Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally advanced rectal cancer: Results of the Spanish GCR-3 randomized phase II trial after a median follow-up of 5 years.

Abstract

383 Background: In locally advanced rectal cancer in contrast with the conventional approach the administration of chemotherapy prior to chemoradiation (CRT) and surgery allow most patients receive planned treatment with better toxicity profile without compromising the pCR and complete resection rates, as we previously demonstrated. (J Clin Oncol 28:859-865, 2010). We now report on the 5-year outcomes of this randomized trial. Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by Magnetic Resonance +/- endorectal ultrasound, were randomly assigned to arm A—preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B— four cycles of CAPOX followed by CRT and surgery. The following five-year outcomes were assessed: the cumulative incidence of local-regional (LRF) and distance failure (DF), disease-free (DFS) and overall (OS) using the Kaplan-Meier method. Results: Of 108 patients accrued, 52 were randomly assigned to arm A and 56 to arm B. According to intention-to-treat analysis with a median follow-up time of 69.5 months, the 5-years DFS rates were 64.3% (95% CI, 49% to 76%) in arm A and 60.7% (95 CI, 46% to 72%) in arm B (P=0.73). The 5-year cumulative incidences of local relapse were 1.9 % and 7.1% in A and B arms respectively (P= 0.36). No significant differences were detected for 5-year cumulative incidence of distant metastases (21.1% and 23.2%; P = 0.80) and 5-years overall survival (77.9% and 74.7%; P= 0.64). Conclusions: Both approaches yield similar 5-y outcomes. Because of the associated acute toxicity sparing and better compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy prior to CRT and surgery may well be the next step in phase III testing versus the standard strategy to capture meaningful differences in DFS.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer

“…We have thus demonstrated that this novel regimen of split-course CRT with concurrent oxaliplatin–5-FU and FOLFOX chemotherapy in the RT-free window is tolerable, deliverable and has demonstrated promising structural and functional imaging response rates for both primary and metastatic disease. There are several ways of optimising the regimen further to increase the control of the systemic disease while maintaining local control, including the utility of initial induction chemotherapy prior to CRT ( Shin et al , 2011 ; Cercek et al , 2013 ; Fernandez-Martos et al , 2014 ), the utility of an irinotecan-5-FU backbone ( Glynne-Jones et al , 2007 ; Nakamura et al , 2014 ), or biological agents ( Crane et al , 2010 ; Gasparini et al , 2012 ; van Dijk et al , 2013 ). The regimen reported here is now being evaluated with the addition of bevacizumab and in patients with locally advanced disease without metastases (TROG 0901).…”

Neoadjuvant Chemotherapy with Capecitabine, Oxaliplatin and Bevacizumab Followed by Concomitant Chemoradiation and Surgical Resection in Locally Advanced Rectal Cancer with High Risk of Recurrence – A Phase II Study

“…Neoadjuvant chemotherapy. Capecitabine was taken orally twice daily during the first 9 weeks (days 1-14, 22-35, [43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Oxaliplatin and bevacizumab were administered intravenous for 3 cycles (days 1, 22, 43).…”

“…It is possible that this new approach leads to prolonged DFS and OS, but phase III trials are currently lacking. Several phase II studies evaluated the role of neoadjuvant chemotherapy with Xeloda ® (capecitabine) and oxaliplatin (CAPOX) or oxaliplatin + 5-fluorouracil (FOLFOX) followed by chemoradiation and surgical resection (19, [45][46][47][48][49][50]. This approach achieved pCR rates of 14-29%.…”

“…Capecitabine was administered at 1,000 mg/m 2 b.i.d. during the first 9 weeks (days 1-14, 22-35, [43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Oxaliplatin was administered at 130 mg/m 2 as a 2-to 6-hour intravenous infusion on days 1, 22 and 43 (±2 days).…”

Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management

“…Evidence from recent investigations suggests that neoadjuvant CTX has the potential to optimize compliance without compromising a patient's ability to undergo planned CRT or increase the risk of surgical complications (Table 2). 43,[56][57][58][59][60][61][62][63][64] A pooled analysis of the phase II trials, EXPERT and EXPERT-C, published outcomes of 269 patients with MRI-defined high-risk tumors who received oxaliplatin-based neoadjuvant CTX and sequential CRT. The experimental arm was associated with an acceptable toxicity profile and established excellent compliance rates of both NA-CTX (91%) and CRT (88%), with adequate objective radiographic tumor responses, 62% and 80% after each modality, respectively.…”