Effectiveness and Safety of Treatments for Early-Stage Merkel Cell Carcinoma: A Systematic Review and Meta-Analysis of Randomized and Non-Randomized Studies

Abstract

Objective: The lack of consensus on the benefits and harms of standard therapies, including surgery (SRx), radiotherapy (RTx), chemotherapy (CTx), and their combinations among early-stage MCC, prompted this study.

Methods: A systematic review and meta-analysis of randomized and non-randomized studies published between January 01, 1972, and January 31, 2023, and having overall survival (OS), local recurrence (LR), regional recurrence (RR), disease-specific survival (DSS), and/or disease-free survival (DFS) as outcomes was conducted using the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed (NCBI), Scopus (ELSEVIER), and Web of Science (CLAVIRATE) databases. Hazard ratios (HRs) and their variances were pooled using the inverse variance heterogeneity model.

Results: Forty-nine studies representing 46,215 participants were included in the meta-analysis. A statistically significant improvement in OS was observed for groups administered adjuvant RTx (SRx + RTx) compared to SRx only (HR = 0.78, 95% CI, 0.62-0.99), albeit with statistically significant heterogeneity (Q = 532.30, p < 0.001) and a large amount of inconsistency (I² = 94%, 95% CI, 93.0-95.5). Both LR (HR = 1.52, 95% CI, 0.37-6.19) and RR (HR = 0.41, 95% CI, 0.09-1.78) were not statistically significant. In addition, DSS (HR = 0.58, 95% CI, 0.24-1.40) was not statistically significant but DFS was (HR = 0.35, 95% CI, 0.13-0.93). Subgroup analyses revealed that adjuvant radiotherapy was more effective in local than regional MCC. The E-value suggested that the RTx dose was a confounder of the observed effectiveness of adjuvant RTx; and also, the use of CTx following adjuvant RTx, did not impact the strength of evidence for OS.

Conclusions: Although adjuvant RTx improves survival and recurrence outcomes among early-stage MCC, the safety and effectiveness of standard therapies in MCC remains poorly studied and, thus, affects the synthesis of evidence across important patient and clinical characteristics. Future research on the comparative effectiveness of different therapies is needed.

Keywords: Merkel cell carcinoma; disease‐free survival; disease‐specific survival; local recurrence; meta‐analysis; overall survival; regional recurrence.

FIGURE 1

Distribution of RCTs and observational studies registered in clinicaltrials.gov and based on MCC treatment and staging. Studies with early stages included also MCC with other stages, whereas studies with late stages featured only patients with late or advanced stages.

FIGURE 2

Flowch, art of screening and selection process leading to the final study pool.

FIGURE 3

Pooled risk of bias of the selected studies.

FIGURE 4

Forest plot for HRs for changes in (a) OS for adjuvant RTx, (b) OS for addition of CTx, (c) LR, (d) RR, (e) DSS, and (f) DFS. The black‐filled squares, sized according to the weight contributing to the overall effect, represent changes in HR from each study while the left and right extremes of the squares represent the lower and upper 95% confidence intervals for changes in outcome (OS, LR, RR, DSS, DFS) from each study. The black diamond represents the pooled effect size change in outcome (OS, LR, RR, DSS, DFS) while the left and right extremes of the diamonds represent the pooled lower and upper 95% confidence intervals for changes in outcome. The red dashed vertical line through the middle of the diamond represents the pooled mean effect while the black dashed vertical line represents the zero (0) point. % Weight: Percentage weight of a particular study.