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Background: Pembrolizumab significantly improved overall survival (OS) versus ipilimumab for unresectable advanced melanoma in KEYNOTE-006 (NCT01866319); 10-year follow-up data are presented., Patients and Methods: Patients with unresectable stage III or IV melanoma were randomly assigned (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 weeks or every 3 weeks for ≤2 years (pooled), or ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles. After KEYNOTE-006, patients could transition to KEYNOTE-587 (NCT03486873) for long-term follow-up. Eligible patients could receive second-course pembrolizumab. The primary endpoint was OS; modified progression-free survival (PFS; censored at date last known alive), modified PFS on second-course pembrolizumab, and melanoma-specific survival were exploratory., Results: Of 834 patients randomly assigned in KEYNOTE-006 (pembrolizumab, n = 556; ipilimumab, n = 278), 333 (39.9%) were eligible for KEYNOTE-587; 211/333 patients (25.3%) transitioned to KEYNOTE-587 (pembrolizumab, n = 159; ipilimumab, n = 52) and 122 (14.6%) did not. For patients who transitioned to KEYNOTE-587 (n = 211), median time from randomization in KEYNOTE-006 to data cut-off for KEYNOTE-587 (1 May 2024) was 123.7 months (range, 122.0-127.3 months). Median OS was 32.7 months [95% confidence interval (CI) 24.5-41.6 months] for pembrolizumab and 15.9 months (95% CI 13.3-22.0 months) for ipilimumab [hazard ratio (HR), 0.71 (95% CI 0.60-0.85)]; 10-year OS was 34.0% and 23.6%, respectively. Among patients who completed ≥94 weeks of pembrolizumab, median OS from week 94 was not reached (NR; 95% CI NR-NR); 8-year OS rate was 80.8%. Median modified PFS was 9.4 months (95% CI 6.7-11.6 months) for pembrolizumab and 3.8 months (2.9-4.3 months) for ipilimumab [HR, 0.64 (95% CI 0.54-0.75)]. Among patients who received second-course pembrolizumab, median modified PFS from start of second course was 51.8 months (95% CI 11.0 months-NR); 6-year modified PFS was 49.2%. Median melanoma-specific survival was 51.9 months (95% CI 30.0-114.7 months) for pembrolizumab and 17.2 months (13.9-25.9 months) for ipilimumab [HR, 0.66 (95% CI 0.55-0.81)]., Conclusions: These results confirm that pembrolizumab provides long-term survival benefits in advanced melanoma, supporting it as a standard of care in this setting., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Aims: To make recommendations on managing the surveillance of patients with stage I, II, III or resectable IV melanoma who are clinically free of disease following treatment with curative intent., Materials and Methods: This guideline was developed by Ontario Health's (Cancer Care Ontario's) Program in Evidence-Based Care and the Melanoma Disease Site Group (including seven medical oncologists, four surgical oncologists, three dermatologists, one radiation oncologist and one patient representative). The MEDLINE, EMBASE, Cochrane Library, PROSPERO databases and the main relevant guideline websites were searched. Internal and external reviews were conducted, with final approval by the Program in Evidence-Based Care and the Melanoma Disease Site Group. The Grading of Recommendations, Assessment, Development and Evaluation approach was followed, and the Modified Delphi method was used., Results: Based on the current evidence (eight eligible original study papers and four relevant guidelines) and the clinical opinions of the authors of this guideline, the initial recommendations were made. To reach 75% agreement for each recommendation, the Melanoma Disease Site Group (16 members) voted twice and one recommendation was voted on three times. After a comprehensive internal and external review process (including national and international reviewers), 12 recommendations, three weak recommendations and six qualified statements were ultimately made., Conclusions: After a systematic review, a comprehensive internal and external review process and a consensus process, the current guideline has been created. The guideline authors believe that this guideline will help clinicians, patients and policymakers make well-informed healthcare decisions that will guide them in clinical melanoma surveillance and ultimately assist in improving patient outcomes., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Introduction: Cutaneous melanoma accounts for more than 70% of all skin cancer deaths. Follow-up surveillance is an integral part of melanoma patient care, to facilitate early detection of recurrences and subsequent primary melanomas. The purpose of this scoping review is to provide an overview of recently published melanoma surveillance guidelines from regional and national melanoma working groups., Methods: A systematic search for relevant studies in MEDLINE and Embase was conducted in September 2022 and was limited to publications from 2010 or later., Results: A total of 1047 articles were retrieved, and after abstract and full text review, 26 articles from 19 different organizations met inclusion criteria. Life-long annual skin surveillance with a physician was recommended by 53% (9/17) of guidelines. Routine laboratory investigations were recommended by 7/19 guidelines. Regional lymph node ultrasound was recommended by 9/16 guidelines, most often in stage IB or higher, and was optional in 7/16 for patients who met specific criteria. Surveillance with PET-CT or CT and MRI was recommended by 15 and 11 guidelines, respectively, most commonly in stage IIC or higher, with a variable frequency and total duration. Five out of 9 guidelines indicated a preference for skin surveillance to be completed with a dermatologist., Conclusion: Guidelines were highly variable for many aspects of melanoma surveillance, which may be partly attributed to regional differences in healthcare workforce distribution and availability of imaging technologies. Further high-level studies are recommended to provide more evidence on the most effective clinical and imaging follow-up surveillance protocols., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients., Competing Interests: Declaration of interests I.R.W. reports grants from Canadian Institutes of Health Research (grant #PJT-152975), the Melanoma Research Alliance (grant #412429), and the Canada Research Chairs Program. I.R.W. also reports collaboration with KEW, Inc. outside the submitted work. T.P. has received funding from Novartis and Roche and has also received honoraria from and has been on advisory boards for Novartis, BMS, Merck, Sunpharma, Sanofi, and Pfizer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this guideline is to provide guidance on appropriate management of satellite and in-transit metastasis (itm) from melanoma., Methods: The guideline was developed by the Program in Evidence-Based Care (pebc) of Ontario Health (Cancer Care Ontario) and the Melanoma Disease Site Group. Recommendations were drafted by a Working Group based on a systematic review of publications in the medline and embase databases. The document underwent patient- and caregiver-specific consultation and was circulated to the Melanoma Disease Site Group and the pebc Report Approval Panel for internal review; the revised document underwent external review., Recommendations: "Minimal itm" is defined as lesions in a location with limited spread (generally 1-4 lesions); the lesions are generally superficial, often clustered together, and surgically resectable. "Moderate itm" is defined as more than 5 lesions covering a wider area, or the rapid development (within weeks) of new in-transit lesions. "Maximal itm" is defined as large-volume disease with multiple (>15-20) 2-3 cm nodules or subcutaneous or deeper lesions over a wide area.■ In patients presenting with minimal itm, complete surgical excision with negative pathologic margins is recommended. In addition to complete surgical resection, adjuvant treatment may be considered.■ In patients presenting with moderate unresectable itm, consider using this approach for localized treatment: intralesional interleukin 2 or talimogene laherparepvec as 1st choice, topical diphenylcyclopropenone as 2nd choice, or radiation therapy as 3rd choice. Evidence is insufficient to recommend intralesional bacille Calmette- Guérin or CO 2 laser ablation outside of a research setting.■ In patients presenting with maximal itm confined to an extremity, isolated limb perfusion, isolated limb infusion, or systemic therapy may be considered. In extremely select cases, amputation could be considered as a final option in patients without systemic disease after discussion at a multidisciplinary case conference.■ In cases in which local, regional, or surgical treatments for itm might be ineffective or unable to be performed, or if a patient has systemic metastases at the same time, systemic therapy may be considered., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: TMP reports grants from Roche, Novartis, Merck, and Bristol– Myers Squibb and has served on advisory boards for Novartis, Merck, Bristol–Myers Squibb, emd Serono, and Sanofi outside the submitted work. FCW, SK, NJLH, AYS, TPH, CN, CAG, CFRO, and XS have no conflicts to disclose., (2020 Multimed Inc.)

Background: Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma., Methods: The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review., Recommendations: For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wild-type disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: TMP reports grants from Roche, Novartis, Merck, and personal fees from Novartis, Merck, Bristol–Myers Squibb, and emd Serono, outside the submitted work. GGF reports grants to the pebc at McMaster University from oh(cco) or the moh during the conduct of the literature review and guideline development. GK reports personal fees from Bristol–Myers Squibb, Merck, Roche, and Sanofi, outside the submitted work. EM reports serving on advisory boards for Novartis, Merck, Bristol–Myers Squibb, and Roche, outside the submitted work, and work as a local principal investigator on the combi-ad, comi-a Plus, and mec.5 trials. XS reports consulting fees from Bristol–Myers Squibb, Merck, and Novartis, outside the submitted work, and work as a research investigator for the Bristol–Myers Squibb CheckMate 067, 047, and 915 trials, the Merck keynote-252 and -054 trials, the brim8 trial, and the combi-dv and combi-ad trials. TDB reports personal fees from Bristol–Myers Squibb, Merck, and Novartis, outside the submitted work. SR has no conflicts to disclose., (2020 Multimed Inc.)

Background: For patients who are diagnosed with early-stage cutaneous melanoma, the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes. The purpose of the present guideline was to update the 2010 Cancer Care Ontario guideline on wide local excision margins and sentinel lymph node biopsy (slnb), including treatment of the positive sentinel node, for melanomas of the trunk, extremities, and head and neck., Methods: Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb for melanoma of the truck and extremities and of the head and neck. Search timelines ran from 2010 through week 25 of 2017., Results: Four systematic reviews were chosen for inclusion in the evidence base. Where systematic reviews were available, the search of the primary literature was conducted starting from the end date of the search in the reviews. Where systematic reviews were absent, the search for primary literature ran from 2010 forward. Of 1213 primary studies identified, 8 met the inclusion criteria. Two randomized controlled trials were used to inform the recommendation on completion lymph node dissection.Key updated recommendations include:■ Wide local excision margins should be 2 cm for melanomas of the trunk, extremities, and head and neck that exceed 2 mm in depth.■ slnb should be offered to patients with melanomas of the trunk, extremities, and head and neck that exceed 0.8 mm in depth.■ Patients with sentinel node metastasis should be considered for nodal observation with ultrasonography rather than for completion lymph node dissection., Conclusions: Recommendations for primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in patients with cutaneous melanoma have been updated based on the current literature., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

Purpose: Variability exists regarding optimal staging for node-positive melanoma. Options include combinations of physical examination (PE), radiography, computed tomography (CT), and positron emission tomography (PET). Cost-effectiveness of regimens has never been investigated., Methods: A modeled cost-effectiveness analysis was performed to examine the cost per surgery performed and per accurate diagnosis achieved with three staging regimens (PE/chest radiography, CT, PET/CT) for node-positive melanoma. Incremental cost-effectiveness ratios were used to compare regimens. Deterministic and probabilistic sensitivity analyses were undertaken to address variation in parameters. Costs are direct from the perspective of the Canadian single-payer system and 2012 valuations., Results: Staging with PE/radiography is the least cost-effective option, resulting in greater costs than CT alone, and fewer accurate diagnoses. Compared to CT alone, PET/CT incurs greater incremental cost ($902.81CAD), but results in 4% fewer lymphadenectomies and 4% more accurate diagnoses. PET/CT costs $22,570.25CAD for each additional accurate diagnosis achieved compared to CT alone. Sensitivity analyses demonstrate that the optimal staging strategy is influenced by diagnostic test characteristics and the willingness-to-pay threshold, but robust to other varied parameters., Conclusions: PE/radiography appears to be the least cost-effective staging regimen. The benefit of PET/CT over CT alone depends on a health system's priorities and willingness-to-pay., (© 2014 Wiley Periodicals, Inc.)

The last couple of years have seen the beginning of a new era in the treatment of metastatic melanoma. This disease is typically characterized by its poor prognosis and limited choice of therapy. Two mechanistically diverse classes of agents - BRAF inhibitors and immune modulators - have demonstrated an overall survival benefit. Along with their significant clinical benefits, there are also unique adverse events (AEs) related to these agents. While most of the AEs are mild and easily managed with supportive treatment, others require more aggressive management strategies. Education of all members of the multidisciplinary care team and awareness of these toxicities are crucial in order to optimize patient outcomes. The landscape of melanoma is continually evolving as ongoing trials are evaluating monotherapy and combination options. While these regimens continue to show promise for the future, understanding and managing toxicities of currently available therapies is required.

After complete resection of melanoma, some patients remain at high risk for recurrence. The efficacy of adjuvant systemic therapy has been inconsistent in randomised trials and remains controversial. An updated systematic review was conducted to identify new evidence on the role of adjuvant interferon therapy in patients with high-risk resected primary melanoma. Outcomes of interest included overall survival, disease-free survival (DFS), adverse effects and quality of life. MEDLINE, EMBASE, Cochrane Library and the proceedings of the American Society of Clinical Oncology were systematically searched to identify new randomised controlled trials, systematic reviews or meta-analyses. An updated meta-analysis of trials comparing high-dose interferon alpha with observation alone was conducted. The new data are presented in this review. Seven randomised controlled trials met the inclusion criteria: six trials of interferon alone and two trials of interferon plus chemotherapy. Two meta-analyses of adjuvant interferon alpha were also identified. Overall survival was not significantly different between adjuvant high-dose interferon and observation alone (hazard ratio 0.93; 95% confidence interval 0.78-1.12; P = 0.45). A meta-analysis of DFS showed a significant benefit for high-dose interferon over control (hazard ratio 0.77; 95% confidence interval 0.65-0.92; P = 0.004). One trial reported a significant DFS benefit for pegylated interferon over observation alone. Our updated literature review indicates that adjuvant interferon therapy does not confer a significant long-term overall survival benefit in patients with high-risk resected primary melanoma; however, a significant DFS benefit for high-dose interferon or pegylated interferon treatment has been shown. An revised practice guideline was developed based on the systematic review., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Regional Metastatic Melanoma has a relatively high mortality rate. Adjuvant interferon-alpha (IFN-α) has been shown to improve disease-free survival, post-resection. Cardiotoxicity associated with IFN-α use has been described previously in the literature, but here we describe the first case of pericardial effusion with cardiac tamponade secondary to IFN-α 2b treatment of melanoma. Clinicians should be aware of this potentially lethal complication and the possible acuity of its onset.

Background: Recently characterized KIT (CD117) gene mutations have revealed new pathways involved in melanoma pathogenesis. In particular, certain subtypes harbor mutations similar to those observed in gastrointestinal stromal tumors, which are sensitive to treatment with tyrosine kinase inhibitors., Objective: The purpose of this study was to characterize KIT gene mutations and patterns of protein expression in mucosal and acral melanoma., Methods: Formalin-fixed, paraffin-embedded tissues were retrieved from our archives. Histologic assessment included routine hematoxylin-eosin stains and immunohistochemical staining for KIT. Genomic DNA was used for polymerase chain reaction-based amplification of exons 11 and 13., Results: We identified 59 acral and mucosal melanoma cases, of which 78% showed variable levels of KIT expression. Sequencing of exons 11 and 13 was completed on all cases, and 4 (6.8%) mutant cases were isolated., Conclusion: We successfully optimized conditions for the detection of KIT mutations and showed that 8.6% of mucosal and 4.2% of acral melanoma cases at our institution harbor KIT mutations; all mutant cases showed strong, diffuse KIT protein expression. Our case series represents the first Canadian study to characterize KIT gene mutations and patterns of protein expression in acral and mucosal melanoma.

Aims: For patients with early-stage melanoma, uncertainty exists regarding optimal surgical excision margins of the primary tumour and surgical management of the clinically node-negative lymph node basin. We describe the process of creating a provincial guideline for the treatment of node-negative melanoma of the trunk and extremities. The following research questions were addressed: What are the optimal excision margins for clinically node-negative cutaneous melanoma and should these patients undergo sentinel lymph node biopsy?, Materials and Methods: Outcomes were local and regional recurrence, overall and disease-free survival, and morbidity. The MEDLINE and EMBASE databases, National Guideline Clearinghouse, CMA Infobase and websites of guideline development organisations were systematically searched. Using the AGREE instrument, relevant guidelines were assessed and an updated literature search completed. A systematic review and practice guideline was written, reviewed and approved by the Melanoma Site Group and the Program in Evidence-based Care Report Approval Panel. External review by three melanoma experts was completed, as was an online consultation with healthcare professionals who were intended users of the guideline., Results: One guideline was selected for adoption: the Australian Cancer Network National Health and Medical Research Council and the New Zealand Guidelines group 2008 melanoma guideline. An updated literature search was undertaken to include relevant studies published since the adopted guideline was completed., Conclusions: Excision margins range from 5mm to 2cm depending on the melanoma depth. Patients with a melanoma greater than 1.0mm in thickness should be given the opportunity to discuss sentinel lymph node biopsy to provide staging and prognostic information., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.

The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing.

Background: This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects., Methods: The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to 2005. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials., Results: Two randomized phase III trials and three randomized phase II trials were located. In addition, 21 phase I or II trials investigating single-agent temozolomide, temozolomide plus interferon-alpha, and temozolomide plus thalidomide were reviewed. A direct comparison of temozolomide and dacarbazine demonstrated equal efficacy for response rates and overall survival; however, no significant difference was reported. A second phase III study comparing single-agent temozolomide with temozolomide combined with interferon-alpha indicated a significantly higher response rate for the combination treatment arm, but no difference in overall survival was noted. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and interferon-alpha or thalidomide., Conclusion: Our review of the available literature suggests that temozolomide demonstrates comparable activity to the current standard treatment, dacarbazine, with the additional benefit of being a convenient oral treatment that penetrates the blood-brain barrier.

Background: The aim of this systematic review was to determine the role of single-agent interleukin-2 in the treatment of adults with metastatic melanoma. Outcomes of interest include objective and complete response rates, duration of response, toxicity and quality of life., Methods: A systematic review of the literature was conducted to locate randomized controlled trials, meta-analyses, and systematic reviews published between 1985 and 2006., Results: Data from three randomized controlled trials demonstrate that single-agent interleukin-2, when given in high-doses, elicited objective response rates of 5-27% with complete responses in 0-4% of patients. High-dose interleukin-2, administered as a single-agent or in combination with lymphokine-activated killer cells, demonstrates complete response rates ranging from 0% to 11% and has shown consistent observations of long-term responses that range from 6 to 66+ months (median 27 months). Non-comparative phase II trials of high-dose single-agent interleukin-2 have consistently reported objective response rates of 10-33% with complete response rates ranging from 0% to 15%. Complete responders in those trials also demonstrate long-term responses ranging from 1.5 to 148 months (median 70 months). No other therapy for metastatic melanoma offers the possibility for a durable complete remission., Conclusion: This systematic review suggests that patients with a good performance status (ECOG 0-1), a normal lactate dehydrogenase level, less than three organs involved or cutaneous and/or subcutaneous metastases, have the highest probability of responding and achieving a durable complete response. This carefully selected group of patients should be considered for treatment with high-dose interleukin-2.

Background: The route of administration and extent of helper T-cell activation are factors that are likely to be important for the development of effective cancer vaccines. In order to optimize CD8(+) cytotoxic T-lymphocyte (CTL) responses, the immunologic effects of direct lymph node (LN) injections of canary pox virus (ALVAC) vectors (expressing the melanoma antigen, gp100) and immunogenic gp100 peptides, along with concomitant injections of the helper adjuvant, tetanus toxoid, were studied in high-risk HLA-A*0201(+) patients., Methods: Forty-two patients were vaccinated using six different protocols. Twenty-three patients were 'primed' with ALVAC(2)-gp100m and 'boosted' with gp100 peptides, either subcutaneously or into an LN. Intranodal (IN) peptides, alone, were administered to six patients. Thirteen patients were given tetanus toxoid initially, and with each gp100 vaccination. Toxicity was recorded and immunologic responses were determined in 35 patients by enzyme-linked immunospot (ELISPOT) and gp100-tetramer binding assays and anti-ALVAC(2) enzyme-linked immunosorbent assays (ELISAs)., Results: All vaccine protocols were tolerated well. Using stringent criteria for immunologic response, 8 of 18 patients responded to the viral vaccines, in striking contrast to peptides only (0 of 6 patients) or with help in trans from tetanus-reactive T-cells (1 of 11 patients). Changes in gp100-reactive CTL frequencies and ALVAC antibodies were greatest when viruses were injected directly into LNs., Conclusions: IN injections of ALVAC(2)-gp100m viruses are feasible, safe, and may be a superior method of vaccination in humans. CTL responses to this vaccine were not enhanced by tetanus toxoid., (Copyright 2006 American Cancer Society.)

Purpose: The therapeutic effectiveness of cancer vaccines, composed of tumor antigens that are also self-antigens, may be limited by the normal mechanisms that preserve immunological tolerance. Consistent with this notion, we found that vaccination of melanoma patients with recombinant viral vaccines expressing gp100 (a melanoma antigen also expressed by normal melanocytes) produced only transient increases in noncytotoxic T cells specific for immunodominant gp100 epitopes. To improve the therapeutic effects of these vaccines, IFN-alpha2b (IFN-alpha) was administered to some high-risk patients., Experimental Design: 7 HLA-A*0201(+) patients were injected with high doses of IFN-alpha (20 MU/m(2) x 20 doses) at various times after completing the vaccination protocol. Clinical toxicity and responses were documented, and the effects on gp100-reactive T cells were measured by IFN-gamma enzyme-linked immunospot assays, tetramers of HLA-A*0201 and gp100 epitopes, and cellular cytotoxicity assays., Results: In patients who had previously responded to vaccination, high doses of IFN-alpha recalled gp100-reactive T cells with the ability to kill gp100-expressing tumor targets in vitro. Concomitant with the reappearance of these cytotoxic T cells, tumor regression was observed in the two patients with clinically evident metastatic disease., Conclusions: The finding that high-dose IFN recalls previously activated tumor-reactive T cells with potent killing ability suggests a strategy to maintain antitumor responses initiated by cancer vaccines.

Background Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. Methods This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. Results Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). Conclusions Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered. [ABSTRACT FROM AUTHOR]

Background The use and detailed costs of services provided for people with advanced melanoma (AMEL) are not well known. We conducted an analysis to determine the use of health care services and the associated costs delineated by relevant attributable costs, which we defined for subjects in the province of Ontario. Methods Through the Ontario Cancer Data Linkage Project, a cohort of AMEL patients with diagnoses between 31 August 2005 and 2012 (follow-up to 2013) and with valid International Classification of Diseases (9th revision, Clinical Modification) 172 codes and histology codes was identified. A cohort of individuals with AMEL having a combination of at least 1 palliative, 1 medical oncology, and 1 hospitalization code was generated. The health system services used by this population were clustered into hospitalization, palliation, physician medical visits, medication, homecare, laboratory, diagnostics, and other resources. Overall rates of use and disaggregated costs were determined by phase of care for the entire cohort. Results The mean age for the 2748 individuals in the cohort was 67 years. The greater proportion of the patients were men (65.6%) and were more than 65 years of age (>50%). In this advanced cohort, fewer than 45% of patients were alive 3 years after the malignant melanoma diagnosis. The average annual cost per patient over the time horizon was $6,551. At $15,830, year 1 after diagnosis was the most expensive, followed by year 2, at $8,166. Conclusions Our data provide a baseline for the costs associated with AMEL treatment. Future studies will include newer agents and comparative effectiveness research for personalized therapies. [ABSTRACT FROM AUTHOR]

Background Detailed epidemiology for patients with advanced metastatic melanoma in Canada is not well characterized. We conducted an analysis of patients with this disease in the province of Ontario, with the aim being to study the presentation, disease characteristics and course, and treatment patterns for malignant melanoma. Methods In this Canadian observational prospective and retrospective study of patients with malignant melanoma, we used data collected in the Canadian Melanoma Research Network (CMRN) Patient Registry. We identified patients who were seen at 1 of 3 cancer treatment centres between April 2011 and 30 April 2013. Patient data from 2011 and 2012 were collected retrospectively using chart records and existing registry data. Starting January 2013, data were collected prospectively. Variables investigated included age, sex, initial stage, histology, mutation type, time to recurrence, sites of metastases, resectability, and previous therapies. Results A cohort of 810 patients with melanoma was identified from the CMRN registry. Mean age was 58.7 years, and most patients were men (60% vs. 40%). Factors affecting survival included unresectable or metastatic melanoma, initial stage at diagnosis, presence of brain metastasis, and BRAF mutation status. The proportion of surviving patients decreased with higher initial disease stages. Conclusions Using registry data, we were able to determine the detailed epidemiology of patients with melanoma in the Canadian province of Ontario, validating the comprehensive and detailed information that can be obtained from registry data. [ABSTRACT FROM AUTHOR]

Background: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. Patients and methods: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. Results: ORR was 26.2% (n=11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. Conclusion: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. [ABSTRACT FROM AUTHOR]