The treatment landscape of solid tumors has changed markedly in the last years. Molecularly targeted treatments and immunotherapies have been implemented and have, in many cancers, lowered the risk of relapse and prolonged survival. Patients with tumors harboring specific targetable molecular alterations or mutations are often of a younger age, and hence future fertility and family building can be important concerns in this group. However, there are great uncertainties regarding the effect of the new drugs on reproductive functions, including fertility, pregnancy and lactation and how young patients with cancers, both women and men should be advised. The goal with this review is to gather the current knowledge regarding oncofertility and the different novel therapies, including immune checkpoint inhibitors, antibody-drug conjugates, small molecules and monoclonal antibody targeted therapies. The specific circumstances and reproductive concerns in different patient groups where novel treatments have been broadly introduced are also discussed, including those with melanoma, lung, breast, colorectal and gynecological cancers. It is clear, that more awareness is needed regarding potential drug toxicity on reproductive tissues, and it is of essence that individuals are informed based on current expertise and on available fertility preservation methods.

Over the past decades, many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma. In this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry were followed for up to 10 years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s, and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs), and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were 2-sided. Of patients with melanoma, 54 884 were included and 2469 were diagnosed, within 10 years, with subsequent melanomas. Over the 5 decades, there was a statistically significant steady increase in the frequency, IR, and SIR for second primary melanoma. For example, in the 1960s cohort, less than 1% (IR = 1.0, 95% CI = 0.5 to 1.7, and IR = 1.1, 95% CI = 0.5 to 1.9 per 1000 person-years in women and men, respectively) had second primary melanoma, and this rose to 6.4% (IR = 7.5, 95% CI = 6.8 to 8.3, per 1000 person-years) in the women and 7.9% (IR = 10.3, 95% CI = 9.3 to 11.2, per 1000 person-years) in the men in the 2000s cohort. This rise was seen independent of age, sex, invasiveness, or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having more than 2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P < .001). This is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients’ survival, and precautions are needed to turn this steep upgoing trend.

Adjuvant treatments with PD-1 and BRAF+MEK inhibitors statistically significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have considerable side effects and costs, and overall survival effect remains a highly anticipated outcome. Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed up until the end of 2021. In this cohort study, melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. There were 1371 patients diagnosed with stage III primary melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the precohort and the 737 in the postcohort, were 84.3% (95% confidence interval [CI] = 81.4% to 87.3%) and 86.1% (95% CI = 83.4% to 89.0%), respectively, with an adjusted hazard ratio of 0.91 (95% CI = 0.70 to 1.19, P = .51). Further, no statistically significant overall or melanoma-specific survival differences were seen when comparing the precohort and the postcohort in different subgroups for age, sex, or tumor characteristics. In this nationwide population-based and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.

Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Since the 1960s, there has been a well-documented and steady increase in the incidence of primary invasive cutaneous malignant melanoma (hereafter, melanoma) throughout Europe, North America, and Oceania.^1-5 The increased incidence has been most prominent among older individuals, and although it has remained low in prepubertal children, there have been reports of rising rates among them as well as among adolescents and young adults.^1,6-8 However, in recent years, Australia and the US have experienced a downward trend in melanoma incidence in younger age groups.^1,8,9 Furthermore, in some countries—eg, Canada, New Zealand, Norway, Spain, and the United Kingdom—an incidence stabilization has been reported in younger age groups.^1,2,5-7,9-12 Yet, none of the European countries have reported a significant decline in melanoma incidence in any age group. The mortality from melanoma on a population level has increased in many countries, but at a substantially slower rate than melanoma incidence.^5,13,14 Furthermore, in several countries, a decrease in melanoma mortality among younger individuals has been reported.^5,9,15

Therapeutic advances have reshaped the treatment landscape for patients with resectable melanoma, particularly for those with stage IIB/C and stage III disease. In this article, we discuss the current status and future outlook of adjuvant immunotherapy for melanoma in Europe. Adjuvant immunotherapy offers significant benefits in terms of recurrence-free survival and distant metastasis-free survival. Uncertainties regarding overall survival (OS) benefits, however, remain. Trials such as Keynote-054, which are expected to provide crucial OS information, have delayed their final analyses until 2027. Additionally, real-world studies have raised questions about the correlation between recurrence-free survival/distant metastasis-free survival improvements observed in clinical trials and OS outcomes in routine clinical practice. These uncertainties have led to ongoing debates about the cost-effectiveness of adjuvant therapies, with disparities in reimbursement policies across Europe reflecting these concerns. Looking ahead to 2028, adjuvant immunotherapy will remain a key option of comprehensive melanoma care, particularly for patients with stage IIB/C and stage III with micrometastatic disease, where neoadjuvant immunotherapy is not feasible.