Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer
Elske C. Gootjes, Lotte Bakkerus, Anviti A. Adhin, Barbara M. Zonderhuis, Kathelijn S. Versteeg, J. Tuynman, Martijn R. Meijerink, Cornelis J.A. Haasbeek, Johannes H. W. de Wilt, Dirk J. Grünhagen, Ewoud J. Smit, John Primrose, J.A. Bridgewater, Esther van Meerten, Jan-Willem B. de Groot, Mathijs P. Hendriks, Esther Oomen-de Hoop, T. Buffart, Cornelis Verhoef, Henk M. W. Verheul, ORCHESTRA Study Group, Aart Beeker, Laurens V. Beerepoot, Haiko J. Bloemendal, Daan ten Bokkel Huinink, Joyce M van Dodewaard-de Jong, Cecile Grootscholten, Brigitte Haberkorn, Henk van Halteren, Paul Hamberg, Helgi H. Helgason, Ronald Hoekstra, Roel Hompes, Geke A.P. Hospers, Rob LH Jansen, Frank JF Jeurissen, Maartje Los, Daniëlle Mathijssen-van Stein, Leonie J. Mekenkamp, Hielke J. Meulenbeld, Marco Polée, Johannes FM Pruijt, Mirte Mayke Streppel, Pieter J Tanis, Frederiek Terheggen, Jetske M. Meerum Terwogt, Hans Torrenga, Monique M. Troost, Marija Trajkovic-Vidakovic, Maarten Vermaas, M M Vleugel, Gerard Vreugdenhil, Annette A. van Zweeden
Abstract
Importance: 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. Objective: To investigate whether tumor debulking added to palliative chemotherapy improves survival of patients with multiorgan mCRC. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01792934.