Current research desiderata on melanoma were presented at this year’s ASCO Congress. Immunotherapy is considered the basis of today’s adjuvant treatment, as radiotherapy is no longer recommended due to too low benefit in terms of survival rates. Prognostic genetic analysis is promising because it could be used for diagnosis. In addition, it may be possible to use it in the future to predict therapy responses, for example to immune treatment.
Adjuvant treatment of melanoma was addressed by Prof. John M. Kirkwood, MD, of the University of Pittsburgh. Adjuvant therapy is not yet used for resectable low-risk melanomas in stage IA, IB, IIA, and prevention is most important here. It is used only for resectable intermediate- and high-risk melanomas of stage IIB, IIIA, and IIIB.
In advanced, inresectable stage III or IV forms, systemic therapy is necessary. In principle, the following applies to adjuvant therapy:
- This setting provides a better opportunity to reduce mortality, recurrence rates, and morbidity.
- Systemic efficacy in advanced disease provided the rationale for adjuvant research until now.
Adjuvant therapies
Radiotherapy: “There is a history of failed trials that attempted to use radiotherapy (RT) adjuvantly. Firm beliefs exist regarding efficacy, but no firm data exist regarding regional RT with conventional or hypofractionated regimens. For example, both the RTOG93-10 and ECOG 3695 trials were stopped early due to lack of significance of the data,” Prof. Kirkwood said. In contrast, a 2012 randomized trial by Burmeister and colleagues [1] concluded that adjuvant radiotherapy (ART) should be discussed in patients with metastatic melanoma who are at high risk for recurrence in the lymph node region and have already undergone lymph node removal. The risk of recurrence was significantly reduced with ART compared with the control group, but recurrence-free and overall survival rates were not.
Radiotherapy also poses several hazards: Subcutaneous tissue fibrosis and lymphedema were worse with ART, and widespread late effects include dermatitis and seroma and other damage to the skin.
Overall, according to Prof. Kirwood, it can be summarized that although ART leads to locoregional control, it can no longer be recommended for melanoma treatment because of the small benefit for recurrence-free and overall survival.
VEGF inhibitor bevacizumab: The AVAST-M trial was presented by Philippa Corrie, MD, Cambridge. This randomized trial evaluated the VEGF inhibitor bevacizumab (Avastin®) as adjuvant therapy performed after resection of AJCC stage IIB, IIC, and III cutaneous melanomas. The interim analysis of this study presented at the Congress showed no improvement in overall survival, but a longer observation period is needed to capture 5-year survival. Overall, however, adjuvant treatment with bevacizumab increased the disease-free interval and was well tolerated in this patient group during the one-year period.
IFNα therapy: Regarding adjuvant therapy with pegylated interferon alfa-2b (PEG-IFN-α-2b) in stage III melanoma, long-term results [2] from 2012 show that it had a narrowly significant positive effect on recurrence-free survival, even after 7.6 years. However, the effect was smaller compared to the results obtained after 3.8 years. Furthermore, there was no significant change in the
Demonstrate impact on so-called distant metastasis-free survival (DMFS) or overall survival.
Current research paths
Immunotherapy is the cornerstone of adjuvant therapy in 2013, according to Prof. Kirkwood. The role of ipilimumab is being evaluated, as are combinations designed to improve relapse-free and overall survival and reduce toxicity. Molecular inhibitors have revolutionized BRAF melanoma therapy, and their relevance to adjuvant treatment is explored. Similarly, research on adjuvant use of anti-PD1 and anti-PDL1 is planned. A MAGE A3 vaccine is under development.
Gene analyses
Gene analyses are valuable because they could be of diagnostic relevance, correlate with clinical phenotypes, and predict prognosis and therapeutic response (Table 1). However, reliable markers to predict response to immunotherapies, for example, are still scarce because prospective data from large patient cohorts are lacking.
BRAF mutations, particularly rare forms such as the V600K and V600R, are relatively common in patients with head and neck melanomas. Many of these patients with V600K/R mutations subsequently develop lymphatic metastases. Furthermore, V600K seems to be more associated with sun-damaged skin, increasing age, and a shortened disease-free time between diagnosis and the formation of distant metastases compared to the widely used V600E [3]. BRAF/NRAS mutations are
differs in distribution depending on the geographical region, depending on whether a population is genetically homogeneous or heterogeneous (e.g., the island of Sardinia compared to Italy). Mostly, they seem to correlate with age and increasing body size (Table 2).
Source: American Society of Clinical Oncology (ASCO) Annual Meeting, May 31-June 4, 2013, Chicago.
Literature:
- Burmeister BH, et al: Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. The Lancet Oncology 2012; 13(6): 589-597.
- Eggermont AMM, et al: Long-Term Results of the Randomized Phase III Trial EORTC 18991 of Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma. Published online before print September 24, 2012, doi: 10.1200/JCO.2011.41.3799.
- Menzies AM, et al: Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012 Jun 15; 18(12): 3242-3249. doi: 10.1158/1078-0432.CCR-12-0052. epub 2012 Apr 24.
HAUSARZT PRAXIS 2013; 8 (10): 32-34
