Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial.

Abstract

Local therapy, including surgery, radiation, and ablation, is increasingly used in patients with multiorgan metastatic colorectal cancer (mCRC). However, prospective evidence for a survival benefit of tumor debulking is lacking. To investigate whether tumor debulking added to palliative chemotherapy improves survival of patients with multiorgan mCRC. This investigator-initiated, open-label, multicenter, randomized clinical trial enrolled patients with multiorgan mCRC between May 2013 and May 2023. The last date of follow-up was April 4, 2024. Patients were enrolled in 27 hospitals in the Netherlands and 1 in the UK. Adult patients with multiorgan mCRC were considered eligible if more than 80% tumor debulking was deemed feasible by resection, radiotherapy, and/or thermal ablation prior to starting first-line palliative chemotherapy. After achieving objective tumor response or stable disease after 3 cycles of capecitabine and oxaliplatin or 4 cycles of 5-fluorouracil and oxaliplatin with or without bevacizumab, patients were randomized 1:1 to receive chemotherapy alone (standard care group) or tumor debulking followed by chemotherapy. The primary end point was overall survival. Secondary end points included progression-free survival and serious adverse events. These outcomes were analyzed in the intention-to-treat population, applicable from randomization. A prespecified interim analysis performed after the initial 100 participants were enrolled revealed that the trial was both safe and feasible to proceed. A total of 382 of 454 enrolled patients were randomized: 192 in the chemotherapy alone group (133 [69%] male) and 190 in the chemotherapy plus tumor debulking group (127 [67%] male). The median age was 64 years in both groups. After a median follow-up of 32.3 months, median overall survival in the chemotherapy alone group was 27.5 months vs 30.0 months in the chemotherapy plus tumor debulking group (adjusted hazard ratio, 0.88 [95% CI, 0.70-1.10]; P = .26). Median progression-free survival in the chemotherapy alone group was 10.4 months vs 10.5 months in the chemotherapy plus tumor debulking group (adjusted hazard ratio, 0.83 [95% CI, 0.67-1.02]; P = .08). More patients in the chemotherapy plus tumor debulking vs chemotherapy alone group had any serious adverse events (101 [53%] vs 74 [39%]; P = .006). Tumor debulking in addition to first-line palliative systemic treatment failed to improve overall survival compared with systemic treatment alone for patients with multiorgan mCRC and should not be considered standard care. ClinicalTrials.gov Identifier: NCT01792934.