Study design
This was a historical observational cohort study among patients diagnosed with metastatic (stage IV) melanoma, based on prospectively collected data obtained from population-based medical databases in Denmark. According to Danish legislation, purely registry-based studies do not need permission from an ethical board. Our study was approved by the Danish Data Protection Agency (Jr no 2009-41-3653). Moreover, we were granted permission to abstract information from the medical files without obtaining informed consent by the National Board of Health.
The Danish National Health Service provides tax-supported health care for all inhabitants of Denmark. The Danish Cancer Registry (DCR) established in 1943 contains records of all incident cancers diagnosed in living patients or identified through autopsy. The 10th revision of the International Classification of Diseases (ICD-10) has been used to code tumors since 1978. DCR files include information on cancer type, site, morphology, and cancer history. It has been found to have a high degree of completeness [21, 22] and the proportion of morphologically verified tumors is 89 % [23]. The National Pathology Registry (NPR), which has been nationwide since 1997, contains data on type of pathological specimens, procedures, pathological tests and results, and the diagnoses assigned. Diagnoses are coded according to the SNOMED classification. The Danish Civil Registration System (CRS) has recorded data on residency, vital status, and marital status for the entire Danish population since 1968 [24]. The data on death (yes/no) are more than 99 % complete and very accurate [25].
Study population
We identified all patients (age ≥18 years) diagnosed with metastatic (stage IV) melanoma from 1997 to 2010 in Denmark. Eligible patients included those who had initial diagnoses of metastatic (stage IV) cutaneous melanoma during 1997 to 2010 and those who had earlier stage melanoma at initial diagnosis who then progressed to metastatic (stage IV) melanoma during 1997 to 2010. Only those who had melanoma as their first primary cancer were included. Patients were excluded if they had a history of cancer, other than melanoma, basel-cell carcinoma (BCC), cuSCC, Bowen’s disease, AK and KA, before the metastatic melanoma diagnosis.
Metastatic melanoma patients were identified using two national databases ― the DCR and the NPR, based on the ICD-10 Diagnosis Code and SNOMED Morphology Codes (Appendix). The DCR documents the initial diagnoses of all primary cancers; the NPR captures a large number of metastatic melanomas identified during the follow-up post initial melanoma diagnosis, although it is not 100 % complete. The index date for a patient was defined as the date of metastatic melanoma diagnosis. The Danish Civil Registration Number, a unique identification number assigned to every Danish citizen at birth or immigration, was used to link the DCR and NPR to the CRS for obtaining data on patient demographics, medical history, immigration, and death. All metastatic melanoma patients were followed until death, emigration, or end of study period, i.e., December 31, 2011.
Outcome definitions and measures
Overall survival status for these patients was described at 3, 6, 12, 36, and 60 months after metastatic melanoma diagnosis. Non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma were identified over the continuous intervals of 1, 2, 3, 6, 9, and 12 months after the index date, and over the total follow-up. Events of cuSCC, BCC, Bowen’s disease, AK, and KA were identified with SNOMED codes (Appendix), with restriction to the non skin topology site.
Validation of metastatic melanoma diagnosis in the NPR
Medical charts were reviewed for a random sample of 65 metastatic melanoma patients, with a registration of metastatic melanoma (including lymph node metastases) in the NPR. Of these, 40 (62 %) patients were admitted to Department of Oncology in Aarhus and 25 (38 %) patients were admitted to the Department of Plastic Surgery in Aalborg. Medical records for one patient from Aalborg could not be located. Of the remaining 64 patients, all had metastatic cutaneous melanoma according to the medical records, yielding a positive predictive value (PPV) of 100 % (95 % confidence interval [CI]: 96.2-100.0).
Statistical analysis
Mean, standard deviation, median, and range were derived for continuous variables, and number and proportion were described for categorical variables. All patients were followed from date of metastatic melanoma diagnosis until death, migration out of Denmark, or the end of study period (i.e., December 31, 2011). Kaplan-Meier survival curves were derived to describe time to death over the 3, 6, 12, 36, and 60 months after metastatic melanoma diagnosis. Patients were considered as censored if they were lost during the follow-up or if there was no enough follow-up time allowed at the end of the study period. Mortality rate and the CIs were calculated using the method outlined by Simon et al. [26].
We described the number and proportion (and 95 % CI) of patients with a history or pre-existing non-melanoma malignant skin lesions (i.e., BCC, cuSCC, Bowen’s disease, AK and KA, eligible) prior to metastatic melanoma diagnosis. None of these melanoma patients had a history or pre-existing non-cuSCC, by study design.
To be consistent with most clinical trial studies, for the current study, the incidence analysis on non-melanoma malignant skin lesions was first conducted among patients regardless of whether they had a history or pre-existing non-melanoma malignant skin lesions. The incidence analysis was further conducted among patients who had no history or pre-existing non-melanoma malignant skin lesions. The incidence analysis of non-cuSCC was conducted among all eligible patients. The sites of non-cuSCC were described. We described cumulative incidence in proportion, and incidence rate in person-year of non-melanoma malignant skin lesions (or non-cuSCC) over the continuous intervals of 0–1, 0–2, 0–3, 0–6, 0–9, 0–12 months (i.e., 0–30, 0–60, 0–90, 0–180, 0–270, 0–365 days), and over the total follow-up, following metastatic melanoma diagnosis. The numerator was the number of metastatic melanoma patients with non-melanoma malignant skin lesions (or non-cuSCC) occurring during the specified time period post metastatic melanoma diagnosis. For the determination of cumulative incidence, the denominator was the number of eligible metastatic melanoma patients. For the determination of incidence rate, the denominator was the total person-years of eligible metastatic melanoma patients, with the person-year for each patient calculated as the time from metastatic melanoma diagnosis to date of the event, death, last contact, or end of the study period, whichever occurred first. The incidence analyses were further stratified by age at diagnosis (18- < 65, 65- < 75, 75- < 85, and 85+ years).
All analyses were further stratified and compared between two subgroups, patients with metastatic disease at initial diagnosis and patients diagnosed with early stage melanoma initially who then progressed to metastatic stage during the follow-up. All analyses were done using SAS 9.2 software (Cary, NC, USA).