Among patients with stage I or II cutaneous melanoma, women have been found to have a consistent 30% advantage over men in overall survival, disease-specific survival, rate of distant metastasis, rate of lymph node metastasis, and rate of relapse, a study published online April 30 in the Journal of Clinical Oncology has shown.
"The 30% advantage extends to the whole spectrum of melanoma disease behavior," reported Dr. Arjen Joosse of Erasmus University Medical Center, Rotterdam, the Netherlands, and his associates.
Women with melanoma are known to have higher survival rates than men, but the details of the difference had never been thoroughly explored. Some experts have proposed that men have more advanced disease at diagnosis because they are less aware of melanoma, less likely to be screened, and less likely to seek medical care for a suspect lesion. Others contend that biologic differences between the sexes account for survival differences, and point to estrogen as a likely contributor.
Dr. Joosse and his colleagues examined the issue by analyzing the pooled results of four large, randomized phase III clinical trials of localized melanoma performed by the European Organisation for Research and Treatment of Cancer (EORTC). The trials, which investigated different therapies for the disease, involved detailed medical records and "meticulous" follow-up of 2,672 patients (48% men and 52% women).
"Women exhibited an independent, significant, and consistent advantage of approximately 30%" for overall survival, relapse-free survival, disease-specific survival, time to in-transit metastasis, lymph node metastasis, and distant metastasis, the investigators reported (J. Clin. Oncol. 2012 April 30 [doi:10.1200/JCO.2011.38.0584]).
This sex-based difference persisted across numerous prognostic subgroups of patients, regardless of the location of the initial lesion, Breslow thickness, the presence or absence of ulceration, and whether the patient underwent sentinel node biopsy or elective lymph node dissection. If the hypothesis about sex differences in melanoma detection, screening, and diagnostic delays were true, there should be marked differences in the discrepancy between men and women across such subgroups; but no such differences were found.
Moreover, because women showed both a longer delay before relapse and a higher cure rate, compared with men, "it seems that whatever the cause of the female advantage may be, it causes both a delay in progression and a larger subset of melanomas being cured in women, compared with men," the researchers wrote.
To explore the hypothesis that estrogen might be the source of women’s survival advantage, the investigators classified the female patients by age to approximate their menopausal status.
Postmenopausal women (defined as those aged 60 years and older) retained the 30% advantage in overall survival, relapse-free survival, time to lymph node metastasis, and time to distant metastasis, compared with premenopausal women (aged 45 and younger). The advantage for disease-specific survival declined significantly in this analysis, but that may be a chance finding because of the small sample sizes and low event rates in these subgroups.
Thus, estrogen alone cannot account for the sex-based differences in survival. Other factors that may be involved include androgen receptors in melanoma cells; differences in oxidative stress between men and women; differences between the sexes in vitamin D metabolism, because vitamin D levels appear to affect melanoma prognosis; and differences in immune homeostasis, since melanoma is thought to be immunogenic.
Unravelling the underlying cause of the survival difference between men and women could point the way to targeted therapies, the investigators noted.
They added that the 30% survival advantage in their study is consistent with a 30% advantage in 5 of the 7 published studies in the literature that included 10,000 or more patients.
The study investigators reported no relevant financial disclosures.