No OS Benefit for Adjuvant Treatment of Stage III Melanoma

Adjuvant treatment following resection of stage III melanoma is standard practice, based largely on trials that showed it improves recurrence-free survival.

However, oncologists have long wondered whether that improvement in recurrence-free survival translates to improved overall survival (OS).

Unfortunately, it seems that it may not. No such benefit was seen in a review of virtually every case of stage III melanoma treated in Sweden from 2016 to 2020.

“No improvement in survival can be detected after the introduction of adjuvant melanoma treatment” in Sweden, say investigators led by Hildur Helgadottir, MD, PhD, a melanoma researcher and specialist at the Karolinska Institutet, Stockholm.

The review was published May 25 in the Journal of the National Cancer Institute.

“We believe that this finding is of potential interest to the melanoma community” and should “encourage a careful assessment of the current recommendations on adjuvant treatment,” particularly in light of the side effects and costs of adjuvant treatment, the team comments.

They note that the phase III trials that show an improvement in recurrence-free survival, which led to guidelines recommending that adjuvant treatment be used, have still not reported their OS data.

If further studies confirm “that there is no long-term impact on overall survival, certainly these adjuvant therapies need to be reconsidered as a standardized recommendation,” said Jennifer Choi, MD, chief of medical dermatology and oncodermatology at Northwestern University, Chicago. She was not involved in the review and was approached by Medscape Medical News for comment.

However, she also pointed out that the review of Swedish data has several limitations.

Study Details

For their review, Helgadottir included patients with stage III melanoma who were diagnosed before and after 2018. This was the year that adjuvant treatment with either immunotherapy with nivolumab and pembrolizumab or with targeted agents dabrafenib and trametinib were approved and recommended in Sweden for adjuvant stage III melanoma.

Because of strict adherence to guidelines in the country, the team says that virtually no patients received adjuvant treatment for stage III disease before the approval and that afterward, just about every patient did.

The team compared OS among 634 patients diagnosed 2 years before the approvals to OS among 737 patients diagnosed in the subsequent 2 years and found no significant difference. Two-year OS rates were 84.3% in the pre-approval group vs 86.1% in the post-approval cohort. The median follow-up was 57 months in the earlier cohort and 27 months in the later group. There was no significant difference in melanoma-specific survival.

The results held across subgroups by age, sex, and tumor characteristics. There was no trend toward better melanoma-specific survival with adjuvant treatment among younger patients, patients with ulcerated tumors, and those with stage IIIB melanoma.

There were fewer cases of stage IIIB disease and more cases involving thinner melanomas in the pre-approval cohort, but there were more in-transit metastasis. “Adjustments for these factors in the multivariate analyses did…not significantly change the results,” the investigators say.

The study was powered to detect a 2-year survival difference of 5% or more, so if there is in fact an OS benefit, it’s likely to be minimal. If nothing else, there is “a clear need for better tools to identify patients” who might experience a survival benefit with adjuvant treatment, the team comments. Genetic profiling and liquid biopsies are among the candidates, they added.

Experts Respond

Although this is “an interesting and necessary study,” Choi pointed out that follow-up was relatively short and that an OS benefit for adjuvant treatment “is definitely a possibility” with longer follow-up.

Also, if OS was assessed separately for immunotherapy instead of together with BRAF/MEK inhibitors, a survival benefit might emerge, since “immunotherapy has been shown to have a more effective long-term benefit” for patients with metastatic melanoma, she noted.

Overall, “more studies are needed,” Choi said.

Another person Medscape Medical News reached out to for comments ― Douglas Johnson, MD, leader of the melanoma research program at Vanderbilt University, Nashville, Tennessee ― also thought the study was “intriguing,” but, like Choi, he was concerned about the short follow-up and also noted that adjuvant therapy can have value beyond OS, such as preventing highly morbid metastatic recurrences that require more toxic treatments.

However, “the relatively unclear benefit in overall survival in this and other studies does raise the question whether observation after resection of stage III disease and treatment at progression would be an optimal strategy,” Johnson said.

The study was funded by the Swedish Cancer society and others. Helgadottir has received speaker honorarium from Bristol-Myers Squibb, Merck Sharp & Dohme (MSD), and Pierre Fabre, and has served as an advisor to MSD and Novartis. Other authors report relationships with industry, as detailed in the article. Johnson has served as an advisor for BMS, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, and other companies and has received grants from BMS and Incyte. Choi has disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online May 25, 2023. Abstract

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

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