The incidence of cutaneous melanoma (CM) has risen rapidly over the past few decades.1 In Spain, the incidence rate is approximately 15 cases per 100,000 inhabitants per year, and about 1000 deaths are reported annually, according to the Spanish Network of Cancer Registries (REDECAN) and the Spanish Society of Medical Oncology (SEOM).2

Most patients (approximately 85%) are diagnosed with localized melanoma, which can be managed by resection of the primary tumor with sentinel lymph node biopsy for stages IB and higher according to the American Joint Committee on Cancer (AJCC), 8th edition.3 However, 25–35% of these patients will develop recurrence, with approximately 50% occurring in regional lymph nodes, 20% as local recurrences, and 30% as distant recurrences.3

Although stage II melanoma represents localized disease, it is associated with a greater absolute number of eventual deaths than stages III and IV because of its much higher incidence. In addition, stages IIB and IIC are associated with worse prognosis than stages IIIA and IIIB, respectively.4 Prospective data show 5-year recurrence-free survival (RFS) rates of 54.7% for stage IIB and 26.5% for stage IIC disease.5 Retrospective analyses report slightly higher RFS rates of 64.4% and 41.5% for stages IIB and IIC, respectively.6 Comparisons between stage II and stage III subgroups should be interpreted with caution, because melanoma staging does not always follow a linear prognostic progression. For instance, stage IIB may have worse outcomes than stage IIIA, and stage IIC may have poorer prognosis than stage IIIB.7

Over the last decade, immune and targeted therapies have significantly improved survival in patients with metastatic melanoma.8 As patients with advanced disease live longer, locoregional control has become increasingly important. While surveillance guidelines and adjuvant therapy options are well established for stage III melanoma, follow-up protocols for stage II disease remain inconsistent, with no standardized intervals, imaging recommendations, or treatment strategies. Recently, adjuvant nivolumab and pembrolizumab have been shown to improve RFS in patients with resected stage IIB/C melanoma, leading to approval by the US Food and Drug Administration and the European Medicines Agency.9,10 However, further research is needed to guide treatment and monitoring in this population and to identify biomarkers that may support personalized decision-making. Clear guidance for monitoring patients with stage II CM is lacking, mainly because of limited research on recurrence patterns in this group. Understanding these patterns is essential for developing effective surveillance strategies and may require updates to current substage-specific guidelines.

In this context, the METHEOR study was designed to explore recurrence patterns in stage II cutaneous melanoma and to describe healthcare resource utilization in real-world clinical practice in Spain.

In the METHEOR study, we examined recurrence patterns in patients with pathologic stage II primary CM and changes in HCRU at disease progression in real-world clinical practice in Spain. We identified 324 adult patients: 44% had stage IIA, 36% stage IIB, and 20% stage IIC disease. After a median follow-up of more than 5 years, 27.8% had melanoma recurrence, similar to rates reported in other studies of stage II CM (27.2–29.6%).6,11,12

In our study, 54.4% of patients had distant first recurrences, a proportion similar to that reported by Bleicher et al.6 (50.6%). Furthermore, the proportion of patients with distant recurrence was similar across all 3 stages (>50%), and almost half of patients had a 2nd recurrence despite treatment. These findings suggest that new management approaches are needed to reduce recurrence.

Consistent with previous reports, recurrence occurred more often in stage IIB (34%) and stage IIC (32%) than in stage IIA disease (21%). In addition, patients with stage IIB or IIC disease have been shown to have worse outcomes than those with stage IIIA disease,17,18 which has prompted discussion as to whether staging should be revisited.7 However, unlike previous reports,17 we observed that stage IIB CM was associated with a significantly increased recurrence risk.

The absence of significant differences in OS among stage IIA, IIB, and IIC patients in our cohort may appear inconsistent with previously published data. One possible explanation lies in the exclusion criteria used in this study. Specifically, patients with vascular invasion or incomplete excision of the primary tumor were excluded to ensure sample homogeneity and avoid potential misclassification. Vascular invasion may be interpreted as an indicator of micrometastatic spread19 and has been associated with a higher risk of dissemination, as well as being an independent prognostic factor for both progression-free survival and OS.20 However, lymphovascular invasion is not currently used to upstage patients under AJCC criteria, and this exclusion may limit the generalizability of survival estimates. It is reasonable to assume that a proportion of stage IIB/IIC patients in real-world settings may present with lymphovascular invasion, which could influence survival curves and explain the lack of prognostic gradient observed in our results.

Because the effectiveness of adjuvant anti–PD-1 therapy for stage III melanoma has been established,21–23 similar strategies have been investigated in resected high-risk stage IIB/IIC melanoma. In the CheckMate 76K study, adjuvant nivolumab in patients with stage IIB or IIC melanoma resulted in a statistically significant improvement in RFS, with a 58% reduction in risk of recurrence or death compared with placebo,24 leading to regulatory approval. Similarly, in the KEYNOTE-716 study, adjuvant pembrolizumab significantly improved RFS and DMFS versus placebo (HR, 0.64 for both) in patients with stage IIB or IIC melanoma, leading to approval.10

Despite these approvals, stage IIB/IIC melanoma remains a high-risk setting requiring further perioperative investigation. Additional studies are needed to identify which patients benefit most from adjuvant therapy. Advancing personalized care will depend on improved biomarker identification and evaluation of the potential role of neoadjuvant therapy in this group.

Further research is also required to identify recurrence risk factors and predictors beyond staging criteria.25 Consistent with previous population-based findings, we identified older age and mitotic rate greater than 5/mm2 as predictors of recurrence, highlighting the prognostic value of mitotic activity.26,27

As previously reported, recurrence in our cohort was associated with a substantial increase in HCRU and related costs.28 Mean healthcare costs were slightly higher in patients with stage IIB or IIC disease than in those with stage IIA. Given the expected future burden of melanoma in Europe, driven by population aging and increased awareness and early detection, the number of new cases is likely to rise. Allocation of resources for disease control is therefore crucial, particularly as new therapies are rapidly being developed.29 In addition, healthcare resources should be focused on the highest-risk patients, especially those with stage IIB and IIC disease, who are most likely to benefit from adjuvant anti–PD-1 therapy, while treatment may be de-escalated in lower-risk patients to optimize resource use.

This study was limited by its retrospective design. After the inclusion period defined for this study, the EMA approved adjuvant anti-PD-1 therapies (nivolumab or pembrolizumab) for stage II CM, so real-world data on the effect of these therapies on survival outcomes were not available. In addition, some patients did not receive treatment after recurrence, which may have led to underestimation of associated health care resource use.

In conclusion, more than one-quarter of patients with stage II CM developed recurrence. More than half of these patients developed distant metastases, which may have a substantial impact on survival. These results highlight the need for improved follow-up and treatment strategies to reduce recurrence risk in patients with stage II CM, especially in stage IIB/IIC disease. However, patients with stage IIA disease also had a substantial recurrence risk, and clinical trials of adjuvant therapy in this setting are warranted.

This study was sponsored by Bristol Myers Squibb.

E. Nagore participated as principal investigator and coordinator of the METHEOR study funded by BMS; received grants from the Generalitat Valenciana; consulting fees from Almirall; and support for attending meetings and/or travel from Cantabria Labs and ISDIN. He is a member of the Project & Proposals Committee of the EADV and Director of Actas Dermosifiliográficas of the AEDV.

E. Samaniego received payment or honoraria for presentations or educational events from Sun Pharma, Novartis, and BMS, and participated in advisory boards with Sun Pharma.

R. Fernández-de-Misa received payment or honoraria for presentations from Takeda, Kyowa Kirin, Recordati, and BMS.

F. Vílchez-Márquez received payment or honoraria for presentations and participated in advisory boards with Sun Pharma, Pierre Fabre, Almirall, and Kyowa Kirin.

S. Puig received payment or honoraria for presentations from Almirall, Avène, Bioderma, Cantabria Labs, Eucerin, ISDIN, La Roche-Posay, Pierre Fabre, Regeneron, and Sanofi; participated in advisory boards with Almirall, ISDIN, La Roche-Posay, MSD, Novartis, Pfizer, Sanofi, and Sun Pharma; received grants from Almirall, La Roche-Posay, and Cantabria Labs; has other financial interests with Damae Médica; and has nonfinancial interests with La Roche-Posay and Leo Pharma.

L. Ostios-García and D. Vilanova are employees of BMS.

A. Boada, A. Diago, P. Ortiz-Romero, S. Moreno, L. Ferrándiz, and A. Flórez declare no conflicts of interest.