The EXPERT-C Trial Defines a Reference for Future Research: Quality of Life and Bowel Function in Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemotherapy Followed by Chemoradiation Therapy Before Surgery

Abstract

A combined treatment approach, including preoperative 5-fluorouracil–based chemoradiation therapy (CRT), surgery, and postoperative chemotherapy, achieves excellent local control in locally advanced rectal cancer (LARC). However, with distant metastasis rates of approximately 30% after 10 years, the control of systemic disease remains unsatisfactorily low ( 1 Sauer R. Liersch T. Merkel S. et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012; 30: 1926-1933 Crossref PubMed Scopus (1327) Google Scholar ). Against this background, numerous clinical trials have focused on intensified treatment strategies to improve clinical outcomes. The addition of further pharmaceutical agents, such as oxaliplatin, to multimodal treatment has been investigated extensively ( 2 Nussbaum N. Altomare I. The neoadjuvant treatment of rectal cancer: A review. Curr Oncol Rep. 2015; 17: 434 Crossref PubMed Scopus (13) Google Scholar ). Furthermore, recent findings raise serious and, to some degree, controversial questions concerning the effectiveness of postoperative 5-fluorouracil–based chemotherapy ( 3 Bosset J.F. Calais G. Mineur L. et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: Long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014; 15: 184-190 Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar ). For various reasons, such as patient refusal, or surgical and postoperative complications, the proportion of patients completing the planned treatment appears unacceptably low ( 3 Bosset J.F. Calais G. Mineur L. et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: Long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014; 15: 184-190 Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar ). Therefore, the use of neoadjuvant chemotherapy (NACT) before CRT and surgery seems reasonable. This strategy may enable the application of systemic treatment at a suitable dose and intensity, thus confronting the high rates of distant metastasis. In a handful of trials, promising clinical response rates, pathologic response rates, or both with acceptable toxicity profiles were demonstrated for this approach ( 4 Chua Y.J. Barbachano Y. Cunningham D. et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: A phase 2 trial. Lancet Oncol. 2010; 11: 241-248 Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar , 5 Dewdney A. Cunningham D. Tabernero J. et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012; 30: 1620-1627 Crossref PubMed Scopus (295) Google Scholar , 6 Fernandez-Martos C. Pericay C. Aparicio J. et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo Cancer de Recto 3 study. J Clin Oncol. 2010; 28: 859-865 Crossref PubMed Scopus (327) Google Scholar , 7 Marechal R. Vos B. Polus M. et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: A randomized multicentric phase II study. Ann Oncol. 2012; 23: 1525-1530 Crossref PubMed Scopus (110) Google Scholar ). Nevertheless, clear evidence of improvement in long-term outcomes is pending ( 2 Nussbaum N. Altomare I. The neoadjuvant treatment of rectal cancer: A review. Curr Oncol Rep. 2015; 17: 434 Crossref PubMed Scopus (13) Google Scholar ). Although not a major feature of this editorial, the risk of overtreatment for some patients must not be ignored. It is therefore also appropriate to investigate strategies to reduce the intensity of the treatment.