Therapy for melanoma has experienced a revolution as a result of targeted therapies with BRAF and MEK inhibitors and immunotherapies with checkpoint inhibitors [12, 13]. However, as these therapies were introduced in Europe in the mid-2010s, their possible influence would not be shown in the present population-based figures. Data from the Stockholm Melanoma Register showed that 98.9% of all patients underwent surgery as the first-line treatment, and thus therapeutic side-effects are unlikely to influence the current survival estimates . Many survival studies on cancer, including melanoma, focus on disease-specific survival, which may be different from overall survival, particularly for cancers of good survival, such as melanoma. For treatment-specific effects, disease-specific survival is of main interest but for the study of co-morbidities (such as SPCs), overall survival is of primary interest. Thus SPCs as cause of mortality in melanoma have largely been overlooked. According to an Australian study based on 20-year survival in thin melanoma (1 mm or less, accounting for 71% of all) only 2.2% of the patients had died of melanoma . In a Swedish study covering years 1958 through 2015 and median follow-up time since melanoma of 8 years, 74.2% of patients without SPC died of melanoma while for those diagnosed with SPC, first melanoma was the cause of death only among 24.5% of the patients; 43.1% died of SPC other than melanoma .
Age at diagnosis is known to influence negatively both melanoma-specific and overall survival and we showed here that it also negatively influences overall survival in patients with SPC [1, 16]. Similarly, females survive better in primary melanoma than males, and we showed here that the difference was also seen in SPCs after melanoma, including second melanoma [1, 2, 16]. The survival advantage in women may be related to known enhanced immunoreactivity in women which is manifested in the overall excess of autoimmune diseases in women compared to men; it is believed to be related at least in part to estrogen modulation of immune functions [17, 18].
The current data on overall survival in melanoma patients, focusing on the time interval from first melanoma to SPCs, revealed two novel features. One with practical clinical implications suggests that in young melanoma patients, diagnosed before age 60, second melanomas may not decrease survival; however, case numbers were few. This applied even to melanomas diagnosed before age 60 with development of SPCs in skin, breast and prostate cancers after more than 10 years of melanoma diagnosis; this was even true when diagnosis was 6 or more years after melanoma. However, the numbers of deaths in these age groups were small, thus warranting caution. The possible explanation could be an increased awareness of patients to detect early signs of some cancers following the initial melanoma diagnosis. However, the information on cancer screening and clinical staging is not available in the current study.
The second novel feature was that, overall, the HRs were relatively uniform over the time intervals for diagnostic age- and SPC-specific overall survival. This appears to be contradictory to the Kaplan-Meier data shown in Figs. 1 to 2, which described an ever steeper decline in overall survival when the interval time was extended. However, the HRs were calculated using time-dependent Cox proportional hazard regression analysis which adjusted for the interval-defined waiting time (referred to as for ‘immortal time’) when no deaths occur by definition . In this model the time interval to diagnosis of SPC is treated as a time-dependent variable to avoid the immortal time bias . Time-dependent data describe the true clinical situation, i.e., the overall survival for melanoma patients diagnosed with SPC was fairly constant whether SPC was diagnosed shortly after the first diagnosis or 10 years later. The only exception was for relatively young patients, as discussed in the previous paragraph.
We showed also for a number of specific cancers as SPC that those known to be fatal as first cancer were also fatal as SPC. Similar results have been reported for second cancers after hematological malignancies [19, 20]. However, even for cancers with moderate overall survival as first cancers, such as colorectal cancer and Hodgkin lymphoma, HRs as SPC were as high as around 13 and 15, respectively, when melanoma was diagnosed at age 60 to 79 years; in melanoma patients without SPC the background HR was 3.87. In melanoma patients in that age group who were unfortunate to be diagnosed with second lung cancer or CUP, HRs ranged from 30 to about 100 which is practically a death sentence. CUP is diagnosed as metastases and it is highly fatal also as first cancer [21,22,23].
The strengths of the present study include practically complete coverage of histologically verified cancers diagnosed in Sweden and a complete coverage of deaths. The potential weaknesses are related to epidemiology of melanoma with vastly increasing incidence and improved survival which may introduce inaccuracies in the calculations. Although the law mandates reporting all cancers to the cancer registry there is only a small study verifying a high rate of reporting of SPCs .
In conclusion, survival analysis on melanoma patients with SPCs showed a lower overall survival in patients with second melanoma and in particular those with other SPCs. The overall survival in SPC followed the expected overall survival from first cancer, patients with second lung cancer and CUP showed a very poor overall survival. For patients with SPC, a female overall survival advantage was noted over males, in addition to a strongly worsening overall survival in older patients, both in line with survival data in primary melanoma. Time-dependent analysis suggested that young melanoma patients diagnosed with SPC 6 or 10 years later may not have worse overall survival. It further showed that for melanoma diagnosed at common age groups, overall survival was relatively constant in patients with particular SPCs irrespective of the time interval between first melanoma and SPC. As the outcome of patients with many types of SPC is unfavorable, the cancer prevention and early detection should be considered for melanoma patients. For the most fatal SPCs of the lung and unknown primary smoking is an important risk factor and advice about smoking cessation may be particularly well received at diagnosis of primary cancer . For the other common SPCs of the breast, prostate and colorectum screening methods are available and could be recommended at least for elderly patients with the highest risk.