Remarkable cases of complete regression of metastatic melanoma and other cancers with prolonged survival, with or without therapeutic intervention, are noteworthy events and represent highly instructive natural clinical experiments. The immune system is again being considered the likely contributor to such events following successful results from the recent use of immunomodulatory agents.
Metastatic malignant melanoma represents a highly aggressive form of skin cancer, with an overall 5-year survival of less than 2% and a median survival time of 6–9 months for stage IV disease.1–3 The incidence of melanoma is rising, affecting over 150,000 new patients per year worldwide. This is likely due to both increased levels of exposure to ultraviolet radiation and improved diagnostic awareness and detection procedures.
Although primary melanoma is often curable, the risk of metastasis directly increases with Breslow depth.4 Other poor prognostic factors include ulceration, high mitotic rate, increasing Clark level, increased age, elevated lactate dehydrogenase levels, and lymph node involvement, as these are associated with a higher potential for metastasis.5
Current standard therapy for primary melanoma is wide local excision (WLE) of the skin and subcutaneous tissues around the primary lesion with surgical margins determined by Breslow thickness.6,7 Lymphatic tracing and sentinel node biopsy is recommended for melanomas >1 mm in thickness for staging and therapy because regional draining lymph nodes are typically the first site of metastases.8 The status of the sentinel nodes is the most important prognostic factor in patients with primary melanoma. Patients with regional or local lymphatic spread have a high risk of widespread disseminated disease and poorer survival rates.7 Observed patterns of metastases are, however, highly variable.
While localized disease can be effectively managed with surgery, there is currently no effective treatment for disseminated disease. Management options differ depending on the sites and rate of progression of the disease and usually involve a multidisciplinary approach. Surgical resection of operable metastases has been shown to significantly improve the patient’s survival rate, but is predominantly employed only if one or few metastases are present and resectable.3,9–11
Adjuvant radiotherapy may be employed postoperatively; however, several studies have demonstrated no improvement in survival when used after nodal dissection in stage III patients,12–14while one showed improved local disease control.15 In advanced disease, radiotherapy plays a larger role in effective symptom palliation, especially for bone metastases.
Standard approved chemotherapy with single-agent dacarbazine, fotemustine, or temozolomide has been used for the treatment of late-stage melanoma; however, overall response rates (ORR) remain uniformly low (5%–20%) and are often short lived.2,3 Complete responses (CRs) from chemotherapy are rare. Isolated limb perfusion or infusion chemotherapy techniques are effective for recurrent disease localized to the arm or the leg and have reported regional CR rates of between 40% and 60%.12,16,17
Recent advances in the development of inhibitory agents, which target key checkpoint molecules within metabolic pathways of melanoma cells, have led to a range of new experimental therapies. These include B-raf and mitogen-activated protein kinase inhibitors, which offer much promise for the more effective treatment of selected B-raf mutation-positive advanced melanoma.17,18 However, despite some impressive initial clinical responses, these seldom translate into CRs or durable long-term survival.
Immunotherapy has also emerged over the last three decades as a potentially viable field of therapy. In particular, interleukin-2 (IL-2), cytotoxic lymphocyte antigen-4 (CTLA-4), and programmed death receptor-1 (PD-1), and programmed death-1 receptor ligand inhibitory monoclonal antibody (PDL-1) therapies, vaccines, and other cytokine-based therapies have been a major area of research.18–20Notably, IL-2 therapy has stood the test of time, with some 5%–10% of patients achieving CRs and long-term survival.21,22 More recently, studies have demonstrated a 17% CR rate from combined CTLA-4 inhibitor and IL-2 therapy and similar CR rates using a melanoma lysate vaccine therapy.17,20,23
In contrast to the pathway inhibitors, immunotherapeutic strategies produce higher reported rates of CRs and are associated with a higher proportion of long-term survivors.20,23 Importantly, almost irrespective of the therapy type considered, when CRs occur, these often translate into long-term survival beyond 5 years, especially for immunotherapies.
The primary objective of this study was to identify and document advanced melanoma cases where longer-term survival of at least 3 years was observed, in one clinician’s experience. A second objective was to evaluate the published literature to date for reported clinical outcomes from advanced melanoma therapies.