Abstract
Purpose
The aim of our study was to evaluate the feasibility and the effectiveness of an intensified neoadjuvant protocol with the addition of weekly oxaliplatin in the preoperative strategy of rectal cancer treatment.
Patients and methods
Patients with locally advanced rectal cancer received continous infusion 5-Fluorouracil (5-FU) 200 mg/m2/day in combination with weekly oxaliplatin at a dose of 50 mg/m2. Doses of radiotherapy were 45 Gy to the whole pelvis plus 5.4–9 Gy to the tumour mass. The primary end-points of the study were evaluation of toxicity, compliance with radiotherapy and chemotherapy, downstaging, pathological complete response (pCR) and the rate of sphincter preservation for distal cancers. Secondary end-points were relapse-free and overall survival.
Results
From November 2006 to June 2009, 51 patients were enrolled into the study. Compliance with chemotherapy was 80%. The incidence of G3 diarrhoea and proctitis were 17.6% and 21.5%, respectively. Surgery was performed in 48 patients with 100% R0 resection. 76.4% of low-lying tumours underwent conservative treatment. Seventy-nine percent of patients were downstaged: T and N downstaging were observed in 71% and 75% of patients, respectively. A pCR was obtained in 11 (22.9%) patients.
Conclusions
Intensification of neoadjuvant treatment for rectal cancer with the addition of weekly oxaliplatin is feasible, with remarkable rates of downstaging and pathological complete response. Data on sphincter preservation for distal cancers were excellent. Phase III trials with a longer follow-up will establish whether this good outcome in terms of surrogate end-points will translate into better rates of disease-free and overall survival.
Similar content being viewed by others
References
Heald RJ, Husband EM, Rtall RDH et al (1986) Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479–1482
Kapiteijn E, Marijnen CA, Nagtegaal ID et al (2001) Dutch colorectal cancer group: preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638–646
Gerard A, Buyse M, Nordiinger B et al (1988) Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 208(5):606–614
Thomas PR, Lindblad AS (1988) Adjuvant postoperative radiotherapy in rectal carcinoma: a review of the gastrointestinal tumour study group experience. Radiother Oncol 13(4):245–252
Gerard JP, Conroy T, Bonnetain F et al (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Orthod 24:4620–4624
Bosset JF, Collette L, Calais G et al (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123
Sauer R, Becker H, Hohenberger W, For the German Rectal Cancer Study Group et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1741
Collette L, Bosset JF, Den Dulk M et al (2007) European organisation for research and treatment of cancer radiation oncology group. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? a trial of the European organisation for research and treatment of cancer radiation oncology group. J Clin Orthod 1(25(28)):4379–4386
Hartley A, Ho KF, McConkey C et al (2005) Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials. Br J Radiol 78:9334–9338
Capirci C, Valentini V, Cionini L et al (2008) Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 72:99–107
Andrè T, Boni C, Boudiaf-Mounedji L et al (2004) Oxaliplatin, fluoruracil and leucovorin as adjuvant treatment for rectal cancer. N Engl J Med 350:2343–235
Espinosa M, Martinez M, Aguilar JL et al (2005) Oxaliplatin activity in head and neck cancer cell lines cancer chemother. Pharmacol 55:301–305
Cividalli A, Ceciarelli F, Livdi E et al (2002) Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule. Int J Radiat Oncol Biol Phys 52(4):1092–1098
Hermann RM, Rave-Frank M, Pradier O (2006) Combining radiation with oxaliplatin: a review of experimental results. Cancer Radiothér 12:61–67
Kjellstrom J, Kjellen E, Johnsson A (2005) In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line. Acta Oncol 44:687–693
Ryan DP, Niedzwiecki D, Hollis D (2006) Phase I–II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: cancer and leukaemia Group B 89901. J Clin Oncol 24:2557–2562
Aschele C, Friso ML, Pucciarelli S et al (2005) A phase I–II study of weekly oxaliplatin, 5-fluoruracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 16:1140–1146
Rödel C, Liersch T, Hermann RM et al (2007) Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:110–117
Dionisi F, Musio D, Spinelli GP et al (2009) Preoperative radio-chemotherapy of rectal cancer: toxicity and preliminary results with the addition of weekly oxaliplatin. In: Banetti E et al (eds) Platinum and other heavy metal compounds in cancer chemotherapy Humana press. Springer, Berlin, pp 295–305
Glynne-Jones R, Mawdsley S, Pearce T et al (2006) Alternative clinical end-points in rectal cancer: are we getting closer? Ann Oncol 17:1239–1248
Cancer Therapy Evaluation Program (2006) Common Terminology Criteria for Adverse Events, Version 3.0. http://ctep.cancer.gov, publish date: August 9, 2006
Kim JS, Kim JS, Cho MJ, Song KS et al (2002) Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 54:403–408
Benson A (2007) New approaches to assessing and treating early-stage colon and rectal cancers: cooperative group strategies for assessing optimal approaches in early-stage disease. Clin Cancer Res 13(22S):6913–6918
Machiels JP, Duck L, Honhon B et al (2005) Phase II study of preoperative oxaliplatin, capecitabine and external beam radiation in patient with rectal cancer: the radiooxcape study. Ann Oncol 16:1898–1905
Gerard JP, Chapet O, Nemoz C et al (2003) Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 phase II trial. J Clin Orthod 21:1119–1124
Rosenthal DI, Catalano PJ, Haller DG et al (2008) Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for T3/T4 rectal adenocarcinoma: ECOG E1297. Int J Radiat Oncol Biol Phys 1(72(1)):108–113
Sebag-Montefiore D, Glynne-Jones R, Falk S et al (2005) A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study. Br J Cancer 93(9):993–998
Keam SJ, Dunn CJ, Figgitt DP (2005) Oxaliplatin: in operable rectal cancer. Drugs 65:89–96
Saif MW, Shah MM, Shah AR (2009) Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf 8(2):191–202
Chau I, Brown G, Cunningham D et al (2006) Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor risk rectal cancer. J Clin Oncol 24:668–673
Ng M, Cunningham A, Norman RA (2005) The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC). Eur J Can 41:1542–1546
Rodel C, Sauer R (2007) Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 183:227–235
Debucquoy A, Libbrecht L, Roubrock V et al (2008) Morphological features and molecular markers in rectal cancer from 95 patients included in the European organisation for research and treatment of cancer 22921 trial: Prognostic value and effects of preoperative radio (chemo) therapy. Eur J Can 44:791–797
Schaffzin DM, Wong WD (2004) Endorectal ultrasound in the preoperative evaluation of rectal cancer. Clin Colorectal Cancer 4:124–132
Carlomagno C, Farella A, Bucci L et al (2009) Neo-adjuvant treatment of rectal cancer with capecitabine and oxaliplatin in combination with radiotherapy: a phase II study. Ann Oncol 20:906–912
Janjan AN, Abbruzzese J, Pazdur R et al (1999) Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer. Radiother Oncol 51:153–160
Ben-Josef E (2007) Capecitabine and radiotherapy as neoadjuvant treatment for rectal cancer. Am J Clin Oncol 30(6):649–655
Valentini V, Coco C, Picciocchi A et al (2002) Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664–674
Kaminsky-Forrett MC, Conroy T, Luporsi E et al (1998) Prognostic implications of downstaging following preoperative radiation therapy for operable T3-T4 rectal cancer. Int J Radiat Oncol Biol Phys 42:935–941
Kim KN, Bayk HS, Seong JS et al (2006) Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer. Ann Surg 244(6):1024–1030
Lezoche G, Baldarelli M, Guerrieri M (2008) A prospective randomized study with a 5-year minimum follow-up evaluation of transanal endoscopic microsurgery versuslaparoscopic total mesorectal excision after neoadjuvant therapy. Surg Endosc 22(2):352–358
Bujko K, Richter P, Kolodziejczyk M et al (2009) Preoperative radiotherapy and local excision of rectal cancer with immediate radical re-operation for poor responders. Radiother Oncol 92:195–201
Osti MF, Valeriani M, Masoni L et al (2004) Neoadjuvant chemoradiation for locally advanced carcinoma of the rectum. Tumori 90:303–309
Gambacorta MA, Valentini V, Coco C et al (2007) Sphincter preservation in four consecutive phase II studies of preoperative chemoradiation: analysis of 247 T3 rectal cancer patients. Tumori 93(2):160–169
Baxter NN, Garcia-Aguilar J (2007) Organ preservation for rectal cancer. J Clin Oncol 25(8):1014–1020
Mohiuddin M, Mohiuddin MM, Marks J (2009) Future directions in neoadjuvant therapy of rectal cancer: maximizing pathological complete response rates. Cancer Treat Rev 35(7):547–552
Kuo LJ, Liu MC, Jer-Min Jian J et al (2007) Is Final TNM Staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy? Ann Surg Oncol 14(10):2766–2772
Das P, Skibber MJ, Rodriguez-Bigas AM et al (2007) Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer 109(9):1750–1755
Habr-Gama A, Perez RO, Nadalin W et al (2004) Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 240:711–718
Aschele C, Pinto C, Cordio S et al (2009) Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol 27:18s
Gerard JP, Azria D, Gourgou-Bourgade S et al (2010) Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer. Results of the phase II trial ACCORD 12/0405-Prodige 2. J Clin Oncol 28:1638–1644
Tepper JE, Wang ZA (2010) Improving local control in rectal cancer: radiation sensitizers or radiation dose? J Clin Oncol 28:1623–1624
Hospers AG, Punt JAC, Tesselaar EM et al (2007) Preoperative chemoradiotherapy with capecitabine and oxaliplatin in locally advanced rectal cancer. A phase I–II multicenter study of the dutch colorectal cancer group. Ann Surg Oncol 14(10):2773–2779
Gambacorta MA, Valentini V, Coco C et al (2004) Chemoradiation with raltitrexed and oxaliplatin in preoperative treatment of stage II–III resectable rectal cancer: phase I and II studies. Int J Radiat Oncol Biol Phys 60(1):139–148
Fakih GM, Rajput A, Yang GY et al (2006) A phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 65(5):1462–1470
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dionisi, F., Musio, D., Raffetto, N. et al. Preoperative intensified radiochemotherapy for rectal cancer: experience of a single institution. Int J Colorectal Dis 26, 153–164 (2011). https://doi.org/10.1007/s00384-010-1064-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-010-1064-9