GRECCAR 8: impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis: a randomized multicentre study

BMC Cancer

Eddy Cotte¹  Laurent Villeneuve³  Guillaume Passot¹  Gilles Boschetti²  Sylvie Bin-Dorel³  Yves Francois¹  Olivier Glehen¹ 

[1] Université Lyon 1, EMR 3738, Lyon-Sud/Charles Mérieux Medical University, Oullins, France

[2] Department of Gastroenterology, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France

[3] Hospices Civils de Lyon, Unité de Recherche Clinique, Pôle IMER, Lyon, France

关键词: Quality of life;    Survival;    Palliative treatment;    Unresectable metastasis;    Primary tumor resection;    Rectal cancer;   

Others  :  1134644
DOI  :  10.1186/s12885-015-1060-0

 received in 2014-12-12, accepted in 2015-01-29,  发布年份 2015

【 摘 要 】

Background

A majority of patients with rectal cancer and metastasis are not eligible to curative treatment because of an extensive and unresectable metastatic disease. Primary tumor resection is still debated in this situation. Rectal surgery treats or prevents the symptoms and avoids the risk of acute complications related to the primary tumor. Several studies on colorectal cancers seem to show interesting results in terms of survival in favor to the resection of the primary tumor. To date, no randomized trial or even a prospective study has assessed the impact of primary tumor resection on overall survival in patients with colorectal cancer with unresectable metastasis. All published studies were retrospective and included colon and rectal cancers. Rectal cancer is associated with specific problems related to the rectal surgery. Surgery is more complex, and may be source of more morbidity and postoperative functional dysfunctions (stoma, digestive, sexual, urinary) than colic surgery. On the other hand, symptoms related to the progression of rectal tumor are often very disabling: pain, rectal syndrome.

Methods/Design

GRECCAR 8 is a multicentre randomized open-label controlled trial aimed to evaluate the impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis. Patients must undergo upfront systemic chemotherapy for at least 4 courses before inclusion. Patients with progressive metastatic disease during upfront chemotherapy will be excluded from the study. Patients will be randomly assigned in a 1:1 ratio to Arm A: primary tumor resection followed by systemic chemotherapy versus Arm B: systemic chemotherapy alone. Primary endpoint will be overall survival measured from the date of randomization to the date of death or to the end of follow-up (2 years). Secondary endpoints will include progression-free survival, quality of life, toxicity of chemotherapy, response of the primary tumor and metastatic disease to chemotherapy, postoperative morbidity and mortality, rate of patient not eligible for postoperative chemotherapy (arm A), primary tumor related complications and rate of emergency surgery (arm B). The number of patients needed is 290.

Trial registration

ClinicalTrial.gov: NCT02314182 webcite

【 授权许可】

   
2015 Cotte et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Belot A, Grosclaude P, Bossard N, Jougla E, Benhamou E, Delafosse P, et al.: Cancer incidence and mortality in France over the period 1980–2005. Rev Epidemiol Sante Publique 2008, 56(3):159-75.
• [2]Verberne CJ, de Bock GH, Pijl ME, Baas PC, Siesling S, Wiggers T: Palliative resection of the primary tumour in stage IV rectal cancer. Colorectal Dis 2012, 14(3):314-9.
• [3]Golfinopoulos V, Salanti G, Pavlidis N, Ioannidis JP: Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol 2007, 8(10):898-911.
• [4]Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al.: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009, 360(6):563-72.
• [5]Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22(2):229-37.
• [6]Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360(14):1408-17.
• [7]Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, et al.: Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009, 20(11):1842-7.
• [8]Zampino MG, Magni E, Massacesi C, Zaniboni A, Martignetti A, Zorzino L, et al.: First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first-line treatment for metastatic colorectal cancer. Cancer 2007, 110(4):752-8.
• [9]Scoggins CR, Meszoely IM, Blanke CD, Beauchamp RD, Leach SD: Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol 1999, 6(7):651-7.
• [10]Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD: Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg 2003, 196(5):722-8.
• [11]Tebbutt NC, Norman AR, Cunningham D, Hill ME, Tait D, Oates J, et al.: Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut 2003, 52(4):568-73.
• [12]Michel P, Roque I, Di Fiore F, Langlois S, Scotte M, Teniere P, et al.: Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected? Gastroenterol Clin Biol 2004, 28(5):434-7.
• [13]Mik M, Dziki L, Galbfach P, Trzcinski R, Sygut A, Dziki A: Resection of the primary tumour or other palliative procedures in incurable stage IV colorectal cancer patients? Colorectal Dis 2010, 12(7 Online):e61-7.
• [14]Law WL, Chan WF, Lee YM, Chu KW: Non-curative surgery for colorectal cancer: critical appraisal of outcomes. Int J Colorectal Dis 2004, 19(3):197-202.
• [15]Bajwa A, Blunt N, Vyas S, Suliman I, Bridgewater J, Hochhauser D, et al.: Primary tumour resection and survival in the palliative management of metastatic colorectal cancer. Eur J Surg Oncol 2009, 35(2):164-7.
• [16]Benoist S, Pautrat K, Mitry E, Rougier P, Penna C, Nordlinger B: Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 2005, 92(9):1155-60.
• [17]Stelzner S, Hellmich G, Koch R, Ludwig K: Factors predicting survival in stage IV colorectal carcinoma patients after palliative treatment: a multivariate analysis. J Surg Oncol 2005, 89(4):211-7.
• [18]Karoui M, Roudot-Thoraval F, Mesli F, Mitry E, Aparicio T, Des Guetz G, et al.: Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study. Dis Colon Rectum 2011, 54(8):930-8.
• [19]Kaufman MS, Radhakrishnan N, Roy R, Gecelter G, Tsang J, Thomas A, et al.: Influence of palliative surgical resection on overall survival in patients with advanced colorectal cancer: a retrospective single institutional study. Colorectal Dis 2008, 10(5):498-502.
• [20]Konyalian VR, Rosing DK, Haukoos JS, Dixon MR, Sinow R, Bhaheetharan S, et al.: The role of primary tumour resection in patients with stage IV colorectal cancer. Colorectal Dis 2007, 9(5):430-7.
• [21]Chan TW, Brown C, Ho CC, Gill S: Primary tumor resection in patients presenting with metastatic colorectal cancer: analysis of a provincial population-based cohort. Am J Clin Oncol 2010, 33(1):52-5.
• [22]Costi R, Mazzeo A, Di Mauro D, Veronesi L, Sansebastiano G, Violi V, et al.: Palliative resection of colorectal cancer: does it prolong survival? Ann Surg Oncol 2007, 14(9):2567-76.
• [23]Yun HR, Lee WY, Lee WS, Cho YB, Yun SH, Chun HK: The prognostic factors of stage IV colorectal cancer and assessment of proper treatment according to the patient’s status. Int J Colorectal Dis 2007, 22(11):1301-10.
• [24]Galizia G, Lieto E, Orditura M, Castellano P, Imperatore V, Pinto M, et al.: First-line chemotherapy vs bowel tumor resection plus chemotherapy for patients with unresectable synchronous colorectal hepatic metastases. Arch Surg 2008, 143(4):352-8. discussion 358
• [25]Evans MD, Escofet X, Karandikar SS, Stamatakis JD: Outcomes of resection and non-resection strategies in management of patients with advanced colorectal cancer. World J Surg Oncol 2009, 7:28. BioMed Central Full Text
• [26]Frago R, Kreisler E, Biondo S, Salazar R, Dominguez J, Escalante E: Outcomes in the management of obstructive unresectable stage IV colorectal cancer. Eur J Surg Oncol 2010, 36(12):1187-94.
• [27]Aslam MI, Kelkar A, Sharpe D, Jameson JS: Ten years experience of managing the primary tumours in patients with stage IV colorectal cancers. Int J Surg 2010, 8(4):305-13.
• [28]Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, et al.: Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol 2011, 18(12):3252-60.
• [29]Ferrand F, Malka D, Bourredjem A, Allonier C, Bouche O, Louafi S, et al.: Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601. Eur J Cancer 2013, 49(1):90-7.
• [30]Stillwell AP, Buettner PG, Ho YH: Meta-analysis of survival of patients with stage IV colorectal cancer managed with surgical resection versus chemotherapy alone. World J Surg 2010, 34(4):797-807.
• [31]Gresham G, Renouf DJ, Chan M, Kennecke HF, Lim HJ, Brown C, et al.: Association between palliative resection of the primary tumor and overall survival in a population-based cohort of metastatic colorectal cancer patients. Ann Surg Oncol 2014, 21(12):3917-23.
• [32]Ishihara S, Hayama T, Yamada H, Nozawa K, Matsuda K, Miyata H, et al.: Prognostic impact of primary tumor resection and lymph node dissection in stage IV colorectal cancer with unresectable metastasis: a propensity score analysis in a multicenter retrospective study. Ann Surg Oncol 2014, 21(9):2949-55.
• [33]Legendre H, Vanhuyse F, Caroli-Bosc FX, Pector JC: Survival and quality of life after palliative surgery for neoplastic gastrointestinal obstruction. Eur J Surg Oncol 2001, 27(4):364-7.
• [34]Longo WE, Virgo KS, Johnson FE, Oprian CA, Vernava AM, Wade TP, et al.: Risk factors for morbidity and mortality after colectomy for colon cancer. Dis Colon Rectum 2000, 43(1):83-91.
• [35]Makela J, Haukipuro K, Laitinen S, Kairaluoma MI: Palliative operations for colorectal cancer. Dis Colon Rectum 1990, 33(10):846-50.
• [36]Costi R, Di Mauro D, Veronesi L, Ardizzoni A, Salcuni P, Roncoroni L, et al.: Elective palliative resection of incurable stage IV colorectal cancer: who really benefits from it? Surg Today 2011, 41(2):222-9.
• [37]Kleespies A, Fuessl KE, Seeliger H, Eichhorn ME, Muller MH, Rentsch M, et al.: Determinants of morbidity and survival after elective non-curative resection of stage IV colon and rectal cancer. Int J Colorectal Dis 2009, 24(9):1097-109.
• [38]Rosen SA, Buell JF, Yoshida A, Kazsuba S, Hurst R, Michelassi F, et al.: Initial presentation with stage IV colorectal cancer: how aggressive should we be? Arch Surg 2000, 135(5):530-4. discussion 534–535
• [39]Stillwell AP, Buettner PG, Siu SK, Stitz RW, Stevenson AR, Ho YH: Predictors of postoperative mortality, morbidity, and long-term survival after palliative resection in patients with colorectal cancer. Dis Colon Rectum 2011, 54(5):535-44.
• [40]Vibert E, Bretagnol F, Alves A, Pocard M, Valleur P, Panis Y: Multivariate analysis of predictive factors for early postoperative death after colorectal surgery in patients with colorectal cancer and synchronous unresectable liver metastases. Dis Colon Rectum 2007, 50(11):1776-82.
• [41]Yamamura T, Tsukikawa S, Akaishi O, Tanaka K, Matsuoka H, Hanai A, et al.: Multivariate analysis of the prognostic factors of patients with unresectable synchronous liver metastases from colorectal cancer. Dis Colon Rectum 1997, 40(12):1425-9.
• [42]Karoui M, Soprani A, Charachon A, Delbaldo C, Vigano L, Luciani A, et al.: Primary chemotherapy with or without colonic stent for management of irresectable stage IV colorectal cancer. Eur J Surg Oncol 2010, 36(1):58-64.
• [43]Sarela AI, Guthrie JA, Seymour MT, Ride E, Guillou PJ, O’Riordain DS: Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg 2001, 88(10):1352-6.
• [44]Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al.: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004, 22(1):23-30.
• [45]Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, et al.: Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer 2007, 7:91. BioMed Central Full Text
• [46]Ychou M, Viret F, Kramar A, Desseigne F, Mitry E, Guimbaud R, et al.: Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol 2008, 62(2):195-201.
• [47]Muratore A, Zorzi D, Bouzari H, Amisano M, Massucco P, Sperti E, et al.: Asymptomatic colorectal cancer with un-resectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol 2007, 14(2):766-70.
• [48]Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, et al.: Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol 2009, 27(20):3379-84.
• [49]Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al.: 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(9617):1007-16.
• [50]Eisenberger A, Whelan RL, Neugut AI: Survival and symptomatic benefit from palliative primary tumor resection in patients with metastatic colorectal cancer: a review. Int J Colorectal Dis 2008, 23(6):559-68.
• [51]Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al.: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007, 25(12):1539-44.
• [52]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350(23):2335-42.
• [53]Ghiringhelli F, Bichard D, Limat S, Lorgis V, Vincent J, Borg C, et al.: Bevacizumab efficacy in metastatic colorectal cancer is dependent on primary tumor resection. Ann Surg Oncol 2014, 21(5):1632-40.
• [54]Vigano L, Capussotti L, Barroso E, Nuzzo G, Laurent C, Ijzermans JN, et al.: Progression while receiving preoperative chemotherapy should not be an absolute contraindication to liver resection for colorectal metastases. Ann Surg Oncol 2012, 19(9):2786-96.
• [55]Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B, et al.: Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg 2004, 240(6):1052-61. discussion 1061–1054
• [56]Allen PJ, Kemeny N, Jarnagin W, DeMatteo R, Blumgart L, Fong Y: Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg 2003, 7(1):109-15. discussion 116–107
• [57]Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, et al.: Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008, 26(11):1830-5.
• [58]Stelzner S, Hellmich G, Jackisch T, Ludwig K, Witzigmann H: Selective surgical treatment of patients with rectal carcinoma and unresectable synchronous metastases based on response to preoperative chemotherapy. J Gastrointest Surg 2008, 12(7):1246-50.
• [59]Dindo D, Demartines N, Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004, 240(2):205-13.
• [60]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228-47.