lymphoscintigraphy and routine SLNB. Suspected metastases were confirmed with cytologic puncture. Results: A total of 20 patients were screened. Seven patients (35%) had metastases detected by imaging: one by PET/CT, three by US and three by both imaging modalities. Three of these metastases were detected by US as well as PET/CT. All metastases were nodal. For all seven patients treatment was altered to lymph node dissection with adjuvant therapy. Of the 13 patients in whom no metastases were identified by imaging, six (46%) still had a positive sentinel node (SN). Conclusions: This study showed that this select group of patients had a high risk of metastases prior to SLNB and that all recurrences except one, were detected by ultrasound. This suggests that nodal staging with US is sufficient and can replace the need for SLNB when metastases is proven with cytology. Despite negative imaging, SLNB cannot be foregone for pT3b-pT4N0 melanoma patients, as many still have an involved SN. Cross-sectional imaging can be reserved for patients after positive cytology or SN to confirm the absence of distant visceral metastases.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma

Statins may restrict the cellular functions required for melanoma growth and metastasis. To determine whether long-term statin use commenced before diagnosis of a primary melanoma is associated with reduced risk of melanoma recurrence. We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localized tumour-stage T1b to T4b melanoma in Queensland, Australia. We used Cox regression analyses to examine associations between long-term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration, due to evidence of effect modification. Among 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62 years, 59% male, 28% with ulcerated tumours), 94 patients (13%) developed melanoma recurrence within 2 years. Long-term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence than nonusers [adjusted hazard ratio (HRadj ) 0·55, 95% confidence Interval (CI) 0·32-0·97] regardless of statin subtype or potency. Compared with nonusers of statins, risk of recurrence was significantly decreased in male statin users (HRadj 0·39, 95% CI 0·19-0·79) but not in female statin users (HRadj 0·82, 95% CI 0·29-2·27) and in statin users with ulcerated (HRadj 0·17, 95% CI 0·05-0·52) but not nonulcerated (HRadj 0·91, 95% CI 0·46-1·81) primary melanoma. Statins commenced before melanoma diagnosis may reduce the risk of melanoma recurrence, especially in men and in those with ulcerated tumours. Clinical trial evaluation of the potential role of statins in improving the prognosis of high-risk melanoma is warranted.

Adjuvant Therapy for Melanoma.

In recent years, the number of patients with malignant melanoma has continued to increase globally; surgery remains the first treatment option for patients with resectable melanoma. Adjuvant therapy for patients with stage III and IV melanoma following surgical resection has gradually been approved. After complete resection, these patients can probably derive significant benefit from adjuvant therapy. New treatments that improve the long-term survival of patients with unresectable advanced or metastatic melanoma are currently under evaluation in adjuvant therapy to increase relapse-free survival and overall survival. We here review several relevant clinical trials of radiotherapy, systemic immune therapies, molecular-targeted therapies, and neoadjuvant therapies in order to shed light on most suitable adjuvant therapy. The findings of this review include the following: The use of interferon-α2b will be restricted for patients with ulcerated primary melanoma in countries with no access to new drugs in adjuvant therapy. Ipilimumab should not be considered as the first-line therapy due to its lower efficacy and severe toxicity. The use of anti-programmed death-1 antibody would be a relevant adjuvant therapy for patients without BRAF mutation. If the BRAF mutation status is positive, the combination of dabrafenib and trametinib is a plausible option. The establishment of appropriate therapeutic planning and clinical endpoints in adjuvant therapy should affect the standard of care. The choice of optimal adjuvant therapy for individual patients is an important issue.

Increased tumour cell PD-L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas.

Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated. We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome. Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour cell expression of programmed death-ligand 1 (PD-L1), transporter of antigen processing 1 and the MxA protein was also analysed. Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (P=0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 vs. 3.6% of pts, P=0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68+ macrophages (P=0.028) as well as with increased numbers of intratumoural CD11c+ dendritic cells (P=0.014) and CD163+ macrophages (P=0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours [40 (72.7%) vs. 25 (44.6%), P=0.003]. A positive correlation between intratumoural CD11c+ (Spearman's correlation coefficient ρ: 0.42) and CD163+ (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected. Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.

Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma

Ulcerated primary melanomas are associated with an inflammatory tumor microenvironment. We hypothesized that systemic proinflammatory states and anti-inflammatory medications are also associated with a diagnosis of ulcerated melanoma. In a cross-sectional study of 787 patients with newly diagnosed clinical stage IB or II melanoma, we estimated odds ratios for the association of proinflammatory factors (high body mass index, diabetes, cardiovascular disease, hypertension, and smoking) or the use of anti-inflammatory medications (statins, aspirin, corticosteroids, and nonsteroidal anti-inflammatory drugs), with ulcerated primary melanoma using regression models and subgroup analyses to control for melanoma thickness and mitotic rate. On the basis of information from 194 patients with ulcerated and 593 patients with nonulcerated primary melanomas, regular statin users had lower likelihood of a diagnosis of ulcerated primary melanoma (odds ratio 0.67, 95% confidence interval 0.45-0.99), and this association remained after adjusting for age, sex, thickness, and mitosis. When analysis was limited to melanomas that were ≤2 mm thick and had ≤2 mitoses/mm2 (40 ulcerated; 289 without ulceration), patients with diabetes had significantly raised odds of diagnosis of ulcerated melanoma (odds ratio 2.90, 95% confidence interval 1.07-7.90), adjusted for age, sex, body mass index, and statin use. These findings support our hypotheses that statin use is inversely associated, and diabetes is positively associated, with ulcerated melanoma.

Abstract B003: A randomized controlled phase II clinical trial on mRNA electroporated autologous dendritic cells for stage III/IV melanoma patients who are disease-free following the local treatment of macrometastases

Abstract Autologous monocyte-derived synthetic mRNA electroporated dendritic cells (TriMixDC-MEL) are immunogenic and can induce anti-tumor activity in pretreated advanced melanoma patients when administered by the intradermal (id) and intravenous (iv) route. We investigated the safety and activity of TriMixDC-MEL in stage III/IV melanoma patients who are disease free following the local treatment of macrometastases. We performed a randomized, controlled, non-comparative phase II clinical trial where TriMixDC-MEL was administered iv (20.106 DCs) and id (4.106 DCs) at 2 separate sites of the body every 2 weeks for a total of 4 administrations and a fifth administration after 16 weeks in patients randomized to the treatment arm. Patients on the control arm did not receive treatment but were allowed to “cross-over” and be treated with TriMixDC-MEL at the time of non-salvageable recurrence. Tumor evaluations on both arms were performed by total-body 18-FDG-PET/CT every 12 weeks. The primary endpoint was the percentage of patients who were alive and free from melanoma macrometastases at 1 year following randomization. Patients were allowed to undergo local salvage treatments for loco-regional melanoma recurrences during the study (week 0-52). If local salvage treatment during the study resulted in a disease-free status that was confirmed at any of the planned assessment, but not earlier than 16 weeks after the salvage treatment, these patients were considered not to have reached the primary endpoint of the study. Between November 2012 and November 2014, 41 eligible patients were randomized between the TriMixDC-MEL treatment arm (n = 21) and control-arm (n = 20). Baseline characteristics (22M/19F; median age 57.5y (range 24-81); AJCC stage III/IV-M1a/-M1b/-M1c: 33/1/6/1 patients, ulcerated primary melanoma: 12 patients) were well balanced between both groups. After a median follow-up of 28 months (range 15 to 40 months) 21 patients experienced a non-salvageable melanoma recurrence (7 on the DC- and 14 on the control-arm). The rate of patients who were disease-free at 1 year (evaluable population = 41 patients) was higher in the TriMixDC-MEL treated group (68% [95%CI 46-86] vs. 35% [14-55]). The time-to-non-salvageable melanoma recurrence was significantly lower in the TriMixDC-MEL treated group (log-rank p = .021). Seven patients in the TriMixDC-MEL group and 3 patients in the control arm were offered local salvage therapy at first recurrence (surgery: 9 patients; RT: 1pt). TriMixDC-MEL was well tolerated (there were no grade ≥3 AE related to TriMixDC-MEL). AE were limited to: local skin injection reactions (grade 1-2; 17/21 patients), flu-like symptoms (grade 1-2; 4/21 patients), and post-infusion chills (grade 1-2; 4 [19%] patients). The results of this non-comparative randomized controlled phase II clinical trial of TriMixDC-MEL id/iv versus observation support the further evaluation of TriMixDC-MEL as a well-tolerated adjuvant therapy for melanoma patients following the resection of macrometastases. Citation Format: Bart Neyns, Yanina Jansen, Jurgen Corthals, Sofie Wilgenhof, Max Schreuer, Carlo Heirman, Kris Thielemans. A randomized controlled phase II clinical trial on mRNA electroporated autologous dendritic cells for stage III/IV melanoma patients who are disease-free following the local treatment of macrometastases [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B003.

Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

The clinicopathological and gene expression patterns associated with ulceration of primary melanoma

Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinicopathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502-gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion, and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up-regulation of pro-inflammatory cytokines suggests that ulceration is associated with tumor-related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signaling pathways involved in inflammation.

S-100B: A Stronger Prognostic Biomarker than LDH in Stage IIIB–C Melanoma

In melanoma patients with nodal macrometastases, the distinction between good and poor prognosis is based on the presence of primary melanoma ulceration or metastatic involvement of 4 or more lymph nodes in the 7th edition of the American Joint Committee on Cancer (AJCC) classification. We hypothesized that biomarkers would increase the accurateness of staging in these patients. The aim was to assess and compare the prognostic impact of biomarkers S-100B and LDH and to determine the best timing of their measurement in stage IIIB-C melanoma. A total of 119 patients underwent therapeutic lymph node dissection (TLND) for nodal macrometastases with serum S-100B and LDH level measurements preoperatively. In 75 of them, S-100B and LDH were also measured on postoperative days 1 and 2. S-100B and LDH levels on days 0, 1, and 2 were compared for their association with disease-free survival (DFS) and disease-specific survival (DSS). At a median follow-up of 17 (range 1-89) months, S-100B levels at all time points were associated with DFS. In multivariable analysis, preoperative S-100B and S-100B measured on day 2 showed the strongest association with DFS (hazard ratio [HR] 2.55, P=0.007 and HR 3.80, P=0.01). For DSS, the preoperative S-100B level was the strongest independent predictor (HR 2.81, P=0.01). LDH measurements showed a significant association with DSS in univariate analysis only when measured preoperatively (HR 2.46, P=0.01). In multivariable analysis, LDH measurement was not associated with melanoma prognosis. The S-100B level measured preoperatively is, in contrast to LDH, one of the most important independent predictors of melanoma prognosis in patients undergoing TLND for nodal macrometastases.

Immuntherapie des Melanoms

Even early clinical studies showed that adjuvant chemotherapy achieved no therapeutic benefit for melanomas so that in the current guidelines its use is only recommended within the framework of clinical studies. For over 30 years interferons have been used in the adjuvant treatment of primary high risk melanomas as well as in the treatment of metastasized melanomas. They function in an antiviral, immune modulating and antitumor fashion. Direct and indirect effects on tumor cells could be demonstrated for interferons. In Europe low dosage interferon therapy is approved and has become widely established for stage II melanomas, whereas in the USA high dosage therapy for stage III and since March 2011 therapy with pegylated interferon in stage III are also approved. In this article the most important study results will be dealt with in detail. In summary, according to the current study situation therapy with interferon should be offered especially to patients with ulcerated primary melanoma and microscopic lymph node infiltration. Many attempts have been made in the last decades to positively influence the survival time of distant metastasized melanoma by systemic therapy. The recent development of the antibody ipilimumab against cytotoxic T-lymphocyte protein 4 (CTLA-4) could show for the first time a survival advantage in the therapy of melanoma patients in advance stage disease. The licensing of ipilimumab has meant that there is now a new standard available for the second line therapy of malignant melanoma which will be included in the guidelines on therapy of malignant melanoma. A further interesting option for adjuvant therapy is currently vaccination with the recombinant melanoma-associated protein 3 (MAGE-A3) protein in combination with the adjuvant AS015.

Prognostic Value of BRAF V600 Mutations in Melanoma Patients After Resection of Metastatic Lymph Nodes

BRAF (V600) mutations are frequent in melanomas, and BRAF(V600)-targeted therapy have dramatic, but often transitory, efficacy in stage IV patients. Prognosis of patients with American Joint Committee on Cancer (AJCC) stage III melanoma is heterogeneous. We aimed to determine the overall survival (OS) of stage III patients with a nodal deposit of ≥2 mm according to BRAF (V600) mutations and other previously reported prognostic criteria. This retrospective study included 105 consecutive patients with stage III cutaneous melanomas. Most patients underwent a prospective follow-up. BRAF (V600) mutations were detected by sequencing and pyrosequencing of DNA in samples containing >60 % melanoma cells. BRAF mutations (p.V600E and p.V600K in 83 and 14 % of cases, respectively) were detected in 40 % of the patients. For patients with and without BRAF mutations, death occurred in 83.3 and 60.3 %, with a median OS of 1.4 and 2.8 years, respectively. Patient age, primary melanoma ulceration, number of invaded lymph nodes, AJCC staging at study entry, and BRAF status were linked to OS in the univariate analysis. The only characteristics associated with OS in the multivariate analysis were number of invaded lymph nodes (P = 0.005, hazard ratio 2.2, 95 % confidence interval 1.3-3.9) and BRAF status (P = 0.005, hazard ratio 1.9, 95 % confidence interval 1.2-3.1). BRAF (V600) status could be used to stage melanoma patients with nodal deposits. Our results may also help to plan adjuvant trials in these patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies.

Prognostic value of BRAFV600 mutations in melanoma patients after resection of metastatic lymph nodes.

8540 Background: Prognosis of AJCC stage III melanoma is heterogeneous. BRAFV600 mutations are frequent in melanomas. BRAFV600-targeted therapy has dramatic, but often transitory, efficacy in stage IV patients (pts). We aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with sufficient nodal invasion. Methods: We searched all pts with cutaneous melanoma who had radical lymphadenectomy in our institution between 1/1/00 and 15/6/10 and included those with a nodal deposit &gt;2 mm. BRAFV600 mutations were detected by DNA sequencing and pyrosequencing in formalin-fixed nodal samples containing &gt;60% melanoma cells. Samples were considered mutated when &gt;15% of DNA was positive. Endpoints were overall survival (OS) and distant metastasis free survival (DMFS). 92 patients had to be included to demonstrate a doubling of OS in patients without (40 months (m)) and with BRAFV600 mutation (20 m). Log-rank test and multivariate Cox proportional hazards regression model were used. Results: 105 consecutive pts were included, with 72% prospectively followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death occurred in 83% and 60% of pts with and without BRAF mutations, respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF status influenced OS and DMFS in the univariate analysis. The multivariate analysis showed the major prognostic role of BRAF status and of the number of invaded nodes (table). Conclusions: Provided our findings are independently replicated, BRAFV600 status should be used to stage melanoma pts with nodal metastasis. Our results also help to plan adjuvant trials with BRAFV600-targeted therapy in such patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. [Table: see text]

Long-term follow-up reveals that ulceration and sentinel lymph node status are the strongest predictors for survival in patients with primary cutaneous melanoma

Purpose To assess the long-term outcome after sentinel lymph node biopsy (SLNB) in melanoma patients. Methods Between 1995–2009 450 melanoma patients underwent SLNB in a single center. Survival and prognostic factors were analyzed for 429 patients. Results Median age was 53 (range 11–84) years. Median Breslow thickness was 2.4 (range 1–20) mm and 36% were ulcerated melanomas. Median follow-up time was 64.8 (range 2–174) months. A tumor-positive SLN was present in 140 patients (31%). Completion lymph node dissection (CLND) was performed in 119 patients and these patients were analyzed for recurrence and survival. 124 Patients (29%) relapsed during follow-up; 55 in the node-positive group who underwent CLND (55/119; 46%) and 69 in the node-negative group (69/310; 22%; p < 0.001). In the node-negative group 17 patients developed recurrence in the regional node field; false-negative rate 11%. On multivariate analysis strongest prognostic factors for disease free survival (DFS) were primary melanoma ulceration and SLN positivity (Hazard Ratio (HR) of 2.2 and 2.3; p < 0.001). For disease specific survival (DSS) the same was found to be true with an HR of 2.1 for ulceration and 2.0 for SLN positivity ( p = 0.001 and p = 0.002 respectively). 10-Year DFS was 71% for node-negative patients compared with 48% for node-positive patients ( p < 0.001). 10-Year DSS was 77% for node-negative patients compared to 60% for node-positive patients ( p < 0.001). Conclusions This study shows a remarkably high percentage of tumor-positive SLN. The long-term follow-up data confirm that tumor-positive SLN patients have a worse DFS and DSS than tumor-negative SLN patients. Ulceration and SLN status proved to be the strongest prognostic factors for long-term DFS and DSS.

CO19. Is primary melanoma ulceration a factor of good response to adoptive immunotherapy?

Peuvrel, L.; Nguyen, J.M.; Khammari, A.; Quéreux, G.; Brocard, A.; Dréno, B. Author Information

Is primary melanoma ulceration a factor of good response to adoptive immunotherapy?

Primary melanoma ulceration is a factor of poor prognosis at the local and regional stage. The physiopathological mechanisms which explain its prognostic impact are still little known. However, two recent studies suggest that it could be a predictive factor of good response to a non-specific immunotherapy (interferon-alpha) and to an active immunotherapy (vaccine). The aim of this study was to determine whether ulceration could be a factor of good prognosis in the context of an adoptive immunotherapy with tumour infiltrating lymphocytes (TIL) in stage III regional lymph node metastatic melanoma (sixth American Joint Committee on Cancer staging system) and whether it was associated with an improvement in the effectiveness of this treatment compared with the control group. We have included all the patients treated in open prospective randomized TIL vs. control protocols in our unit from 1997 to 2009. Clinical data were derived retrospectively from patient files. Statistical analysis was performed using log-rank tests, Cox models and tests for interaction. A total of 144 patients were included. In the group of 80 patients treated with TIL, primary melanoma ulceration remained a pejorative factor for relapse-free and overall survival in univariate and multivariate analysis. The presence of ulceration did not change the effectiveness of TIL treatment in comparison with the control group with regards to relapse-free and overall survival. Our study demonstrates that primary melanoma ulceration does not have any impact on the response to TIL adoptive immunotherapy and thus does not confirm its positive prognostic value suggested by two other immunotherapy approaches.

31. Prognostic importance of the extent of ulceration of clinically localised cutaneous melanoma

Background The presence of ulceration is an adverse prognostic factor in clinically-localised cutaneous primary melanoma (PM). However, whether the extent of ulceration has any prognostic importance remains unclear. We sought to determine the prognostic value of the extent of ulceration categorised as diameter of ulceration and as percentage of invasive melanoma. Methods Clinico-pathological data on patients with PM were collected from the Melanoma Institute Australia database. In patients with ulcerated melanomas, diameter and percentage ulceration (ratio of diameter of ulceration to diameter of invasive melanoma) were identified from the database or measured if slides were available for review. Ulceration was defined as full-thickness loss of epidermis overlying melanoma. The impact of clinico-pathologic parameters and extent of ulceration on survival was analysed. Results Male sex, head/neck anatomical location, increasing Breslow thickness and presence of mitoses were independent predictors of poorer melanoma-specific survival (MSS). Presence of ulceration was an independent predictor of poorer MSS (HR=1.55, 95%CI 1.21-2.00). Patients with tumours ulcerated ≤70% and ≤5 mm had significantly poorer MSS than non-ulcerated melanoma [HR = 1.53, 95%CI 1.07-2.21 and HR=1.39, 95%CI 1.04-1.87, respectively). Compared with all patients with ulcerated melanoma (HR = 1.55) patients with tumours ulcerated >70% or >5 mm had a significantly higher risk of death (HR = 2.20, 95%CI 1.26-3.82 and HR = 2.03, 95%CI 1.37-3.03, respectively). Conclusions Extent of ulceration provides more prognostic information than the mere presence of ulceration, and this has important implications for melanoma patients with regard to prognosis, staging, management and eligibility for clinical trials. We recommend that extent of ulceration be recorded in pathology reports for all ulcerated PMs.

Anti–CTLA-4 Antibody Adjuvant Therapy in Melanoma

Thus far the development of adjuvant therapies in melanoma has suffered greatly from the lack of effective drugs in stage IV melanoma. Chemotherapy, cytokines, vaccines, and combinations of drugs have been used with minimal success. This has led to adjuvant therapies that are not used uniformly or widely because of the rather marginal benefits, as no consistent and clinically significant impact on survival has been demonstrated. A new development for interferon-based adjuvant therapy seems to be the observation that better effects are observed in patients with lower tumor load and in patients with an ulcerated primary melanoma. A benefit for patients with more advanced lymphnodal involvement is quite unsure, clearly requiring new drugs to be explored. A new era in the treatment of melanoma treatment has arrived with the anti-cytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibodies. The randomized trial in advanced metastatic melanoma demonstrated a clear benefit with prolongation of survival. The anti-CTLA-4 monoclonal antibody ipilimumab has finally changed the landscape. It is therefore only logical that a worldwide adjuvant trial with ipilimumab versus placebo, the European Organization for Research and Treatment of Cancer (EORTC) 18071, is ongoing in patients with lymph node metastases, and that another adjuvant trial with ipilimumab compared to high-dose interferon (HDI) is planned in the United States. The EORTC 18071 trial will reach full accrual in 2011 and thus results are expected in 2013 or 2014.