It is incumbent on melanoma and radiation oncology researchers alike to further our understanding of when and how RT can help patients.
Radiation therapy (RT) was once thought to be ineffective for cutaneous melanoma. Research has demonstrated the value of RT across the disease spectrum, from definitive treatment of melanoma in situ, to adjuvant treatment of resected high-risk disease, to palliative treatment of metastases. In the current issue of ONCOLOGY, Drs. Mahadevan, Patel, and Dagoglu discuss preclinical and clinical data that guide the use of RT to treat melanoma. The authors undertook a challenging task, given the many roles that RT can play in the treatment of melanoma of different origins (skin, uvea, and mucosa) and different stages. Nevertheless, given the advances in melanoma therapy over the last few years, a contemporary review highlighting ongoing clinical trials (Table) is timely.
Early in vitro studies of melanoma radiosensitivity in clonogenic assays suggested that successful treatment required high-dose-per-fraction RT. At least two randomized clinical trials[3,4] have failed to support this hypothesis, demonstrating similar rates of response with low to medium dose fractions (2.5 to 5 Gy) and larger dose fractions (8 to 9 Gy). Moreover, the clinical trial demonstrating an improvement in regional disease control with RT was conducted using low dose fractions (2.4 Gy/fraction), further dispelling the myth that RT is only effective for melanoma if given with high doses per fraction. Although Mahadevan et al suggest that fractionation in melanoma is controversial, evidence suggests that clinicians should be comfortable using low-dose-per-fraction RT in appropriate settings.
A better understanding of the cellular and immunologic pathogenesis of melanoma has led to advances in treatment. Some of the findings from research into pathogenesis have had relevance for the use of RT. For example, an analysis of 37 melanoma cell lines corroborated prior observations that melanoma exhibits a wide range of radiosensitivity in vitro. Mutations in recurrently altered genes in melanoma (BRAF and NRAS) were not associated with radiosensitivity. However, a clinically available RAF inhibitor (vemurafenib) was able to increase radiosensitivity of BRAF-mutant cell lines. A recent clinical analysis demonstrated the radiosensitizing effect of vemurafenib in patients with melanoma receiving RT. Immunobiologic studies of a murine melanoma model demonstrated that immunodeficiency, depletion of CD8+ lymphocytes, and lymphotoxic chemotherapy abrogate the antitumor effect of RT. With future preclinical studies related to melanoma, we are likely to gain a better understanding of the optimal use of RT.
Mahadevan et al discuss the notion that RT at the site of the primary tumor may improve disease control; additional data and ongoing trials support this contention. A recent systematic review of 537 patients treated with RT found a high rate (95%) of local control in patients with lentigo maligna (melanoma in situ). This prompted development of a randomized trial comparing two nonsurgical therapies (RT and topical immunotherapy) for lentigo maligna (ClinicalTrials.gov identifier: NCT02394132). Moreover, for patients with desmoplastic melanoma, two recent analyses have suggested improvements in local tumor control with adjuvant RT to the site of the resected tumor.[10,11] An ongoing international randomized trial will evaluate RT in this setting in a prospective fashion (NCT00975520).
The authors discuss the controversial use of adjuvant RT in patients with resected stage III melanoma. Investigators recently updated results of the randomized trial of observation vs regional lymph node basin RT for patients with high-risk stage III melanoma after lymphadenectomy. The investigators report a significant reduction in the likelihood of regional recurrence after RT (21%) as compared with observation (36%). Grade 2, 3, and 4 late RT-related adverse effects were observed in 74%, 20%, and 2% of patients, respectively. The National Comprehensive Cancer Network categorizes adjuvant RT as a level 2B recommendation, and many melanoma specialists do not recommend it because of side effects and lack of survival benefit. However, these data provide a basis for future studies evaluating novel approaches to adjuvant RT that employ improved patient selection or better delivery techniques; for example, patients might be selected who are at high risk for regional recurrence but at low risk for distant recurrence. Our preliminary investigations suggest that fewer side effects may be possible using contemporary RT modalities, such as intensity-modulated RT (IMRT), which have not yet been employed in melanoma clinical trials (Mattes M et al, submitted).
Finally, Mahadevan et al discuss the use of RT for patients with metastatic melanoma. RT has a well-established role in the palliation of patients with symptomatic metastases. For patients with unresectable metastases, ablative RT may provide durable control. Brain metastases are frequently treated with stereotactic radiosurgery (SRS) for this reason. However, for patients with many (4 to 10) brain metastases, the role of SRS vs whole-brain RT (WBRT) is unclear; this is being investigated in a randomized trial (NCT01644591). In a related study, the value of WBRT to prevent recurrence in the brain after SRS is being studied (NCT01503827).
A novel concept is the use of RT as an immunotherapeutic “adjuvant.” Radiation itself has several immunomodulatory properties, and many preclinical studies have demonstrated the interaction of immunotherapy and RT in models of melanoma (Samstein et al, submitted). This has been reported in clinical case reports,[14,15] series,[16-18] and early clinical trials of RT and immunotherapy.[19,20] A significant number of clinical trials are underway to further explore the hypothesis that RT may improve the outcomes of systemic therapy for patients with metastatic melanoma, but data from randomized trials clarifying the question of whether RT improves the response to immunotherapy are not available.
It is incumbent on melanoma and radiation oncology researchers alike to further our understanding of when and how RT can help patients. Considering that the last melanoma trial completed by the Radiation Therapy Oncology Group (83-05) was conceived over 30 years ago, it is clear that cooperative, international efforts are required to yield the advances that are needed to positively change clinical practice. In addition, as more effective therapies for melanoma become available, the importance of investigating rational therapeutic combinations will also grow. The rich history of research in melanoma has led to advances in treatment, as well as to a number of active investigations of RT. Results of these studies and future directions for the field are eagerly awaited.
Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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