Alice M Couwenberg1, Johannes P M Burbach2, Maaike Berbee3, Miangela M Lacle4, René Arensman5, Mihaela G Raicu6, Frank J Wessels7, Joanne Verdult7, Jeanine Roodhart8, Onne Reerink9, Sieske Hoendervangers10, Jeroen Buijsen3, Heike I Grabsch11, Apollo Pronk12, Esther C J Consten13, Anke B Smits14, Joost T Heikens15, Ane L Appelt16, Wilhelmina M U van Grevenstein17, Helena M Verkooijen18, Martijn P W Intven10. 1. Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: A.M.Couwenberg@umcutrecht.nl. 2. Department of Surgery, Medical Center Leeuwarden, the Netherlands. 3. Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands. 4. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Department of Pathology, Meander Medical Centre, Amersfoort, the Netherlands. 6. Department of Pathology, St. Antonius Hospital, Nieuwegein, the Netherlands. 7. Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands. 8. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. 9. Department of Radiation Oncology, Insala Clinic, Zwolle, The Netherlands. 10. Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. 11. Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom. 12. Department of Surgery, Diakonessenhuis, Utrecht, The Netherlands. 13. Department of Surgery, Meander Medical Center, Amersfoort, The Netherlands; Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands. 14. Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. 15. Department of Surgery, Hospital Rievierenland, Tiel, The Netherlands. 16. Radiotherapy Research Group, Leeds Institute of Medicine at St James's, University of Leeds, Leeds, United Kingdom; Leeds Cancer Centre, St James University Hospital, Leeds, United Kingdom. 17. Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. 18. Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands; Faculty of Medicine, Utrecht University, Utrecht, The Netherlands.
Abstract
PURPOSE:Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC. METHODS AND MATERIALS: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521. RESULTS:Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22). CONCLUSIONS: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC.
RCT Entities:
PURPOSE: Pathologic complete tumor response after chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with a favorable prognosis and allows organ-sparing treatment strategies. In the RECTAL-BOOST trial, we aimed to investigate the effect of an external radiation boost to the tumor before chemoradiation on pathologic or sustained clinical complete tumor response in LARC. METHODS AND MATERIALS: This multicenter, nonblinded, phase 2 randomized controlled trial followed the trials-within-cohorts design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can either accept or refuse this), whereas patients in the control group are not notified about the randomization. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of 2 radiation therapy centers were eligible. Patients were randomized to no boost or an external radiation boost (5 × 3 Gy) without concurrent chemotherapy, directly followed by standard pelvic chemoradiation (25 × 2 Gy with concurrent capecitabine). The primary outcome was pathologic complete response (ie, ypT0N0) in patients with planned surgery at 12 weeks, or, as surrogate for pathologic complete response, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCT01951521. RESULTS: Between September 2014 and July 2018, 128 patients were randomized. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4 stage and a low rectal tumor (31.3% vs 17.2% and 56.3% vs 45.3%, respectively), and more patients had a cN2 stage (59.4% vs 70.3%, respectively). Rate of pathologic or sustained clinical complete tumor response was similar between the groups: 23 of 64 (35.9%; 95% confidence interval [CI], 24.3-48.9) in the intervention group versus 24 of 64 (37.5%; 95% CI, 25.7-50.5) in the control group (odds ratio [OR] = 0.94; 95% CI, 0.46-1.92). Near-complete or complete tumor regression was more common in the intervention group (34 of 49; 69.4%) than in the control group (24 of 53; 45.3%; (OR = 2.74, 95% CI 1.21-6.18). Grade ≥3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR = 1.22; 95% CI, 0.35-4.22). CONCLUSIONS: Dose escalation with an external radiation therapy boost to the tumor before neoadjuvant chemoradiation did not increase the pathologic or sustained clinical complete tumor response rate in LARC.
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