Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study.

BACKGROUND: Multiple studies showed conflicting results on the association between oral contraceptive (OC) use and the development of cutaneous melanoma (CM). We investigated the association between estrogen use and CM incidence. PATIENTS AND METHODS: Data from PHARMO Pharmacy database and PALGA, the pathology database in The Netherlands, were linked. Women, >or=18 years, with a pathology report of a primary CM from 1 January 1991 to 14 December 2004 and >or=3 years of follow-up before CM diagnosis were eligible cases. Controls were matched for age and geographic region. Multivariate logistic regression was used to calculate adjusted odds ratio (OR) and 95% confidence interval (CI) for the association between CM incidence and estrogen use, OCs and hormonal replacement therapy (HRT), separately. RESULTS: In total, 778 cases and 4072 controls were included. CM risk was significantly associated with estrogen use (>or=0.5 year; adjusted OR = 1.42, 95% CI 1.19-1.69). This effect was cumulative dose dependent (P trend < 0.001). CM risk was also significantly associated with the use of HRT (>or=0.5 year: OR = 2.08; 95% CI 1.37-3.14) and OC (>or=0.5 year: OR = 1.28; 95% CI 1.06-1.54). CONCLUSION: Our study suggests a cumulative dose-dependent increased risk of CM with the use of estrogens.

Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin?

BACKGROUND: Statins show anticancer activity in melanoma cells. We investigated the association between statins and incidence and Breslow thickness of cutaneous melanoma (CM). METHODS: Data were used from PHARMO, a pharmacy database, and PALGA, a pathological database, in the Netherlands. Cases had a primary CM diagnosis between January 1st 1991 and December 14th 2004, were 18 years and had 3 years of follow up in PHARMO before CM diagnosis. Controls were matched for gender, date of birth and geographic region. Analyses were adjusted for age, gender, year of diagnosis, number of medical diagnoses and the use of NSAIDs and oestrogens. FINDINGS: Finally, 1318 cases and 6786 controls were selected. CM risk was not associated with statin use (> or = 0.5 years) (adjusted odds ratio (OR)=0.98, 95% confidence interval (CI)=0.78-1.2). However, statin use was associated with a reduced Breslow thickness (-19%, 95% CI=-33, -2.3, p=0.03). CONCLUSION: Our study suggests protective effects of statins on melanoma progression.