MORPHEUS Phase II–III Study: A Pre-Planned Interim Safety Analysis and Preliminary Results

SIMPLE SUMMARY: This prospective phase II–III randomized trial explores the value of modern technology for prudent radiation dose escalation in the curative management of patients with rectal cancer. It includes 40 operable patients with locally advanced operable rectal cancer. This manuscript illustrates the planned interim analysis, which was intended to confirm safety, including the absence of unexpected toxicities and the inability to perform salvage surgery. The treatment approach involves pelvic chemoradiotherapy followed by either an additional external beam radiation boost or three weekly boosts of brachytherapy, which are adapted in real-time to tumor response. This proof-of-principle study shows that careful radiotherapy dose escalation leads to high proportions of sustained complete clinical response in patients with rectal cancer with acceptable toxicity. Ongoing accrual to the phase III component of the trial is in progress. ABSTRACT: Background: We explored image-guided adaptive endorectal brachytherapy patients electing non-operative management for rectal cancer. We present the first pre-planned interim analysis. Methods: In this open-label phase II–III randomized study, patients with operable cT2-3ab N0 M0 rectal cancer received 45 Gy in 25 fractions of pelvic external beam radiotherapy (EBRT) with 5-FU/Capecitabine. They were randomized 1:1 to receive either an EBRT boost of 9 Gy in 5 fractions (Arm A) or three weekly adaptive brachytherapy (IGAEBT) boosts totaling 30 Gy (Arm B). Patient characteristics and toxicity are presented using descriptive analyses; TME-free survival between arms with the intention to treat the population is explored using the Kaplan–Meier method. Results: A total of 40 patients were in this analysis. Baseline characteristics were balanced; acute toxicities were similar. Complete clinical response (cCR) was 50% (n = 10/20) in Arm A and 90% in Arm B (n = 18/20). Median follow-up was 1.3 years; 2-year TME-free survival was 38.6% (95% CI: 16.5–60.6%) in the EBRT arm and 76.6% (95% CI: 56.1–97.1%) in the IGAEBT arm. Conclusions: Radiation intensification with IGAEBT is feasible. This interim analysis suggests an improvement in TME-free survival when comparing IGAEBT with EBRT, pending confirmation upon completion of this trial.