Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.
[en] BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Marechal, R.
Vos, B.
POLUS, Marc ; Centre Hospitalier Universitaire de Liège - CHU > Gastro-Entérologie-Hépatologie
Delaunoit, T.
Peeters, M.; Universitair Ziekenhuis Gent - UZ > Gastroenterology
Demetter, P.
Hendlisz, A.
Demols, A.
Franchimont, D.
VERSET, Gontran ; Centre Hospitalier Universitaire de Liège - CHU > Gastro-Entérologie-Hépatologie
Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study.
O'Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Eng J Med 1994; 331: 502-507.
Heald RJ, Moran BJ, Ryall RD et al. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 1998; 133: 894-899.
Kapiteijn E, Marijnen CAM, Nagetgaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Eng J Med 2001; 345: 638-646.
Mariijen CAM, Peeters KCMJ, Putter H et al. Long term results, toxicity and quality of life in the TME trial. Radiother Oncol 2004; 73 (Suppl 1): S127.
Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Eng J Med 2004; 351: 1731-1740.
Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-T4 rectal cancers: results of the FFCD 9203 randomized trial. J Clin Oncol 2006; 24: 4620-4625.
Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Eng J Med 2006; 355: 1114-1123.
Chua YJ, 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 study. Lancet Oncol 2010; 11: 241-247.
Gerard JP, Azria D, Gourgou-Bourgade S et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010; 28: 1638-1644.
Aschele C, Pinto C, Cordio S et al. Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: pathologic response analysis of the Studio Terapia Adjuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol 2009; 27 (Suppl): 170s (Abstr CRA4008).
Chau I, Allen M, Cunningham D et al. Neoadjuvant systemic fluorouracil and mytomicin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer 2003; 88: 1017-1024.
Chau I, Brown G, Cunningham D et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006; 24: 668-674.
Calvo FA, Serrano FJ, Diaz-Gonzalez JA et al. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 2006; 17: 1103-1110.
Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumour spread and surgical excision. Lancet 1986; 2: 996-999.
Greene FL, Page DL, Fleming ID. Colon and rectum. In: Greene FL, Page DL, Fleming ID, Fritz AP, Balch C, Haller DG, Morrow M (eds), AJCC Cancer Staging Manual, 6th edition. Vol. 99. New York, NY: Springer 2002; 113-124.
Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997; 12: 19-23.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10.
Fernandez-Martos C, Pericay C, Aparicio J et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatine (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imagingdefined, locally advanced rectal cancer: Grupo Cancer de Recto 3 Study. J Clin Oncol 2010; 5: 859-865.
Guillem JG, Díaz-González JA, Minsky BD et al. cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 2008; 26: 368-373.
MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer. BMJ 2006; 222: 779.
Methy N, Bedenne L, Conroy T et al. Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial. Ann Oncol 2010; 21: 518-524.
Maas M, Nelemans PJ, Valentini V et al. Long-term outcome in patients with pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2011; 11: 835-844.