ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Correction to: Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

C.R. Farley and M.C. Perez contributed equally to this publication and are co-first authors. J.S. Zager and M.C. Lowe contributed equally to this publication and are co-corresponding authors.

Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

INTRODUCTION: The eighth edition of the American Joint Committee on Cancer (AJCC8) Staging Manual provides important information for staging and prognostication; however, survival estimates for patients with Stage I-III Merkel cell carcinoma (MCC), a rare disease, may be as practical using data from large-volume centers as that collated for the AJCC analysis. As such, we compared our institutional outcomes to AJCC8. METHODS: Patients who presented from 2005 to 2017 with MCC to two high-volume centers were included. Demographics, clinicopathologic characteristics, survival and recurrence data were compiled, and outcomes compared to AJCC8. RESULTS: A total of 409 patients were included. Median age was 75 (range 29-98) years, and 68% were male. Median follow-up was 16 months (0-157). Five-year overall survival (OS) was 70%; 5-year disease-specific survival (DSS) was 84%. When stratified by extent of disease, 5-year OS was higher for patients with local disease compared to those with nodal disease (72.6% vs 62.7%, p=0.005). Similarly, patients with local disease had higher 5-year DSS than those with nodal disease (90.1% vs 76.8%, p=0.002). Five-year recurrence-free survival was 59.2% for all patients, 65.0% for local disease and 48.3% for nodal disease (p=0.033). CONCLUSIONS: Here, MCC patients with local or nodal disease have substantially higher OS rates than predicted in AJCC8 (5-year: 72.6% vs 50.6%; 62.7% vs 35.4%, respectively). Importantly, 5-year DSS was significantly better than the OS rates reported presently and in AJCC8. As clinicians and patients rely on AJCC to accurately prognosticate and guide treatment decisions, these estimates should be reassessed and updated to more accurately predict survival outcomes.

Beyond BRAF: where next for melanoma therapy?

In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases­even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.

Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.

Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.

BACKGROUND: Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. METHODS: The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. RESULTS: BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. CONCLUSION: Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.

Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma.

BACKGROUND: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. METHODS: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). CONCLUSION: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.

Diagnostic techniques for primary cutaneous melanoma.

Despite the rising incidence of melanoma in the Caucasian population, there has not been a concomitantly dramatic increase in mortality, which is due, in part, to the advent of better tools that have been made available for the early detection of melanoma. This article presents an overview of some of the recent diagnostic developments that are of potential interest to practicing dermatologists. Some of these diagnostic advances include: total body photography; dermoscopy; multispectral imaging; confocal scanning laser microscopy; teledermatology; high-frequency ultrasound; computed tomography; magnetic resonance imaging; immunohistochemical stains; comparative genomic hybridization; microphthalmia transcription factor; and melanoma sniffing dogs. Although not all of these tools are uniformly accepted nor mandatory, a passing familiarity with them will be helpful as additional data regarding their use evolves.

Staged margin control techniques for surgical excision of lentigo maligna.

For melanoma in situ (MIS) arising in chronically photodamaged skin (a.k.a. lentigo maligna, LM), the preferred treatment remains surgical excision. Yet, the standard 5-mm margins of excision recommended for other subtypes of MIS have proven insufficient for LM, due to the its indistinct borders. In this report, authors review specialized surgical techniques for the treatment of LM that focus on meticulous assessment of peripheral margins prior to closure (staged margin control) conducted with analysis of either frozen or permanent histologic sections. Techniques utilizing permanent sections include variations of the ''square'', ''perimeter'', and ''contoured'' excisions, and recurrence rates with these techniques are reportedly low based on short-term follow-up. Similarly, Mohs micrographic surgery (MMS) has been reported to be effective in LM, with recurrence rates generally less than 1% over three-five years of follow-up. In order to simplify margin assessment for MMS, many investigators have begun to rely on intraoperative immunohistochemistry (IHC) to identify melanocytes in frozen sections, and MART-1 is surrently the preferred immunostain for this purpose. Other methods of IHC are currently under investigation. Regardless, surgical methods that employ this degree of margin assessment offer superior cure rates compared to standard excision, and should be seriously considered when encountering patients with LM. Total peripheral margin assessment using staged excisions and analysis of permanent sections appears to be a simple and effective alternative to MMS, especially for institutions that prefer examination of permanent sections to frozen sections.

Economic implications of hepatic arterial infusion chemotherapy in treatment of nonresectable colorectal liver metastases. Meta-Analysis Group in Cancer.

BACKGROUND: Approximately 20% of patients with colorectal cancer die of metastases confined to the liver. A meta-analysis recently performed by our group confirmed that in these patients hepatic arterial infusion of 5-fluoro-2'-deoxyuridine, compared with intravenous chemotherapy with fluoropyrimidines or supportive care (including symptom palliation when necessary), improved tumor response. PURPOSE: Because of the high cost of hepatic arterial infusion, we undertook a cost-effectiveness analysis that related the cost of such therapy to its medical efficacy. METHODS: The patient population was drawn from the seven randomized clinical trials included in the meta-analysis and included individual data on 654 patients. Of these seven trials, five compared hepatic arterial infusion and intravenous chemotherapy and two compared hepatic arterial infusion and a control group in which some patients could be left untreated. Patients assigned to receive hepatic arterial infusion made up the hepatic arterial infusion group; the other patients constituted the control group. The measures of efficacy were survival and tumor response. Health-care costs (in 1995 U.S. dollars) were computed over the duration of patient follow-up and were derived from actual costs in two centers, one at Henri Mondor Hospital (Paris, France) and the other at Stanford University Medical Center (Palo Alto, CA). The total cost of treatment included the initial procedure, chemotherapy cycles, and main complications. RESULTS: The mean gain in life expectancy in the hepatic arterial infusion group compared with the control group was 3.2 months (standard error = 1.0 month). For patients treated by hepatic arterial infusion in Paris, the hepatic arterial infusion pump, initial hospitalization, and the entire process (including follow-up and complications) cost, on average, $8400, $15172, and $29562, respectively; in Palo Alto, these costs were $4700, $13784, and $25 208, respectively. For patients in the control groups in Paris and Palo Alto, the total treatment costs were, on average, $9926 and $5928. The additional costs of hepatic arterial infusion over control treatment were $19636 in Paris and $19280 in Palo Alto. The cost-effectiveness (i.e., the additional cost divided by the additional benefit) with respect to survival of the patients in the hepatic arterial infusion group compared with the patients in the control group was $73635 per life-year in Paris and $72300 per life-year in Palo Alto. CONCLUSIONS AND IMPLICATIONS: The cost-effectiveness of localized chemotherapy for colorectal liver metastases is within the range of accepted treatments for serious medical conditions, although it might be considered borderline by policy-makers in some countries. Prospective clinical trials should be conducted to more definitively answer this question.

Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro.

The adoptive immunotherapy of human malignancy requires reliable methods to sensitize and expand patients' T-cells reactive to autologous tumors. In animal studies, we have generated therapeutic effector cells against a poorly immunogenic tumor by a two-step procedure: vaccination of the host followed by the secondary stimulation of vaccine-primed lymph node (LN) cells by in vitro sensitization (IVS) with tumor in the presence of interleukin 2 (IL-2). Based on these observations, we performed a clinical trial in patients with advanced cancer to evaluate the antitumor efficacy of vaccine-primed LN cells which were similarly activated in vitro. Patients were vaccinated with irradiated autologous tumor admixed with Bacillus Calmette-Guérin and had draining LN excised 10 days later for IVS culture. During IVS culture, LN cells expanded up to 14-fold (average of 8.4-fold). A mean of 6.7 x 10(9) cells was infused in ten patients (seven melanoma, three renal cell cancer) along with the concomitant i.v. administration of IL-2 (180,000 IU/kg every 8 h for 5 days). Phenotype analysis of IVS-LN cells revealed 78 +/- 4% CD3+ T-cells which were predominantly CD4+ (67 +/- 5%) with expression of HLA-DR and IL-2 receptor. IVS-LN cells displayed relative specificity of autologous tumor lysis in four of ten cases compared to zero of seven IVS-peripheral blood lymphocytes derived from the same patients as measured by the 51Cr release assay. One mo after therapy, seven of nine patients treated with IVS-LN cells and IL-2 developed delayed-type hypersensitivity reactivity to autologous tumor compared to zero of nine patients treated with tumor vaccination and IL-2 only (P < 0.002). These observations suggest that antitumor reactivity was passively transferred with the IVS-LN cells. Major toxic side effects including fever, hepatic dysfunction, and weight gain associated with the capillary leak syndrome were associated with exogenous IL-2 administration. Tumor vaccination and cell transfer were well tolerated without significant complications. Of the ten patients treated with IVS-LN cells and IL-2, there were one partial and one minor response, and one patient has had stable disease for 27+ mo. There was no evidence of tumor response in ten patients treated with tumor vaccination and IL-2 only. Further clinical studies evaluating the antitumor reactivity of vaccine-primed LN cells are warranted.

A modified p53 overcomes mdm2-mediated oncogenic transformation: a potential cancer therapeutic agent.

The antiproliferative activities of wild-type (wt) p53 are inhibited by mdm2 (murine double minute2) oncogene product. We tested growth suppression activity of p53 14/19, an engineered p53 variant, which does not bind mdm2 and is completely resistant to the inhibition by mdm2. p53 14/19, unlike wt p53, suppressed the growth of cancer cells that contain amplified mdm2 oncogene efficiently by direct DNA transfection or adenovirus-mediated gene transfer. In addition, p53 14/19 also inhibited the growth of several different cancer cell lines expressing low levels of mdm2 oncogene product as efficiently as wt p53. We further examined the antioncogenic potencies of p53 14/19 in the rat embryo fibroblast cotransformation assay. Addition of wt p53 failed to cause any significant decrease in ras plus mdm2 foci counts. In contrast, cotransfection of p53 14/19 with ras and mdm2 significantly reduced foci number. In similar experiments, cotransfection of wt p53 or 14/19 p53 resulted in significant inhibition of oncogenic transformation in rat embryo fibroblast mediated by an activated ras plus c-myc, adenovirus E1A, or human papillomavirus E7 oncogenes. Therefore, these results suggest that p53 14/19 modified tumor suppressor gene may be a promising therapeutic agent for human cancers that express abnormally high levels of mdm2 oncogene product.

Clinical correlations with chemosensitivities measured in a rapid thymidine incorporation assay.

A rapid assay for in vitro chemosensitivity testing measuring [3H]thymidine incorporation has been developed. Results of this assay correlate highly with chemosensitivities determined by the soft-agar clonogenic assay. A correlative study was carried out on 219 solid tumor specimens to assess the ability of the rapid assay to predict clinical response to antineoplastic therapy. One hundred forty-two of 219 tumors (65%) yielded chemosensitivity data. Of these, 33 were evaluable for in vitro-in vivo correlations. In vitro sensitivity (greater than or equal to 80% inhibition of thymidine uptake) was associated with clinical response in 6 of 13 patients. In vitro resistance was associated with progressive disease in 20 of 20 patients. The rapid assay offers several advantages over the soft-agar clonogenic assay, including higher success rate, avoidance of clumping artifact, shorter time course (5 days), and very low false-negative rate. Further refinement may be necessary, but the rapid assay appears to have potential for individualizing solid tumor chemotherapy.

Development of a miniaturized, improved nucleic acid precursor incorporation assay for chemosensitivity testing of human solid tumors.

Two technological problems limit the usefulness of chemosensitivity assays: low success rates (generally 30-60%); and the requirement for large numbers of tumor cells (5 X 10(5)/dish). To solve these problems, we developed a miniaturized, improved, nucleic acid precursor incorporation assay (MINI-assay). In this new assay, 0.3-1.5 X 10(5) tumor cells were plated in double-layer agarose in 16-mm wells of a Costar (No. 3524) 24-well cluster dish. After 72 h of incubation, 5 microCi [3H]thymidine were added to each well. After an additional 24 h of incubation, the trichloroacetic acid-precipitable material was collected and counted by liquid scintillation. We found that 280 of 351 (80%) human solid tumors gave evaluable chemosensitivity results. Labeling efficiency was optimum when the plating density was between 1.5 and 3 X 10(4) cells/well. Radioisotope uptake was less efficient in 35-mm Petri dishes and in the 7-mm wells. The MINI-assay was particularly suitable for small specimens (less than 1 g) and for tumor types that usually yield small numbers of viable tumor cells (19 of 30 breast cancers and 56 of 71 sarcomas were evaluable). The artifacts of colony counting (cell clumps, debris, clots) were also eliminated with this assay. With high evaluability rates, the requirement of fewer cells, a short duration (5 days), and ease of quantitation, the MINI-assay is widely applicable to chemosensitivity testing in human tumors.

Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells.

The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5ß1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.

High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNalpha2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNalpha2b (HDI) for 1 year and low-dose IFNalpha2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months' median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P(2) =.05); for LDI versus Obs, it was 1.19 (P(2) =.17). By Cox analysis, the impact of HDI on RFS achieved significance (P(2) =.03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNalpha-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNalpha2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690. CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.

Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2.

PURPOSE: In preclinical studies, we have reported the ability to induce immune T cells in lymph nodes (LN) primed by in vivo vaccination with tumor cells admixed with a bacterial adjuvant. These LN cells can be activated and expanded ex vivo for the successful immunotherapy of established tumors. We have applied these methods to generate vaccine-primed LN in patients with advanced melanoma and renal cell cancer (RCC) for therapy. MATERIALS AND METHODS: Irradiated autologous tumor cells admixed with bacille Calmette-Guérin (BCG) were used to vaccinate patients. Seven days later, draining LN were removed for activation with anti-CD3 monoclonal antibody (mAb) followed by expansion in interleukin-2 (IL-2). Activated LN cells were administered intravenously (IV) with the concomitant administration of IL-2. RESULTS: A total of 23 patients were evaluated (11 melanoma and 12 RCC). Vaccine-primed LN were expanded ex vivo with a mean of 8.4 x 10(10) cells administered per patient. Among 20 patients assessed, 15 demonstrated minimal cytotoxicity of autologous tumor cells by the activated LN cells, with the remaining mediating nonspecific cytotoxicity. By contrast, a majority of the activated LN cells showed highly specific release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) to autologous but not allogeneic tumor stimulation. This tumor-specific cytokine release was found to be major histocompatibility complex (MHC) class I-restricted, which indicates the involvement of CD8+ cells. Among 11 melanoma patients, one had a partial tumor response. Among 12 RCC patients, two had complete and two partial responses. A trend (P = .066) between the enhancement of delayed-type hypersensitivity (DTH) reactivity to autologous tumor after therapy and tumor regression was observed. CONCLUSION: Tumor vaccines can be used to induce immunologically specific T-cell responses against melanoma and RCC in draining LN. Anti-CD3/IL-2 activation of primed LN cells can be reliably performed for clinical therapy and appears to have activity in patients with metastatic RCC.

High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801.

PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly x 4 then every 12 weeks x 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to > or = four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers > or = 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P2 = .068 at day 29). CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.