The finding that 18 patients with metastatic melanoma had remained alive for ≥3 years’ duration, and that 17 had survived ≥5 years, was both unusual and notable. Despite considerable research into multiple areas of treatment, the overall usual prognosis of stage IV melanoma still remains poor. Median survival time ranges from 6 to 9 months, with a 5-year survival rate of <2%.1–3 Although there have been recent encouraging therapeutic approaches using pathway and checkpoint blockade approaches and some indication of prolongation of survival, in many centers, the typical treatment options for disseminated disease still remain seriously limited in their ability to induce long-term survival.24–41 Surgical resection can be very effective in selected cases if the metastases are solitary or few in number, or if they are sequential in their clinical appearance,9–11 but this is unpredictable with recurrence being commonplace.

Until recently, DTIC has often been considered the first-line treatment for patients with disseminated disease, conferring response rates of 10%–20% and producing initial complete remission in 0%–5% of patients.14,24 Despite this, the 5-year survival rate for patients using this therapy remains under 2%, and three separate randomized controlled trials conducted by the European Organization for Research and Treatment of Cancer, the World Health Organization, and the Central Oncology Group demonstrated no significant difference in survival after treatment with DTIC compared with placebo.6

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Combination chemotherapy has offered little over single-agent chemotherapy for metastatic melanoma. Studies of nitrosourea- and DTIC-based chemotherapy, taxane-based chemotherapy, and cisplatin-based chemotherapy have found no convincing evidence to support improved efficacy.6

Immunotherapy has been an emerging area of research over the past two decades with mixed results.40 Several studies have examined the value of combined chemotherapy and immunotherapy, again with mixed results. Studies have looked at the role of interferon-α in combination with DTIC, cisplatin, vinca alkaloids, and nitrosoureas and found that the results were comparable to single-agent chemotherapy.6 Similarly, treatment with IL-2 and DTIC has not been shown to be superior to single-agent therapy. In contrast, Phase II trials directed toward the combination of cisplatin and high-dose IL-2 or low-dose IL-2 with the addition of interferon-α showed initial promising results with response rates of 10%–20% and an overall 2-year survival rate of 10% in selected patients.6 Unfortunately, due to the long inpatient hospital stays, high expense, and substantial toxicity, further Phase III investigations were considered not feasible.

Historically, meta-analyses focusing on the use of chemotherapy and immunotherapy in stage IV melanoma have shown their role to be largely palliative rather than curative. However, the concept of vaccines to directly target melanoma cells is particularly attractive. Several vaccine therapies have been investigated, with mixed results. One such example is the polyvalent allogenic whole-cell vaccine, CancerVax. Though early Phase I and II trials were encouraging, Phase III trials of the vaccine in both stage III and IV melanoma patients were discontinued due to negative findings.40

Similarly, neither of the two lysate vaccines that entered Phase III clinical trials – the viral melanoma oncolysate vaccine and the aforementioned VMCL vaccine – have shown statistically significant survival benefit in surgically resected high-risk stage II/III melanoma patients19 although, remarkably, VMCL has shown CR rates of 17% with a 15% 5-year survival rate for advanced stage III/IV metastatic melanoma.23,42

Recent reports using B-raf inhibitors (vemurafenib, dabrafenib) and CTLA-4 blocking antibody therapies (ipilimumab) had promised new hope for improving survival with stage IV melanoma. However, although overall response rates were 69% and 7%, the CR rates have remained very low at 0.9% and 0.5%, respectively.26,27,41 It should be noted that, B-raf V600E expression has been found in 30%–60% of melanomas and that some 69% of these showed a response to B-raf inhibitory antibody therapy, then the true response rate for statistically valid comparison with the unselected melanoma patient population was about 31% (ie, 69% of 45%) overall.26,27

Despite the numerous discouraging results from studies of many therapies for advanced melanoma, some patients defy the usual predicted course of the disease. Those cases cited and detailed in this study represent extraordinary and informative cases. Close evaluation of these patients indicated that their pattern of disease was not uniform. Many of the patients had disease that was indistinguishable from other patients who subsequently encountered progressive disease and died. The main distinguishing feature for many of the patients cited here seemed to be the utilization of a range of therapies, often in sequence. This persistence and repetition in the clinical application of therapies appears to be a vitally important factor for determining patient survival.42–44 The wide disparity between the multitude of variables in those cases reported here was far too divergent to permit useful correlative analysis. That wide divergence further adds to our contention that these cases most likely represent in vivo immunomanipulation of a pre-existing endogenous immune response against the cancer in the patient, often by multiple means, to create successful outcomes.44

The investigation of multiple other pathways, such as neuroendocrine, glucocorticoid, melanogenic, and immunomodulatory influences, may offer associated approaches for overcoming the “resistance” mechanisms that appear to be evident with current therapies.45