Radiotherapy as palliative treatment for metastatic melanoma

This study aimed to assess the response rate and efficacy of palliative radiation therapy in patients with metastatic melanoma. From 1993 to 1999, 28 patients with 35 irradiated areas were treated with palliative radiotherapy for metastatic melanoma in the Radiotherapy Department of the Henri Mondor University Hospital, Créteil, France. Of these, 19 (68%) patients had bone and soft tissue metastases, seven (25%) patients had brain metastases and two (7%) patients had both types of metastases. Most of the patients were treated with 30 Gy of irradiation in 10 fractions over 2 weeks or 20 Gy in five fractions over 1.5 weeks. Of those with bone metastases, 67% responded to palliative bone treatment with good pain relief and/or decompression. Of the patients with brain metastases, 57% had amelioration of neurological function deficits, 29% did not respond, and one patient showed aggravation of his disease and did not finish the course of irradiation. Two patients with unresectable disease obtained partial remission and good palliation of symptoms. In conclusion, short-course radiotherapy has a role to play in the palliation of metastatic melanoma, with good relief of symptoms.     

Updates in adjuvant systemic therapy for melanoma

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.     

Noninterferon-based adjuvant therapy for high-risk melanoma

High-dose interferon is the only treatment approved by the FDA for adjuvant therapy of melanoma. However, its efficacy in this setting is questionable and its administration is associated with considerable toxicity. Many new agents are being tested clinically that hold the promise of greater efficacy and less toxicity but none of these have yet shown efficacy in controlled trials. These include biologics such as vaccines, cytokines, monoclonal antibodies, gene transfer, cellular therapies and angiogenesis inhibitors as well as chemotherapy combinations.     

Noninterferon-based adjuvant therapy for high-risk melanoma

High-dose interferon is the only treatment approved by the FDA for adjuvant therapy of melanoma. However, its efficacy in this setting is questionable and its administration is associated with considerable toxicity. Many new agents are being tested clinically that hold the promise of greater efficacy and less toxicity but none of these have yet shown efficacy in controlled trials. These include biologics such as vaccines, cytokines, monoclonal antibodies, gene transfer, cellular therapies and angiogenesis inhibitors as well as chemotherapy combinations.     

Nodal radiation therapy for metastatic melanoma

Purpose: The aim of this retrospective study was to review our experience of radiation therapy to regional nodes in patients with proven nodal metastases, with respect to regional control, late toxicity, and overall survival.

Methods and Materials: All patients with a histological diagnosis of malignant melanoma, with involvement of the regional nodes but without distant metastases, who commenced nodal irradiation between January 1985 and July 1995 at Peter MacCallum Cancer Institute were studied. The study population of 113 patients was divided into two categories: those with no residual macroscopic disease following nodal surgery (adjuvant group, 42 patients) and those who had no surgery (8) or had macroscopic residual disease following nodal surgery (63) (palliative group, 71 patients).

Results: In the adjuvant group at 5 years following commencement of nodal irradiation 26% were estimated to be failure-free. Of the 74% who had experienced treatment failure by 5 years, an estimated 20% failed first with nodal relapse, 52% with distant metastases, and 2% with both nodal relapse and distant metastases. The estimated 5-year overall survival for this group was 33%. In the palliative group 16 patients (23%) had an objective complete response. Altogether 48 patients (68%) had a symptomatic response. At 5 years the overall survival in this group was 8% and an estimated 4% were failure-free. Of the 96% who had failed by 5 years, 68% failed first in the regional nodes, 25% had distant metastases as the first failure, and 3% had both nodal relapse and distant metastases.

Conclusion: We recommend adjuvant postoperative radiation therapy for patients with proven nodal metastases and high risk of regional recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease) in addition to adjuvant interferon.     

Considering adjuvant therapy for stage II melanoma

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti–CTLA-4 and anti-PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti-PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node-negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma-specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk-stratification and treatment-benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma.     

Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma

Although patients with metastatic disease are usually not offered surgery as part of their comprehensive treatment plan, the authors suggest that surgical reduction of the tumor burden may enhance the host immune response and create a favorable setting for the use of active specific immunotherapy.     

Combating melanoma: the use of photodynamic therapy as a novel, adjuvant therapeutic tool

Metastatic malignant melanoma remains one of the most dreaded skin cancers worldwide. Numerous factors contribute to its resistance to hosts of treatment regimes and despite significant scientific advances over the last decade in the field of chemotherapeutics and melanocytic targets, there still remains the need for improved therapeutic modalities. Photodynamic therapy, a minimally invasive therapeutic modality has been shown to be effective in a number of oncologic and non-oncologic conditions. Using second-generation stable, lipophilic photosensitizers with optimised wavelengths, PDT may be a promising tool for adjuvant therapy in combating melanoma. Potential targets for PDT in melanoma eradication include cell proliferation inhibition, activation of cell death and reduction in pro-survival autophagy and a decrease in the cellular melanocytic antioxidant system. This review highlights the current knowledge with respect to these characteristics and suggests that PDT be considered as a good candidate for adjuvant treatment in post-resected malignant metastatic melanoma. Furthermore, it suggests that primary consideration must be given to organelle-specific destruction in melanoma specifically targeting the melanosomes - the one organelle that is specific to cells of the melanocytic lineage that houses the toxic compound, melanin. We believe that using this combined knowledge may eventually lead to an effective therapeutic tool to combat this highly intractable disease.     

Use of adjuvant therapy in cutaneous melanoma

Surgery remains the principal treatment for local, regional and isolated metastatic melanoma. Adjuvant therapy is now available for patients with high risk of recurrence after surgical treatment but is controversial and inconsistently used around the world. In 1995, high-dose interferon-α2b was approved by the FDA, providing clinicians with the first adjuvant therapy for use outside a clinical trial. In this review, we discuss surgical approaches to the management of the primary lesion and regional lymph nodes and the use of high-dose interferon. We will also provide guidelines for the use of interferon and discuss current clinical trials evaluating alternate forms of adjuvant therapy.     

Use of adjuvant therapy in cutaneous melanoma

Surgery remains the principal treatment for local, regional and isolated metastatic melanoma. Adjuvant therapy is now available for patients with high risk of recurrence after surgical treatment but is controversial and inconsistently used around the world. In 1995, high-dose interferon-alpha 2b was approved by the FDA, providing clinicians with the first adjuvant therapy for use outside a clinical trial. In this review, we discuss surgical approaches to the management of the primary lesion and regional lymph nodes and the use of high-dose interferon. We will also provide guidelines for the use of interferon and discuss current clinical trials evaluating alternate forms of adjuvant therapy.     

The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma.

The efficacy of palliative radiation therapy in the treatment of spinal cord and cauda equina compression due to metastatic malignant melanoma was evaluated in 38 sites in 35 patients treated between 1970 and 1990. All patients had radiographic documentation of epidural compression. The median dose of radiation therapy was 2850 cGy (range, 500 to 4000 cGy), with daily fractions ranging from 200 to 800 cGy. Twenty-eight sites in 26 patients were evaluable 1 month after completion of radiation therapy, and symptoms responded completely in 11 of 28 (39%) sites. Fourteen sites (46%) showed a partial response of symptoms. Response lasting until death was documented in 21 of 26 patients (81%). Patients receiving a total dose of 3000 cGy or greater were more likely to achieve a complete response than those receiving less than 3000 cGy (62% versus 20%) by univariate (P = 0.025) and multivariate (P = 0.048) analyses. A treatment program of radiation therapy and corticosteroids is effective in palliating the symptoms of epidural compression due to metastatic malignant melanoma. It is recommended to deliver an accelerated course of radiation therapy to a dose of 3000 cGy or greater without exceeding spinal cord tolerance (e.g., 3000 cGy in ten fractions at 300 cGy per fraction).     

Randomized adjuvant therapy trials in melanoma: surgical and systemic

The utility of adjuvant surgical procedures in the management of primary melanomas has been evaluated in a large number of phase III randomized trials. These trials have shown that wide margins, elective lymph node dissection, sentinel lymph node (SLN) biopsy, and prophylactic isolated limb perfusion (ILP) do not improve survival but may improve locoregional control. Based on the claim of providing a survival benefit, these surgical procedures cannot be considered standard of care in the routine management of primary melanoma. Regarding the role of SLN biopsy it must be stated that this procedure provides the best information on prognosis and provides us with an important tool to stratify for and study more homogeneous patient populations to evaluate adjuvant systemic therapies in randomized phase III trials. The utility of systemic adjuvant therapy remains marginal as a result of the fact that a lack of effective drugs in stage IV disease is reflected by a lack of effective adjuvant therapies in stage II-III melanoma. Thus far, chemotherapeutic drugs, immunostimulants, and various vaccines have all failed. Interferon (IFN) has an effect on relapse-free survival but not on overall survival. Thus its impact is judged by many to be too small to be considered standard of care. The population of patients that can benefit from IFN needs to be better defined by identifying new biomarkers by genomic and proteomic studies, which are ongoing.     

Choices in adjuvant therapy of melanoma.

BACKGROUND: High-dose interferon (IFN) is the approved agent for adjuvant treatment of melanoma in the United States. This approval is for high-risk, predominantly stage III patients with cutaneous primaries. There are still decisions to be made in the care of these patients. Also, there are questions about whether the IFN data can be extrapolated to patients with other stages of melanoma and whether adjuvant treatment should be offered to these individuals. Clearly there is room for improvement in this area. METHODS: The literature on this topic and ongoing national trials in the United States were reviewed. RESULTS: The data are insufficient to recommend other agents in the adjuvant treatment of melanoma outside a clinical trial. Extrapolation of the IFN data to patient populations other than those studied is problematic at best. National trials are available for most patient populations. CONCLUSIONS: The adjuvant treatment of choice for melanoma patients is participation in a clinical trial.     

Intralesional targeted alpha therapy for metastatic melanoma

This paper reports the development and application of intralesional targeted alpha therapy (TAT) for melanoma, being the first part of a program to establish a new systemic therapy. RATIONALE: Labelling the benign targeting vector 9.2.27 with 213Bi forms the alpha-immunoconjugate (AIC), which is highly cytotoxic to targeted melanoma cells. OBJECTIVE: To investigate the safety and efficacy of intralesional AIC in patients with metastatic skin melanoma. FINDINGS: 16 melanoma patients were recruited. All the patients were positive to the monoclonal antibody 9.2.27. AIC doses from 50 to 450 mCi injected into lesions of different sizes resulted in massive cell death, as observed by the presence of tumour debris. The AIC was very effective in delivering a high dose to the tumour while sparing other tissues. There were no significant changes in blood proteins and electrolytes. There was no evidence of a human-antimouse-antibody reaction. Evidence of significant decline in serum marker melanoma-inhibitory-activity protein (MIA) at 2 weeks post-TAT was observed. CONCLUSIONS: Intralesional TAT for melanoma was found to be quite safe up to 450 mCi, and efficacious at a dose of 200 mCi. MIA, apoptosis and ki67 proliferation marker tests all indicated that TAT is a promising therapy for the control of inoperable secondary melanoma or primary ocular melanoma.     

Cascading adoptive cell therapy for metastatic melanoma

Adoptive tumor-infiltrating lymphocytes (TILs) therapy has demonstrated drastic effects on advanced malignant melanoma. Intensive pretreatment such as chemotherapy and/or total body irradiation has been used to eliminate immunosuppressive components and therefore enhances the antitumor effects of TILs. However, these pretreatments may cause severe side effects, especially for elderly patients. This case observes the complete response of how a patient with metastatic melanoma was treated sequentially with local tumor resection, postoperative adoptive cytokine-induced killer cells and TILs infusion. In addition, the cascading adoptive cell therapy was well-tolerated by the patient. Therefore, being pretreated with cytokine-induced killer cells could ameliorate the immunosuppressive condition in the patient and provide a favorable circumstance for subsequent TILs infusion. The further adoptive TILs therapy could exert the most powerful antitumor activity in such an amicable circumstance.     

Update on adjuvant interferon therapy for high-risk melanoma

Melanoma is almost 100% curable when diagnosed early, but when metastatic to distant organs, it is associated with a poor survival. The interferons have shown the mostpromise in the treatment of melanoma and interferon-alpha has been the most extensively studied. In recent trials, interferon alfa-2b (Intron A) administered at maximally tolerated doses for 1 year produced improvements in both relapse-free and overall survival. The importance and impact of the IV induction component of high-dose interferon regimens is currently being evaluated in an Intergroup randomized trial. A trial of the GMK vaccine vs high-dose interferon in patients with high-risk melanoma closed early when an interim analysis detected a markedly inferior response in the GMK arm compared to the high-dose interferon arm. The use of surgical staging will help to better define prognostic groups and support ongoing efforts for more effective adjuvant therapy.