Cytoreductive surgery for melanoma

Cytoreductive surgery represents a therapeutic attempt to improve patient outcomes by reducing overall tumor burden to render postsurgical therapy effective or at least increase its effectiveness. The intent of cytoreduction differs from palliative or curative-intent surgery for oligometastatic melanoma. Both palliative surgery and attempted curative resection have important roles to play in the management of patients with melanoma that has spread beyond the regional nodes or recurred "in transit" between the primary and the regional nodal basin. To date, however, no evidence shows that cytoreductive surgery offers any meaningful benefit to patients with metastatic melanoma, and, outside of a clinical trial, there is no role for cytoreductive surgery in melanoma. To date, adjuvant vaccine therapy after complete resection of metastatic melanoma has not proved to be efficacious in clinical trials, so there is little reason to believe that the use of currently available immunotherapy strategies will be enhanced after incomplete tumor resections.     

Neoadjuvant therapy for melanoma: A critical appraisal

The treatment of advanced melanoma has significantly changed since the development of targeted and immune therapy. To date, these agents have primarily been used in the adjuvant or metastatic setting. Given several theoretical advantages, there is increased interest in the use of these new therapeutics in the neoadjuvant setting. In this review, we detail the potential benefits and pitfalls of neoadjuvant therapy for melanoma, review the currently available data, and describe ongoing neoadjuvant trials.     

Intermediate- and high-risk melanoma

Opinion statement Intermediate and high risk for recurrence melanoma comprise a unique subset of patients with surgically treatable melanoma for whom cure is possible but relapse and distant metastases likely. Strategies to improve the prognosis for such patients with effective adjuvant therapies are critical. In recent randomized trials conducted by the cooperative groups in the United States of patients at high risk for recurrence (patients with thick primary melanomas and those with regional lymph node metastases) administered adjuvant therapy with high-dose interferon alfa-2b (HDI), relapse-free survival and overall survival rates improved significantly. Research efforts in this area continue to assess the role of intermediate-dose interferon, but there is no convincing evidence of success of the lower-dose regimens, despite the reduction in toxicity. For a subset of patients at highest risk (two or more involved lymph nodes), a regimen of therapy for metastatic stage IV melanoma (interleukin-2 based biochemotherapy) is being compared with HDI in an ongoing phase III trial. For intermediate-risk melanoma, no effective adjuvant therapy is available. For such patients, enrollment in ongoing clinical trials assessing the role of shorter courses of HDI or vaccines should be encouraged.     

Adjuvant therapy for resected stage III melanoma patients: high-dose interferon-alpha versus ipilimumab combined with kinases inhibitors

High-dose interferon-alpha remains the first-line treatment in the adjuvant therapy of metastatic melanoma. More recently, high-dose pegylated interferon-alpha-2b has been approved by the US Food and Drug Administration. Actually, an adjuvant therapy alternative to high-dose interferon-alpha is represented by ipilimumab. Moreover, combination therapy of IFN-alpha or ipilimumab with tyrosine kinase inhibitors has been proved in patients with specific mutations. It is mandatory to understand what the best adjuvant treatment is for resected metastatic melanoma patients, particularly at stage III-N1, in terms of overall survival rather than recurrence-free survival. The ECOG 1609 clinical trial compared high-dose interferon-alpha and ipilimumab alone or combined with tyrosine kinase inhibitors for the treatment of early metastatic melanoma. In the past, ECOG 1684, 1690 and 1694 trials showed improvement in recurrence-free survival more than overall survival for high-risk melanoma patients (stage IIB-III) treated with high-dose interferon-alpha, whereas more recently the EORTC 18991 trial reported successful therapeutic results in terms of recurrence-free survival rather than overall survival for stage III-N1 melanoma patients treated with high-dose pegylated interferon-alpha-2b. Toxicity was more acceptable within one year of treatment. Randomized trials have demonstrated that ipilimumab as second-line therapy is able to increase dose-dependent overall survival rates in advanced melanoma patients despite severe but reversible immune-related adverse events. Old tyrosine kinase inhibitors have been used in combination with interferon for the treatment of advanced melanoma patients with moderate benefits and increased toxicity, but new selective drugs seem to be more efficacious. Early metastatic melanoma patients (stage III-N1) should be the principal subset to be treated with the most suitable adjuvant therapy to achieve the best overall survival. New schedules have to be tested with high-dose interferon-alpha and ipilimumab alone or combined with tyrosine kinase inhibitors while waiting for results from ECOG 1609.     

Early stage (I,II, III) melanoma

Opinion statement Metastatic melanoma beyond the regional nodes (American Joint Committee on Cancer stage IV) is a highly lethal disease. Few affected individuals survive beyond 5 years despite aggressive treatment. Clearly, effective adjuvant therapies to prevent the development of stage IV disease in at-risk patients are worthwhile and acceptable to patients, even if they are associated with significant toxicities. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adherence to the standards of care for the surgical management of melanoma patients with high-risk primary disease or regional disease will help optimize the benefit that can be derived from adjuvant therapy. Clinical trials remain critically important as we seek to improve the outcome for melanoma patients, but for high-risk melanoma patients outside the context of clinical trials, adjuvant therapy with high-dose interferon-alfa2b should be considered a standard treatment option.     

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1–2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.     

Metastatic melanoma

Opinion statement The overall survival for patients with metastatic melanoma ranges from 4.7 to 11 months, with a median survival of 8.5 months. Standard treatment for patients with metastatic melanoma has not been defined. The range of treatment options includes close observation, surgical resection of isolated metastases, therapy with dacarbazine, combination chemotherapy, and participation in clinical trials. Numerous chemotherapeutic agents have shown activity in the treatment of malignant melanoma. Dacarbazine (DTIC-Dome; Bayer Corporation, West Haven, CT) has a response rate of 15% to 20% and remains the reference agent for the treatment of metastatic disease. Additional agents with single-agent activity include cisplatin, (Platinol-AQ; Bristol-Myers Oncology, Princeton, NJ); carmustine (BiCNU; Bristol-Myers Oncology, Princeton, NJ); paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ); and docetaxel (Taxotere; Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, PA). Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ), which is essentially an oral form of dacarbazine but with greater central nervous system penetrance, is associated with a response rate of 20%. Combination chemotherapy with or without tamoxifen has been extensively evaluated in patients with metastatic melanoma. Although the initial results with the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) were associated with overall response rates of 50% to 55% in single-institution studies, results from larger multicenter studies reveal responses rates ranging from 10% to 20%. Based on the results of several clinical trials, there is no evidence that the addition of tamoxifen improves the response rate. Another combination regimen is cisplatin, vinblastine, and dacarbazine (CVD), which is associated with a 20% to 25% response rate. There has been widespread interest in developing immunotherapies against metastatic melanoma. Interferon (IFN)-alfa and interleukin (IL)-2 as single agents have produced response rates in the 15% to 20% range. Biochemotherapy, which is a combination of immunotherapy and cytotoxic chemotherapy, has been studied in patients with metastatic melanoma. Multiple phase II studies have demonstrated high response rates but unclear impact on overall survival. Therapy is associated with significant toxicity. Ongoing randomized clinical trials will clarify the role of biochemotherapy in patients with metastatic melanoma. Ongoing new approaches to treatment include the therapeutic use of vaccines alone or in combination with cytokines.     

Clinical development of the anti-CTLA-4 antibody tremelimumab

Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.     

Systemic therapy for metastatic melanoma in 2012: dawn of a new era

The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for these patients. After decades of failed attempts to improve treatment outcomes, recent successes with ipilimumab and vemurafenib have ushered in a new era in systemic therapy. Both ipilimumab and vemurafenib are associated with significant improvements in overall survival of patients in randomized phase III trials, an end point that had proven elusive so far. These breakthroughs not only provide more treatment options for patients with melanoma but also spur the investigation of a new generation of drugs for cancer therapy in general. This article reviews both the current systemic treatment options for metastatic melanoma and promising investigational approaches.     

Medikamentöse Therapie des metastasierten Melanoms im Rahmen prospektiv-randomisierter Studien

Progress in the systemic treatment of patients suffering from metastatic melanoma has been quite limited over the last 25 years. Over the past 10–15 years, a number of randomized clinical trials were performed to lay the basis for an evidence-based assessment of available compounds. In Germany, the anticancer agents dacarbazine, vindesine, and cisplatin are registered for metastatic melanoma; in other countries fotemustine and the cytokine interleukin-2 are also registered. The overall conclusion of these randomized trials is that there is no survival benefit for patients treated with a combination chemo(bio)therapy, in contrast to the initial expectations. The recommendations are therefore back to single agent treatment approaches and treatment inside of controlled clinical trials. A possible exception may be the treatment of patients with significant tumor-related symptoms that may justify the use of a more toxic polychemotherapy for palliative reasons. Various worldwide registration studies have been completed which have tested the combination of histamine and interleukin-2 or dacarbazine and Bcl-2 antisense oligonucleotides. The results of these trials and possibly licensing of the drug combinations are expected over the next 12 months.     

Targeted therapies in melanoma

In the last decade the incidence of melanoma has been rising. Despite this, survival remains substantially constant because early diagnosis of thin lesions has increased. By contrast, metastatic melanoma continues to have a poor prognosis and it still represents a challenge for oncologists. Response rates with single agent dacarbazine range from 10% to 25% with median survival of 8 months. The advent of new drugs with specific mechanisms of action could help to improve the poor results of traditional therapies. In this review, we focused on the novel agents that entered clinical trials in melanoma patients. We show the results of some clinical trials with target-oriented drugs in melanoma patients. Moreover pre-clinical data and rationale for use in melanoma was explained. Trials with protein-kinase inhibitors, anti-CTLA-4 agents, pro-apoptotic oligonucleotides and anti-angiogenic agents were reviewed. Combinations with chemotherapeutic agents, immunotherapy and vaccine therapy were also analyzed.     

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma

Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.     

Experimental trials of immunotherapy for malignant melanoma

Conventional treatment for metastatic melanoma consists of surgical resection, chemotherapy, and radiation therapy. New approaches toward treatment of this disease include the development of passive and active immunotherapeutic regimens. Malignant melanoma is particularly amendable to immunotherapy since the tumor is relatively immunogenic, expressing unique cell surface protein and lipid antigens. Clinical trials investigating the benefit of active specific immunotherapy documented increased survival of invasive Stage 1 and metastatic Stage 2 melanoma patients following immunization with tumor cell vaccines and BCG. Additional trials showed that the development of specific antibodies after immunization of Stage 2 patients with a viral oncolysate was correlated with an increased survival compared to matched controls given only BCG. Passive immunotherapy approaches using either lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) administered with interleukin 2 have also resulted in regression of disease with complete or partial remissions occurring in 25% of the patients. Additional studies have focused on the generation of specific cytotoxic T lymphocytes by stimulation with autologous tumor in vivo. Future trials will evaluate the therapeutic efficacy of these specific cytologic T lymphocytes relative to LAK and TIL.     

Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases

Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.     

Dendritic cell immunotherapy for stage IV melanoma

Active boosting of the antitumour immune response of patients with solid malignancies has been tested in a large number of trials. Isolated complete clinical responses have been reported, however, they have not been replicated in subsequent studies. We recently reported objective clinical responses to a dendritic cell/irradiated autologous tumour cell 'vaccine' in patients with distant metastatic (stage IV) melanoma. Here we describe our experience in a second cohort of patients with stage IV melanoma, using this dendritic cell-based immunotherapy in a cryopreserved format. Of 46 patients enrolled into the study, three had complete remission of all detectable disease, and a further three had partial clinical responses. These data confirm that dendritic cell-based immunotherapy has potential as a therapy in a limited number of patients with stage IV melanoma. To our knowledge, this is the first demonstration that cryopreserved dendritic cells can elicit complete clinical responses in patients with advanced cancer. Our observations support randomized controlled trials to validate the findings.     

Nab-paclitaxel in patients with metastatic melanoma

Cutaneous melanoma is one of the most aggressive and resistant malignancies in humans. Until recently, progress in the treatment of metastatic melanoma remained dormant for nearly two decades. However, recent advances in immune and targeted therapeutic approaches have led to dramatic and paradigm-shifting advances in the management of metastatic melanoma, that are now leading the way for other malignancies. With the advent of these new therapeutic options, chemotherapy is no longer favored as a first line strategy in metastatic melanoma, but continues to play a role in the salvage treatment of patients that have become refractory to immune-based or targeted therapies. Nab-paclitaxel, a solvent-free alternative to solvent-based paclitaxel, has shown in several trials to be active in metastatic melanoma. Herein, we summarize the role of nab-paclitaxel in the management of patients with advanced melanoma.     

Uveal melanoma: From diagnosis to treatment and the science in between

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age‐adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299–2312 . © 2016 American Cancer Society.     

Individualized therapy of disseminated cancer using malignant melanoma as a model

Approximately 20 to 25% of patients with malignant melanoma will die of metastatic disease. The current standards of care for advanced metastatic melanoma (stage IV, AJCC classification) are poor. To date, randomized trials have failed to demonstrate that one regimen is better than another. It is therefore crucial that patients with disseminated malignant melanoma be recruited into clinical trials. In recent years, there have been impressive advances in our knowledge of the biology and nature of cancer development and the growth and progression to metastasis. The approach “from bench to bedside” is current reality in the treatment of several solid tumors and hematologic malignancies. The identification of new targets to facilitate individualized melanoma treatment is now an important issue. This article will give an overview of recent developments in clinical trials of targeted therapies in metastatic melanoma patients. Presented as Session VII of the First International Symposium on Cancer Metastasis and the Lymphovascular System. April 28–30, 2005, San Francisco, CA; Chaired by Axel Hauschild.     

Prospects of immunotherapy for the treatment of prostate carcinoma--a review.

The treatment of prostate carcinoma is dependent on the stage of the disease. Patients who present with clinically localized cancer or locally advanced tumors can be potentially cured by radical prostatectomy, radiation, and hormonal therapy. However, disease progression can occur in 30-50% of patients diagnosed with clinically localized cancer. The bone is the predominant site of metastases. Metastatic prostate cancer is first treated by androgen blockade but within a few months becomes hormone refractory. Hormone refractory metastatic prostate cancer is not responsive to conventional treatments, and patients have an expected survival of less than a year. It is essential to develop new approaches for the treatment of hormone refractory metastatic disease. Immunotherapy, based on enhancement of the host immune response against the tumor, has been used as an alternative therapy for the treatment of metastatic cancers refractory to conventional therapy in particular for melanoma and renal cell carcinoma. In this review, we will summarize various immunotherapeutic approaches developed over the last 18 years, and we will address the potential of immunotherapy for the treatment of metastatic prostate carcinoma by reviewing preclinical studies and initial clinical trials performed in this field.     

Targeted therapy for uveal melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.