ORCHESTRA Hits a Sour Note for Debulking in Metastatic Colorectal Cancer

# ORCHESTRA Hits a Sour Note for Debulking in Metastatic Colorectal Cancer *Published: 2026 Apr 21* Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial. Gootjes EC(1), Bakkerus L(1), Adhin AA(2), Zonderhuis BM(3), Versteeg KS(4), Tuynman JB(3), Meijerink MR(5), Haasbeek CJA(6), de Wilt JHW(7), Grunhagen DJ(8), Smit EJ(9), Primrose JM(10), Bridgewater J(11), van Meerten E(2), de Groot JB(12), Hendriks MP(13), Oomen-de Hoop E(2), Buffart TE(4), Verhoef C(8), Verheul HMW(2); ORCHESTRA Study Group. Collaborators: Beeker A, Beerepoot LV, Bloemendal HJ, Ten Bokkel Huinink D, van Dodewaard-de Jong JM, Grootscholten C, Haberkorn B, van Halteren H, Hamberg P, Helgason HH, Hoekstra R, Hompes R, Hospers GA, Jansen RL, Jeurissen FJ, Los M, Mathijssen-van Stein D, Mekenkamp LJ, Meulenbeld H, Polée M, Pruijt JF, Streppel MM, Tanis PJ, Terheggen F, Meerum Terwogt JM, Torrenga H, Troost MM, Trajkovic-Vidakovic M, Vermaas M, Vleugel MM, Vreugdenhil G, van Zweeden AA. Author information: (1)Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. (2)Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands. (3)Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. (4)Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. (5)Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam, the Netherlands. (6)Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. (7)Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands. (8)Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands. (9)Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. (10)Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, England, United Kingdom. (11)Department of Oncology, UCL Cancer Institute, University College London, London, England, United Kingdom. (12)Department of Medical Oncology, Isala, Zwolle, the Netherlands. (13)Department of Medical Oncology, Northwest Clinics, Alkmaar, the Netherlands. Comment in JAMA. 2026 Apr 21;335(15):1302-1303. doi: 10.1001/jama.2026.1950. ## 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. DOI: 10.1001/jama.2026.1929 PMCID: PMC12993731 DOI: 10.1001/jama.2026.1950