The first evidence-based consensus statement on tumor immunotherapy for the treatment of patients with melanoma recently has been released by the Society for Immunotherapy of Cancer (SITC) and published online by Nature Reviews Clinical Oncology. The statement provides patients and physicians with expert recommendations for the use of different immunotherapies, including interferon-α2, pegylated interferon, interleukin-2 (IL-2) and ipilimumab (Yervoy, Bristol-Myers Squibb). It also includes recommendations for patient selection, toxicity management, clinical end points, and sequencing or combination of therapy for the different stages of melanoma.
It’s in the Details
While patients with stage III and stage IV melanoma are referred to oncologists, dermatologists often treat patients with stage II disease. Now that several therapies are approved for use in melanoma, the guidelines for immunotherapy are particularly helpful. However, it is worth noting that the statement offers only a broad direction of treatment. That’s because appropriate use of immunotherapy in the treatment of stage II melanoma is a matter of some debate, as the authors of the statement indicate.
High-Risk Stage II Melanoma. For high-risk stage II patients, a majority of the panel recommends standard one-year interferon-α2b. They note that patients treated with interferon-α2b often have a good performance status without evidence of significant depression or psychiatric history or underlying autoimmune disease. However, when unmanageable adverse events persist, even despite a dose reduction of 67-75 percent, the panelists recommend ceasing treatment at the time of documented disease recurrence or after one year of therapy.
Some panelists alternatively recommend participation in clinical trials (in which case availability and eligibility to the protocol-specific patient selection criteria of the trial would need to be met), while others noted that treatment should be individualized based on the particular situation.
Stage III and Stage IV Melanoma.
For patients with stage III melanoma, a majority of the panel recommends a oneyear course of interferon-α2b for the adjuvant therapy of microscopic nodal disease. However, some panelists recommend shorter-course interferon-α2b and favor biochemotherapy, generally consisting of cisplatin, vinblastine, dacarbazine, and low-dose IL-2, while some others recommend no further treatment.
For patients with stage IV melanoma, the panel recommends patients whose tumors harbor a BRAF mutation with a good performance status and no CNS disease be treated with IL-2 as first-line therapy, provided they meet IL-2 eligibility. Vemurafenib (Zelboraf, Genentech) should be reserved for later treatment stages. Panel members recommend targeted therapy or ipilimumab as second-line or third-line therapy. There was general consensus that immunotherapy should be used first, while vemurafenib should be considered when the disease is progressing rapidly or when performance status is poor.
When Issues Arise…
The authors of the statement also took on what they called “special issues” and clinical management recommendations when using immunotherapy for treating melanoma. For management of autoimmune-related toxic effects, the panel recommends routine assessment of thyroid function, as well as complete blood counts, liver function and metabolic panels, as well as serum LDH tests. For patients under IL-2 treatment, most panelists recommend daily laboratory tests.
In terms of the significance of imaging, the panel notes that since clinical responses can be delayed on some forms of immunotherapy, imaging has become increasingly important to assure potential therapeutic benefit. This includes whole-body imaging, CT scans of chest, abdomen, and pelvis, and MRI of brain.
Regarding adverse events, the panel recommends that treatment only be stopped after significant toxic events occur or “unequivocal evidence” of disease progression. For interferon or IL-2 treatment, the appearance of new lesions or significant increase in tumor burden is enough of an indicator to stop treatment, the panelists observe. In addition, for situations in which responses are mixed or incomplete following immunotherapy, the panels suggests considering patients for resection, with some members further recommending biopsy in ambiguous cases.
The task force responsible for authoring the statement has noted that it plans to update the consensus statement as immunotherapy continues to rapidly develop via ongoing trials and the possible approval of new therapies. While these guidelines are likely to be fluid over the next several years, their publication nonetheless represents a significant step in melanoma care. The statement provides the best available evidence and consensus thinking for those interested in pursuing treatment with immunotherapy. Whereas, prior to the guidelines, practicing oncologists and dermatologists faced several obstacles in the treatment of melanoma, the consensus statement signals hope that the therapeutic landscape of melanoma is beginning to take definitive shape.
To read “The Society for Immunotherapy of Cancer Consensus Statement on Tumor Immunotherapy for the Treatment of Cutaneous Melanoma,” visit: www.nature.com/ nrclinonc/journal/vaop/
Jonathan Wolfe, MD is a Clinical Associate Professor of Dermatology at the University of Pennsylvania in Philadelphia, PA, where he is on the staff of the Pigmented Lesion Clinic. He is also in private practice in Plymouth Meeting, PA.