Study Design:
an historical population-based cohort study was set, using the South-Region Cancer Registry (ROR-Sul) to identify cases diagnosed with malignant melanoma of the skin between 01.01.2016 and 30.06.2017. The expected follow-up period was 3 years, meaning each case was followed since the date of first diagnosis for a period of three years, unless death occurred, or case was lost to follow-up (e.g. left the country).
Population & Sample
The population of interest considered for this study is all individuals residing in the area covered by ROR-Sul.
Inclusion criteria:
Having a confirmed cutaneous malignant melanoma diagnosis; first diagnosis must have occurred within the time period defined to be of interest for study; included cases must be aged 18 years or older; and live in the area of influence of the ROR-Sul at the moment of diagnosis.
Exclusion criteria:
not having histopathological or cytological diagnosis, according to the third revision of the International Classification of Diseases for Oncology (12).
Data Sources:
ROR-Sul is a population-based registry covering 4 800 000 inhabitants (46% of the Portuguese population). Population monitoring is ensured by gathering data originating from 24 hospitals and resorting to data linkage between various sources, namely primary care centers, hospitals (including care provided and diagnostic tests made), and ultimately death certificates. Data linkage can occur by automatic data integration or by manual data entry, in both cases validated by a certified registrar. Whenever a cancer diagnosis is made, regardless of the setting, the case enters the registry and is then prospectively followed throughout the years, contacts made in every point of the health care system are captured, until death occurs. Because cases enter the registry upon diagnosis, previous exposure to risk factors is often not captured.
Study variables:
Variables considered of interest were divided into three main categories. Demographic variables comprised sex, age and district of residence at diagnosis; clinical variables referred to primary tumor location, histological subtype, stage at diagnosis (13), BRAF mutation, Clark level, Breslow index, ulceration, mitotic index, Lactate Dehydrogenase (LDH) and Eastern Cooperative Oncology Group Performance Status (ECOG PS); treatment variables considered the use of surgery, radiotherapy, other treatment (e.g., electro therapy) or systemic therapy, and combinations of the former. In addition, to these three categories, patient status during the follow-up period was also considered, namely death and disease recurrence.
Statistical analysis:
Demographic, clinical, district distribution and therapeutic characteristics were summarized as medians and interquartile ranges (IQRs) for continuous variables and as absolute and relative frequencies for categorical variables. Cumulative incidence rates at 18 months were calculated by district of residence and it has been computed the Age-Standardized Incidence Rate per 100,000 World population (ASRW) for the study region. ASRW was further categorized in three groups, defined according to the amplitude of incidence values estimated, into high ] 12.35 - 14.53], medium ]10.17 - 12.35] and low incidence [7.99 - 10.17], and the graphical representation in the region resorted to software GeoDa (14). The association between variables has been evaluated for study region. The χ2 test or Fish exact test was applied to evaluate the association between categorical variables, as applicable, and the t-Student test was used for continuous variables. Only variables with missing values below 20% were considered eligible for bivariate analysis, as suggested elsewhere (15). Median follow-up was computed simply, considering time between date of diagnosis and date of death or date of cut-off (3 years after date of diagnosis). Kaplan-Meier estimates have been used to assess recurrence-free survival (RFS) and overall survival (OS). Time of RFS was considered the time elapsed between date of diagnosis and date of recurrence or date of death. Disease recurrence was estimated at 3 years for stages I-III, where the event of interest was considered recurrence or metastasis following disease remission. Survival time was considered the time elapsed between date of diagnosis and date of death. For both survival analysis, for patients who do not have the event of interest were censored at last contact date or date of cut-off, as applicable. The log-rank test was used to evaluate RFS differences by stage. Multivariable Cox proportional hazards regression was used to evaluate associations between prognostic variables and RFS separated by stages (I-II and III). The proportional hazard assumptions were verified. All estimated p-values were two-sided and a 95% confidence interval (CI) was considered for significance. The software Stata, version 13.0, was used for all statistical analyzes (16).
Ethics:
The current study was conducted according to the principles described in Helsinki Declaration and according to the established national legislation. This implies that informed consent was obtained from all subjects when care delivery is initiated in institutions part of the ROR-Sul network. The study was approved by the institutional review board (IRB) of the Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), on the 2nd July 2019 (UIC/1232).