Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – the RAPIDO trial

BMC Cancer

Per J Nilsson²  Boudewijn van Etten⁶  Geke AP Hospers⁵  Lars Påhlman⁴  Cornelis JH van de Velde⁷  Regina GH Beets-Tan³  Lennart Blomqvist¹²  Jannet C Beukema¹⁰  Ellen Kapiteijn¹  Corrie AM Marijnen¹¹  Iris D Nagtegaal⁸  Theo Wiggers⁶  Bengt Glimelius⁹ 

[1] Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

[2] Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Surgical Gastroenterology, Karolinska University Hospital, Solna P9:03, SE 171 76 Stockholm, Sweden

[3] Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands

[4] Department of Surgical Science, Uppsala University, Uppsala, Sweden

[5] Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands

[6] Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands

[7] Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

[8] Department of Pathology, Radboud University, Nijmegen Medical Center, Nijmegen, The Netherlands

[9] Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden

[10] Department of Radiation Oncology, University Medical Center Groningen, Groningen, The Netherlands

[11] Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

[12] Department of Diagnostic Radiology, Karolinska University Hospital Solna, Stockholm, Sweden

关键词: Magnetic resonance imaging;    Neo-adjuvant;    Chemotherapy;    Radiotherapy;    Rectal cancer;   

Others  :  1079711
DOI  :  10.1186/1471-2407-13-279

 received in 2013-01-20, accepted in 2013-05-30,  发布年份 2013

【 摘 要 】

Background

Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.

Methods and design

Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life.

Discussion

Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.

Trial registration

ClinicalTrials.gov NCT01558921

【 授权许可】

   
2013 Nilsson et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]He J, Efron JE: Screening for colorectal cancer. Adv Surg 2011, 45:31-44.
• [2]Chestovich PJ, Lin AY, Yoo J: Fast-track pathways in colorectal surgery. Surg Clin North Am 2013, 93:21-32.
• [3]Heald RJ, Husband EM, Ryall RD: The mesorectum in rectal cancer surgery–the clue to pelvic recurrence? Br J Surg 1982, 69:613-616.
• [4]Holm T, Ljung A, Haggmark T, Jurell G, Lagergren J: Extended abdominoperineal resection with gluteus maximus flap reconstruction of the pelvic floor for rectal cancer. Br J Surg 2007, 94:232-238.
• [5]Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedemark B: Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet 2000, 356:93-96.
• [6]Pahlman L, Bohe M, Cedermark B, Dahlberg M, Lindmark G, Sjodahl R, Ojerskog B, Damber L, Johansson R: The Swedish rectal cancer registry. Br J Surg 2007, 94:1285-1292.
• [7]Bulow S, Christensen IJ, Harling H, Kronborg O, Fenger C, Nielsen HJ: Recurrence and survival after mesorectal excision for rectal cancer. Br J Surg 2003, 90:974-980.
• [8]MacFarlane JK, Ryall RDH, Heald RJ: Mesorectal excision for rectal cancer. Lancet 1993, 341:457-460.
• [9]Frykholm G, Glimelius B, Påhlman L: Pre- or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 1993, 36:564-572.
• [10]Cedermark B, Johansson H, Rutquist L-E, Wilking N: The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. Cancer 1995, 75:2269-2275.
• [11]Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997, 336:980-987.
• [12]Kapiteijn E, Marijnen CAM, Nagtegaal ID, Putter H, Steup WH, Wiggers T, Rutten HJT, Leer JWH, van Krieken JHJM, Påhlman L: Preoperative radiotherapy in combination with total mesorectal excision improves local control in resectable rectal cancer. Report from a multicenter randomized trial. New Engl J Med 2001, 345:638-646.
• [13]van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011, 12:575-582.
• [14]Bujko K, Bujko M: Point: short-course radiation therapy is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol 2011, 21:220-227.
• [15]Graham JS, Cassidy J: Adjuvant therapy in colon cancer. Expert Rev Anticancer Ther 2012, 12:99-109.
• [16]Petersen SH, Harling H, Kirkeby LT, Wille-Jorgensen P, Mocellin S: Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012., 3CD004078
• [17]Bujko K, Glynne-Jones R, Bujko M: Adjuvant chemotherapy for rectal cancer. Ann Oncol 2010, 21:2443.
• [18]Bujko K, Michalski W, Kepka L, Nowacki MP, Nasierowska-Guttmejer A, Tokar P, Dymecki D, Pawlak M, Lesniak T, Richter P: Association between pathologic response in metastatic lymph nodes after preoperative chemoradiotherapy and risk of distant metastases in rectal cancer: An analysis of outcomes in a randomized trial. Int J Radiat Oncol Biol Phys 2007, 67:369-377.
• [19]Leibold T, Shia J, Ruo L, Minsky BD, Akhurst T, Gollub MJ, Ginsberg MS, Larson S, Riedel E, Wong WD: Prognostic implications of the distribution of lymph node metastases in rectal cancer after neoadjuvant chemoradiotherapy. J Clin Oncol 2008, 26:2106-2111.
• [20]Mawdsley S, Glynne-Jones R, Grainger J, Richman P, Makris A, Harrison M, Ashford R, Harrison RA, Osborne M, Livingstone JI: Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival? Int J Radiat Oncol Biol Phys 2005, 63:745-752.
• [21]Sauer R, Fietkau R, Wittekind C, Rodel C, Martus P, Hohenberger W, Tschmelitsch J, Sabitzer H, Karstens JH, Becker H: Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94. Colorectal Dis 2003, 5:406-415.
• [22]Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006, 355:1114-1123.
• [23]Demicheli R, Retsky MW, Hrushesky WJ, Baum M, Gukas ID: The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008, 19:1821-1828.
• [24]Lacy AM, Garcia-Valdecasas JC, Delgado S, Castells A, Taura P, Pique JM, Visa J: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 2002, 359:2224-2229.
• [25]Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008, 371:1007-1016.
• [26]Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006, 355:11-20.
• [27]Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B: Perioperative Chemotherapy Compared With Surgery Alone for Resectable Gastroesophageal Adenocarcinoma: An FNCLCC and FFCD Multicenter Phase III Trial. J Clin Oncol 2011, 29:1715-1721.
• [28]Foxtrot Collaborative Group: Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 2012, 13:1152-1160.
• [29]Smith N, Brown G: Preoperative staging in rectal cancer. Acta Oncol 2008, 47:20-31.
• [30]Valentini V, Aristei C, Glimelius B, Minsky BD, Beets-Tan R, Borras JM, Haustermans K, Maingon P, Overgaard J, Pahlman L: Multidisciplinary rectal cancer management. Radiother Oncol 2009, 92:148-163.
• [31]Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J: ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 2012, 23:2479-2516.
• [32]Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009, 373:811-820.
• [33]Glimelius B: Multidisciplinary treatment of patients with rectal cancer: Development during the past decades and plans for the future. Ups J Med Sci 2012, 117:225-236.
• [34]Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006, 24:4620-4625.
• [35]Braendengen M, Tveit KM, Berglund Å, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K, Glimelius B: A randomized phase III study (LARCS) comparing preoperative radiotherapy alone versus chemoradiotherapy in non-resectable rectal cancer. J Clin Oncol 2008, 26:3687-3694.
• [36]Radu C, Berglund Å, Påhlman L, Glimelius B: Short course preoperative radiotherapy with delayed surgery in rectal cancer - a retrospective study. Radiother Oncol 2008, 87:343-349.
• [37]Hatfield P, Hingorani M, Radhakrishna G, Cooper R, Melcher A, Crellin A, Kwok-Williams M, Sebag-Montefiore D: Short-course radiotherapy, with elective delay prior to surgery, in patients with unresectable rectal cancer who have poor performance status or significant co-morbidity. Radiother Oncol 2009, 92:210-214.
• [38]Pettersson D, Holm T, Iversen H, Blomqvist L, Glimelius B, Martling A: Preoperative short-course radiotherapy with delayed surgery in primary rectal cancer. Br J Surg 2012, 99:577-583.
• [39]Van Dijk TH, Hospers GAP, Beukema JC: Short-course radiation therapy, neoadjuvant bevacizumab, capecitabine and oxaliplatin, and radical resection of primary tumour and metastases in primary stage IV rectal cancer. A phase II multicenter study of the Dutch colorectal cancer Group. Ann Oncol 2010, 21(suppl 1, abstr):51.
• [40]Taylor FG, Swift RI, Blomqvist L, Brown G: A systematic approach to the interpretation of preoperative staging MRI for rectal cancer. AJR Am J Roentgenol 2008, 191:1827-1835.
• [41]Blomqvist L, Glimelius B: The 'good', the 'bad', and the 'ugly' rectal cancers. Acta Oncol 2008, 47:5-8.
• [42]Radu C, Norrlid O, Braendengen M, Hansson K, Isacsson U, Glimelius B: Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients. Acta Oncol 2013. In press
• [43]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [44]Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H: 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.
• [45]Bujko K, Nowacki M, Nasierowska-Guttmejer A, Michalski W, Benek M, Pudelko M, Kryj M, Oledzki J, Szmeja J, Shuszniak J: Sphincter preservation following reoperative radiotherapy for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 2004, 72:15-24.
• [46]Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA: Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with t3 rectal cancer: trans-tasman radiation oncology group trial 01.04. J Clin Oncol 2012, 30:3827-3833.
• [47]Pettersson D, Cedermark B, Holm T, Radu C, Pahlman L, Glimelius B, Martling A: Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg 2010, 97:580-587.
• [48]Glimelius B, Cavalli Björkman N: Metastatic colorectal cancer: Current treatment and future options for improved survival. Medical approach–present status. Scand J Gastroenterol 2012, 47:296-314.
• [49]Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM: Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 2011, 29:11-16.
• [50]Alberts SR, Sargent DJ, Smyrk TC, Shields AF, Chan E, Goldberg RM: Adjuvant mFOLFOX6 with or without cetuximab in KRAS wild-type patients with resected stage III colon cancer: results from NCCTG intergroup phase III trial N0147. J Clin Oncol 2010, 28:A3507.