Our study set out to investigate the performance of the 8th edition UICC/AJCC TNM (Tumour, Nodes, Metastasis) staging system for cutaneous melanoma using a Canadian population-based sample. We believe our study is the largest population-based validation study to date, with 6,414 eligible participants from stage I-IV. Our study used detailed demographic and disease data from the provincial cancer registry and other administrative sources to estimate overall survival, melanoma-specific survival, and cox regression hazard ratios.
The changes made between TNM7 and TNM8 resulted in the reclassification of many patient’s stage subgroups. Stage IIIC was the largest TNM8 stage III subgroup, representing 54.3% of our sample, 48% of the IMDDP, and 41–65% in the literature [6,7,8,9,10,11,12,13]. It is important for providers and patients – in discussion of risks and treatment options – to be aware that stage IIIC is now the most common stage III subgroup and has higher survival than reported for TNM7 stage IIIC. Notably, the newly introduced stage IIID includes no evidence of distant metastasis, yet the prognosis is poor, and survival is overlapping with stage IV metastatic disease. We found that within stage I, there was substantial movement from IB to IA, due to changes in criteria on thickness, ulceration, and mitosis. However, stages I and II had minimal changes in their 2-year and 5-year MSS. This aligns with the literature reporting little or no changes for stages I and II 5-year survival [6,7,8,9,10].
Very few patients shifted between the broad stage groups (I, II, III, IV) with 8 moving from stage II to stage I. This highlights that differences in stage subgroup survival relates overwhelmingly to shifts within a given stage’s subgroups (e.g. shifts between TNM7 IIIB and TNM8 IIIC). Our findings also suggest that historic data staged with TNM7 can be expected to have very similar underlying major disease factors (e.g. thickness, node positivity, presence of distant metastasis) to TNM8 staged patients for broad stage groups. The small improvement in the percent of variance in survival explained by stage is of a similar magnitude to typical observations for other cancer sites. In general, the percent of variance explained is low [21,22,23].
Survival for melanoma decreases with increasing age, ulceration rate, and male sex. Our median age of 61 (IQR 49–73) aligns with that found in several studies [6, 11, 13]. The sex distribution of our cohort at 51.7% males vs 48.3% females was evenly distributed, and our ulceration rate of 16.84% was lower than several studies (30–50%) [8, 11,12,13]. However, our study sample is composed of 57.6% TNM8 stage IA; a low ulceration rate is expected and consistent with one other study reporting a 16% ulceration rate and a 60% sample proportion of TNM8 stage IA [7].
While the OCR has an excellent tumour-capture rate, some limitations are present. Ulceration, an important prognostic factor, could not be determined in 6.8% of cases. Moreover, risks of misclassification of cause of death from secondary cancers (not counted in MSS) being related to melanoma metastases, and heterogeneous pathology reporting, all introduce potential sources of error.
We demonstrated lower survival for nearly all stages in comparison to the largely institution-based IMDDP that first established the AJCC8 staging system. Our TNM8 5-year MSS for stage I (98.4%), stage II (82.5%) and stage III (66.4%) was comparable or lower than the 5-year MSS for stage I (98%), stage II (90%), and stage III (77%) reported by Gershenwald et al. using the IMDDP [4].
Our 5-year MSS estimates were lower than the IMDDP for all stage subgroups except IA, IIIA, and IIID, which contained the IMDDP value in their 95% CI. Our 5-year MSS was lower than the IMDDP for stage IB (95.6% vs 97%), IIA (90.4% vs 94%), IIB (80.8% vs 87%), IIC (69.0% vs 82%), IIIB (74.8% vs 83%), and IIIC (59.0% vs 69%) [4]. Other validation studies (population-based and institution-based) of the TNM8 similarly reported a lower survival than the IMDDP for many substages [6, 8,9,10,11,12,13].
It is not immediately clear why the IMDDP cohort reported higher survival for most stages. The IMDDP analysis used institutional data of 46,000 patients from ten institutions globally. None of these institutions were Canadian, and 15,746 patients (33.5%) were from three institutions in the U.S. [4], where access to healthcare is influenced by private and public health coverage. As no demographic and disease characteristics were included, it is difficult to ascertain the influence of confounding variables. Disparities in the study population (e.g., young age, unbalanced sex ratio, higher SES) or disease features (e.g., decreased ulceration rate, primary tumour location) may have influenced survival estimates. We note that similar to the IMDDP data, our population-based sample comes predominantly before the adoption of new targeted and immune-based therapies for melanoma. This suggests that differences in use of approved novel targeted therapies and immune-based therapies is less likely to be the primary driver [24]. As such, it is important to recognize that the results from the IMDDP analysis may not be generalizable to Canadian populations, and the institutional dataset may differ from population-based outcomes.
Our findings also emphasize the importance of considering subgroup-specific treatment recommendations, and evaluating novel adjuvant therapies for high-risk stage II patients. We highlight this given that survival for stage III and IV patients is improving with immunotherapies (anti-PD1, anti-CTLA4) and targeted therapies (BRAF inhibitors, MEK inhibitors) [25]. Currently, adjuvant pembrolizumab (anti-PD1), nivolumab (anti-PD1), or combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) are recommended for resected stage III melanoma (dependant on BRAF status) [26, 27]. These same therapies, however, are not recommended for resected stage II melanoma. Notably, stage IIIA has a lower risk of death than stage IIC, and stage IIIB has a similar risk to stage IIC.
Shifts in stage III subgroups are also notable. The MSS for stage IIIC improved between TNM7 and TNM8, and the MSS for stage IIID approximated stage IV metastatic disease. The need for expanded treatment recommendations is clear, and several ongoing phase 3 trials will provide valuable insight (NCT04309409, NCT03553836, NCT04099251). In the future, patients will surely benefit from increased access to innovative therapies and further-refined treatment guidelines.