Recurrent disease in patients with stage III melanoma in the era of adjuvant immune and targeted therapy.
Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.