Current PerspectiveThe 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients
Section snippets
Background
The history of establishing effective adjuvant therapies in high-risk melanoma patients until recently has been marred by a lack of drugs that are effective in advanced melanoma [1]. Now that we have active drugs, the situation has changed dramatically. Ugurel et al. [2] published an important 2017-update of the pooled analysis regarding the currently approved active treatment regimens in advanced melanoma. They demonstrated that chemotherapy regimens are least effective, followed by ipilimumab
The 2017 new landscape
The European Organisation for Research and Treatment of Cancer (EORTC) trial 18071 demonstrated in 2015 that ipilimumab adjuvant therapy prolonged relapse-free survival (RFS) significantly, which led to its approval by the Food and Drug Administration in 2015 [3]. In 2016, a similarly significant prolongation of distant metastasis-free survival (DMFS) and overall survival (OS) was shown [4]. Toxicities, especially immune-related adverse events, were significant and led to drug-related deaths in
Nivolumab for all melanoma patients
Nivolumab adjuvant therapy in resected stage IIIB/IIC/IV patients demonstrated in the Checkmate-238 trial clears superiority over adjuvant therapy with ipilimumab [6]. Patients received nivolumab at 3 mg/kg for 2 weeks or ipilimumab at 10 mg/kg every 3 weeks for the first four doses and then every 12 weeks for a total duration of 1 year. The primary end-point was RFS, which was significantly better for nivolumab at 18 months with an RFS of 65% versus 53% for ipilimumab (hazard ratio [HR]: 0.65;
Dabrafenib plus trametinib combination for BRAF-mutant patients
The COMBI-AD trial compared dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) for up to a year with placebo in stage III (IIIA > 1 mm, IIIB/C) patients. Superiority was demonstrated for primary end-point RFS (HR: 0.47; p < 0.00001) and secondary end-points DMFS (HR: 0.51; p < 0.001) and for OS (HR: 0.57; p = 0.0006). RFS rates at 1 year were 88% versus 66%; at 2 years 67% versus 44% and at 3 years 58% versus 39% for the combination and placebo, respectively. Also DMFS
Only a role for IFN in patients with ulcerated melanoma
Approved adjuvant therapies with IFN are high-dose IFN (alfa2b used in the USA and EU), based on the Eastern Cooperative Oncology Group (ECOG) 1684 trial [20]; low-dose IFN (alfa2a used in the EU), based on the French adjuvant trial [21] and pegylated IFN (alfa2b used in the USA and Switzerland), based on EORTC 18991 trial [22], [23]. In the EORTC adjuvant trials 18952 and 18991, patients were stratified by ulcerated or non-ulcerated primary melanoma status, which led to interesting findings
Staging and the importance of CLND in SN-positive patients
The prognosis of SN-positive patients depends on tumour load in the SN and especially on the number of positive nodes identified in completion lymph node dissection (CLND). It has been demonstrated by the DECOG and the MSLT-2 trial that CLND does not improve outcomes [31], [32]. These results will reduce the number of CLNDs but thereby will also lead to a loss of prognostic information that is crucial in making decisions about adjuvant therapy. This will initiate intensive discussions. A
What is next?
Neoadjuvant use of highly active drugs such as nivolumab, or its combination with ipilimumab, and the use of a BRAF/MEK combination is a very attractive research concept for patients with palpable nodal stage III disease. Both approaches have been reported to yield 40–50% pathologic complete responses and overall response rates of close to 100% [33], [34]. Thereby, this approach may facilitate surgery and reduce the indication for radiotherapy and potentially will result in increased
Conflict of interest statement
None declared.
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Cited by (50)
Future Treatments in Melanoma
2022, Oral and Maxillofacial Surgery Clinics of North AmericaAdjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial
2019, European Journal of CancerCitation Excerpt :The outcomes of the dermatologic cooperative oncology group (DECOG) and the multicenter selective lymphadenectomy trial II (MSLT-II) trials have demonstrated that CLND does not improve outcome in SN-positive patients [23,24]. It would therefore be logical to conclude that CLND is no longer obligatory for a decision to propose adjuvant therapy [25,26]. Moreover, simplified staging requirements may be achieved by incorporating ulceration status of the primary melanoma into the decision-making [27].
Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events
2019, ESMO OpenCitation Excerpt :They are currently tested in other cancer types, and in (neo)adjuvant settings in earlier stage cancers. Moving these effective therapies towards adjuvant and neoadjuvant approaches in stage III disease in a curative setting makes the need for biomarkers for response and severe AEs even more important.7 68 Unfortunately, there are currently no reliable biomarkers to predict occurrence of severe irAEs in response to CPI therapy.
A nomogram to identify high-risk melanoma patients with a negative sentinel lymph node biopsy
2019, Journal of the American Academy of DermatologyCitation Excerpt :Melanoma patients with positive SLNBs are considered stage III patients, and despite any other characteristic, their 5-year survival will be 77%.2 In these patients, there is the discussion of whether or not to offer complete lymph node dissection4,18,19 and adjuvant treatments.5,20 However, most melanoma patients will have a negative SLNB, and it is unclear whether they need further treatments and how long they should be followed.3,8,9
Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment
2024, WIREs Mechanisms of Disease