How can we determine the best neoadjuvant chemoradiotherapy regimen for rectal cancer?

References

• 1 Gunderson LL, Sargent DJ, Tepper JE et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J. Clin. Oncol. 22(10), 1785–1796 (2004).
  MedlineGoogle Scholar
• 2 O'Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy of rectal cancer by combining protracted infusional fluorouracil with radiation therapy after curative surgery. N. Engl. J. Med. 331, 502–507 (1994).
  MedlineGoogle Scholar
• 3 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 2(8514), 996–999 (1986).
  Medline CASGoogle Scholar
• 4 MERCURY Study Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 333(7572), 779 (2006).
  MedlineGoogle Scholar
• 5 Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer 75(9), 2269–2275 (1995).
  Medline CASGoogle Scholar
• 6 Stockholm Colorectal Cancer Study Group Randomized study on preoperative radiotherapy in rectal carcinoma. N. Engl. J. Med. 336, 980–987 (1997).
  MedlineGoogle Scholar
• 7 An Improved survival with preoperative radiotherapy in resectable rectal cancer Swedish Rectal Cancer Trial. Surg. Oncol. 3, 423–430 (1997).
  Google Scholar
• 8 Kapiteijn E, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N. Engl. J. Med. 345(9), 638–646 (2001).
  Medline CASGoogle Scholar
• 9 Sebag-Montefiore D, Stephens RJ, Steele R et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373(9666), 811–820 (2009).
  MedlineGoogle Scholar
• 10 Nagtegaal ID, van de Velde CJ, van der Worp E, Kapiteijn E, Quirke P, van Krieken JH. Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J. Clin. Oncol. 20(7), 1729–1734 (2002).
  MedlineGoogle Scholar
• 11 Quirke P, Steele R, Monson J et al. MRC CR07/NCIC-CTG CO16 Trial Investigators; NCRI Colorectal Cancer Study Group. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 373(9666), 821–828 (2009).
  MedlineGoogle Scholar
• 12 van Gijn W, Marijnen CA, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 12, 575–582 (2011).
  MedlineGoogle Scholar
• 13 Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N. Engl. J. Med. 351(17), 1731–1740 (2004).
  Medline CASGoogle Scholar
• 14 Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N. Engl. J. Med. 355(11), 1114–1123 (2006).
  Medline CASGoogle Scholar
• 15 Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3–4 rectal cancers: results of FFCD 9203. J. Clin. Oncol. 24(28), 4620–4625 (2006).
  MedlineGoogle Scholar
• 16 Braendengen M, Tveit KM, Berglund A et al. Randomized Phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J. Clin. Oncol. 26(22), 3687–3694 (2008).
  Medline CASGoogle Scholar
• 17 Hunter CJ, Garant A, Vuong T et al. Adverse features on rectal MRI identify a high-risk group that may benefit from more intensive preoperative staging and treatment. Ann. Surg. Oncol. 19, 1199–1205 (2012).
  MedlineGoogle Scholar
• 18 Capirci C, Rubello D, Pasini F et al. The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of LARC, treated with preoperative chemoradiation therapy and radical surgery. Int. J. Radiat. Oncol. Biol. Phys. 74, 1461–1469 (2009).
  MedlineGoogle Scholar
• 19 Habr-Gama A, Sabbaga J, Gama-Rodrigues J et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management? Dis. Colon Rectum 56(10), 1109–1111 (2013).
  MedlineGoogle Scholar
• 20 Fornaro L, Lonardi S, Masi G et al. FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a Phase II trial by the Gruppo Oncologico Nord Ovest (GONO). Ann. Oncol. 24(8), 2062–2067 (2013).
  Medline CASGoogle Scholar
• 21 Loupakis F, Cremolini C, Masi G et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med. 371(17), 1609–1618 (2014).
  Medline CASGoogle Scholar
• 22 Hotta T, Takifuji K, Arii K et al. Potential predictors of long-term survival after surgery for patients with stage IV colorectal cancer. Anticancer Res. 26(2B), 1377–1383 (2006).
  MedlineGoogle Scholar
• 23 Goere D, Daveau C, Elias D et al. The differential response to chemotherapy of ovarian metastases from colorectal cancer. Eur. J. Surg. Oncol. 34, 1335–1339 (2008).
  Medline CASGoogle Scholar
• 24 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. 30(14), 1620–1627 (2012).
  Medline CASGoogle Scholar
• 25 Schrag D, Weiser MR, Goodman KA et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J. Clin. Oncol. 32(6), 513–518 (2014).
  Medline CASGoogle Scholar
• 26 Goldberg RM, Rothenberg ML, Van Cutsem E et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 12(1), 38–50 (2007).
  MedlineGoogle Scholar
• 27 Masi G, Vasile E, Loupakis F et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J. Natl Cancer Inst. 103(1), 21–30 (2011).
  MedlineGoogle Scholar
• 28 Bosset JF, Pavy JJ, Hamers HP et al. Determination of the optimal dose of 5-fluorouracil when combined with low dose D,L-leucovorin and irradiation in rectal cancer: results of three consecutive Phase II studies. EORTC Radiotherapy Group. Eur. J. Cancer 29A(10), 1406–1410 (1993).
  Medline CASGoogle Scholar
• 29 Minsky BD, Cohen AM, Kemeny N et al. Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high dose leucovorin chemotherapy. J. Clin. Oncol. 10, 79–84 (1992).
  Medline CASGoogle Scholar
• 30 Rich TA, Skibber JM, Ajani JA et al. Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 32, 1025–1029 (1995).
  Medline CASGoogle Scholar
• 31 Crane CH, Skibber JM, Birnbaum EH et al. The addition of continuous infusion 5-FU to preoperative radiation therapy increases tumour response, leading to increased sphincter preservation in locally advanced low rectal cancer. Int. J. Radiation Oncol. Biol. Phys. 57, 84–89 (2003).
  Medline CASGoogle Scholar
• 32 Berrocal MG, De la Torre A, Arias F et al. Randomized Phase III trial in locally advanced rectal cancer: preoperative chemoradiotherapy with oral uracil and tegafur/leucovorin versus intravenous fluorouracil/leucovorin. Eur. J. Cancer 3/2(Suppl.), 172 (2005).
  Google Scholar
• 33 Kim JS, Kim JS, Cho MJ et al. Comparison of the efficacy of oral capecitabine versus bolus 5-FU in preoperative radiotherapy of locally advanced rectal cancer. J. Korean Med. Sci. 21(1), 52–57 (2006).
  Medline CASGoogle Scholar
• 34 Saif MW, Hashmi S, Zelterman D et al. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review. Int. J. Colorectal Dis. 23(2), 139–145 (2008).
  Medline CASGoogle Scholar
• 35 De la Torre A, Garcia-Berical MI, Arrias F et al. Preoperative chemoradiotherapy for rectal cancer: randomized trial comparing oral uracil and tegafur and oral leucovorin vs. intravenous 5-fluorouracil and leucovorin. Int. J. Radiat. Oncol. Biol. Phys. 17, 102–110 (2008).
  Google Scholar
• 36 O'Connell MJ, Colangelo LH, Beart RW et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from national surgical adjuvant breast and bowel project trial R-04. J. Clin. Oncol. 32(18), 1927–1934 (2014).
  MedlineGoogle Scholar
• 37 Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother. Pharmacol. 45, 291–297 (2000).
  Medline CASGoogle Scholar
• 38 Kovach JS, Beart RW Jr. Cellular pharmacology of fluorinated pyrimidines in vivo in man. Invest. New Drugs 7, 13–25 (1989).
  Medline CASGoogle Scholar
• 39 Dunst J, Reese T, Sutter T et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J. Clin. Oncol. 20, 3983–3991 (2002).
  Medline CASGoogle Scholar
• 40 Ngan SY, Michael M, Mackay J et al. A Phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br. J. Cancer 91, 1019–1024 (2004).
  Medline CASGoogle Scholar
• 41 Veerasarn V, Phromratanapongse P, Lordivhaya V et al. Preoperative capecitabine with pelvic radiotherapy for locally advanced rectal cancer (Phase I trial). J. Med. Assoc. Thai. 89(11), 1874–1884 (2006).
  MedlineGoogle Scholar
• 42 Bosset JF, Calais G, Mineur L et al. Enhanced tomoricidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results of EORTC 22921. J. Clin. Oncol. 23, 5620–5627 (2005).
  Medline CASGoogle Scholar
• 43 Bujko K, Nowacki MP, Nasierowska-Guttmejer A et al. Long-term results of a randomised trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br. J. Surg. 93, 1215–1223 (2006).
  Medline CASGoogle Scholar
• 44 Hofheinz RD, Wenz F, Post S et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, Phase 3 trial. Lancet Oncol. 13(6), 579–588 (2012).
  Medline CASGoogle Scholar
• 45 Conde S, Borrego M, Teixeira T, Teixeira R, Sá A, Soares P. Comparison of neoadjuvant oral chemotherapy with UFT plus Folinic acid or Capecitabine concomitant with radiotherapy on locally advanced rectal cancer. Rep. Pract. Oncol. Radiother. 17(6), 376–383 (2012).
  MedlineGoogle Scholar
• 46 Roh MS, Colangelo LH, O'Connell MJ et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP-R03. J. Clin. Oncol. 27, 5124–5130 (2009).
  MedlineGoogle Scholar
• 47 Bujko K, Nowacki MP, Nasierowska-Guttmejer A et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother. Oncol. 72(1), 15–24 (2004).
  Medline CASGoogle Scholar
• 48 Allegra CJ, Yothers G, O'Connell M et al. Neoadjuvant therapy for rectal cancer: mature results from NSABP protocol R-04. J. Clin. Oncol. 32, 2014 (Suppl. 3; abstract 390).
  MedlineGoogle Scholar
• 49 Rodel C, Arnold D, Hipp M et al. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 1081–1086 (2008).
  MedlineGoogle Scholar
• 50 Mawdsley S, Glynne-Jones R, Grainger J et al. Can the histopathological assessment of the circumferential margin following pre-operative pelvic chemo-radiotherapy for T3/4 rectal cancer predict for three year disease free survival? Int. J. Radiat. Oncol. Biol. Phys. 63, 745–752 (2005).
  MedlineGoogle Scholar
• 51 Sebag-Montefiore D, Glynne-Jones R, Falk S et al. 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, 993–998 (2005).
  Medline CASGoogle Scholar
• 52 Bujko K, Michalski W, Kepka L et al. Polish Colorectal Study Group. 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. 67(2), 369–377 (2007).
  MedlineGoogle Scholar
• 53 Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N. Engl. J. Med. 343(13), 905–914 (2000).
  Medline CASGoogle Scholar
• 54 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355, 1041–1047 (2000).
  Medline CASGoogle Scholar
• 55 Rothenberg ML, Meropol NJ, Poplin EA et al. Mortalityassociated with irinotecan plus bolus fluorouracil/leucovorin:summary findingsof an independent panel. J. Clin. Oncol. 19, 3801–3807 (2001).
  Medline CASGoogle Scholar
• 56 Omura M, Torigoe S, Kubota N. SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids. Radiother. Oncol. 43, 197–201 (1997).
  Medline CASGoogle Scholar
• 57 Chen AY, Choy H, Rothenberg ML. DNA topoisomerase I-targeting drugs as radiation sensitizers. Oncology (Williston Park) 13, 39–46 (1999).
  Medline CASGoogle Scholar
• 58 Mitchell EP, Anne P, Fry R et al. Combined modality therapy of locally advanced or recurrent adenocarcinoma of the rectum: report of a Phase I/II trial of chemotherapy with CPT-11, 5- FU and concomitant irradiation. Proc. Am. Soc. Clin. Oncol. 19, 250a (Abstract 970) (2000).
  Google Scholar
• 59 Mohiuddin M, Winter K, Mitchell E et al. Randomized Phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J. Clin. Oncol. 24, 650–655 (2006).
  Medline CASGoogle Scholar
• 60 Mohiuddin M, Paulus R, Mitchell E et al. Neoadjuvant chemoradiation for distal rectal cancer: 5-year updated results of a randomized Phase 2 study of neoadjuvant combined modality chemoradiation for distal rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 86(3), 523–528 (2013).
  Medline CASGoogle Scholar
• 61 Hofheinz RD, von Gerstenberg-Helldorf B, Wenz F et al. Phase I trial of capecitabine and weekly irinotecan in combination with radiotherapy for neoadjuvant therapy of rectal cancer. J. Clin. Oncol. 23, 1350–1357 (2005).
  Medline CASGoogle Scholar
• 62 Klautke G, Kuchenmeister U, Foitzik T et al. Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a Phase I/II study. Br. J. Cancer 94(7), 976–981 (2006).
  Medline CASGoogle Scholar
• 63 Gollins SW, Myint S, Susnerwala S et al. Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a Phase I trial (NWCOG-2). Br. J. Cancer 101, 924–934 (2009).
  Medline CASGoogle Scholar
• 64 Hong YS, Kim DY, Lim SB et al. Preoperative chemoradiation with irinotecan and capecitabine in patients with locally advanced resectable rectal cancer: long-term results of a Phase II study. Int. J. Radiat. Oncol. Biol. Phys. 79, 1171–1178 (2011).
  Medline CASGoogle Scholar
• 65 Gollins S, Sun Myint A, Haylock B et al. Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term clinical outcomes. J. Clin. Oncol. 29(8), 1042–1049 (2011).
  Medline CASGoogle Scholar
• 66 Mehta VK, Cho C, Ford JM et al. Phase II trial of preoperative 3D conformal radiotherapy protracted venous infusion 5-Fluorouracil, and weekly CPT 11, followed by surgery for ultrasound staged T3 rectal cancer. Int. J. Radiat. Oncol. Biol Phys. 55, 132–137 (2003).
  MedlineGoogle Scholar
• 67 Klautke G, Feyerherd P, Ludwig K et al. Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer. Br. J. Cancer 92, 1215–1220 (2005).
  Medline CASGoogle Scholar
• 68 Navarro M, Dotor E, Rivera F et al. A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 66(1), 201–205 (2006).
  Medline CASGoogle Scholar
• 69 Glynne-Jones R, Falk S, Maughan TS et al. A Phase I/IIstudy of irinotecan when added to 5-fluorouracil and leucovorin and pelvicradiation in locally advanced rectal cancer: a Colorectal Clinical OncologyGroup Study. Br. J. Cancer 96(4), 551–558 (2007).
  Medline CASGoogle Scholar
• 70 Iles S, Gollins S, Susnerwala S et al. Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a Phase I/II study. Br. J. Cancer 98(7), 1210–1216 (2008).
  Medline CASGoogle Scholar
• 71 Willeke F, Horisberger K, Kraus-Tiefenbacher U et al. A Phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer. Br. J. Cancer 296, 912–917 (2007).
  Google Scholar
• 72 Wong SJ, Winter K, Meropol NJ et al. Radiation Therapy Oncology Group 0247: a randomized Phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 82(4), 1367–1375 (2012).
  Medline CASGoogle Scholar
• 73 Lee SU, Kim DY, Kim SY et al. Comparison of two preoperative chemoradiotherapy regimens for locally advanced rectal cancer: capecitabine alone versus capecitabine plus irinotecan. Radiat. Oncol. 8, 258 (2013).
  MedlineGoogle Scholar
• 74 Michell EP, Anne P, Fry R et al. Combined modality therapy of locally advanced or recurrent adenocarcinoma of the rectum: report of a Phase I trial of chemotherapy (CT) with CPT11, 5FU and concomitant irradiation (RT). J. Clin. Oncol. 20, 131a (2001).
  Google Scholar
• 75 Huang J, Nair SG, Mahoney MR et al. Alliance for Clinical Trials in Oncology. Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) Intergroup Trial N0147. Clin. Colorect. Cancer 13(2), 100–109 (2014).
  MedlineGoogle Scholar
• 76 Alberts SR, Sargent DJ, Nair S et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 307(13), 1383–1393 (2012).
  Medline CASGoogle Scholar
• 77 de Gramont A, van Cutsem E, Schmoll HJ et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a Phase 3 randomised controlled trial. Lancet Oncol. 13(12), 1225–1233 (2012).
  Medline CASGoogle Scholar
• 78 ISRCTN Registry. ARISTOTLE: a Phase III trial comparing standard versus novel chemoradiation treatment (CRT) as pre-operative treatment for magnetic resonance imaging (MRI)-defined locally advanced rectal cancer. www.controlled-trials.com/ISRCTN
  Google Scholar
• 79 Rothenberg ML, Oza AM, Bigelow RH et al. Superiority ofoxaliplatin and fluorouracil-leucovorin compared with either therapy alone inpatients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin:interim results of a Phase III trial. J. Clin. Oncol. 21, 2059–2069 (2003).
  Medline CASGoogle Scholar
• 80 De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first line treatment in advanced colorectal cancer. J. Clin. Oncol. 18(16), 2938–2947 (2000).
  Medline CASGoogle Scholar
• 81 Tesniere A, Schlemmer F, Boige V et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29(4), 482–491 (2010).
  Medline CASGoogle Scholar
• 82 Kuebler JP, Wieand HS, O'Connell MJ et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J. Clin. Oncol. 25(16), 2198–2204 (2007).
  Medline CASGoogle Scholar
• 83 André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27(19), 3109–3116 (2009).
  Medline CASGoogle Scholar
• 84 Schmoll HJ, Cartwright T, Tabernero J et al. Phase III trial of capecitabine plus oxaliplatin asadjuvant therapy for stage III colon cancer: a planned safety analysis in 1864patients. J. Clin. Oncol. 25, 102–109 (2007).
  Medline CASGoogle Scholar
• 85 Allegra CJ, Yothers G, O'Connell MJ et al. Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J. Clin. Oncol. 31(3), 359–364 (2013).
  Medline CASGoogle Scholar
• 86 Aschele C, Friso ML, Pucciarelli S et al. A Phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann. Oncol. 16, 1140–1146 (2005).
  Medline CASGoogle Scholar
• 87 Glynne-Jones R, Sebag-Montefiore D, Maughan TS et al. A Phase I dose escalation study of continuous oral capecitabine in combination with oxaliplatin and pelvic radiation (XELOX-RT) in patients with locally advanced rectal cancer. Ann. Oncol. 17, 50–56 (2006).
  Medline CASGoogle Scholar
• 88 Freyer G, Bossard N, Romestaing P et al. Addition of oxaliplatin to continuous fluorouracil, l-folinic acid, and concomitant radiotherapy in rectal cancer: the Lyon R 97–03 Phase I trial. J. Clin. Oncol. 19, 2433–2438 (2001).
  Medline CASGoogle Scholar
• 89 François E, Ychou M, Ducreux M et al. Groupe Digestif de la Fédération Nationale des Centres de Lutte Contre le Cancer. Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: a Phase I study. Eur. J. Cancer 41(18), 2861–2867 (2005).
  Medline CASGoogle Scholar
• 90 Loi S, Ngan SY, Hicks RJ et al. Oxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer: a Phase I trial. Br. J. Cancer 92, 655–661 (2005).
  Medline CASGoogle Scholar
• 91 Reerink O, Mulder NH, Verschueren RC et al. Addition of oxaliplatin to neo-adjuvant radiochemotherapy for irresectable rectal cancer, a Phase I study. Anticancer Res. 25, 629–633 (2005).
  Medline CASGoogle Scholar
• 92 Ryan DP, Niedzwiecki D, Hollis D et al. Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901. J. Clin. Oncol. 24, 2557–2562 (2006).
  Medline CASGoogle Scholar
• 93 Rosenthal DI, Catalano PJ, Haller DG et al. 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. 72, 108–113 (2008).
  Medline CASGoogle Scholar
• 94 Rodel C, Grabenbauer GG, Papadopoulos T et al. Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J. Clin. Oncol. 21, 3098–3104 (2003).
  MedlineGoogle Scholar
• 95 Fakih MG, Rajput A, Yang Gy et al. 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, 1462–1470 (2006).
  Medline CASGoogle Scholar
• 96 Hospers GA, Punt CJ, Tesselaar ME et al. 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, 2773–2779 (2007).
  MedlineGoogle Scholar
• 97 Machiels JP, Duck L, Honhon B et al. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann. Oncol. 16, 1898–1905 (2005).
  MedlineGoogle Scholar
• 98 Fakih MG, Bullarddunn K, Yang GY et al. Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 72, 650–657 (2008).
  Medline CASGoogle Scholar
• 99 Carraro S, Roca EL, Cartelli C et al. Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a Phase II IATTGI study. Int. J. Radiat. Oncol. Biol. Phys. 54, 397–402 (2002).
  Medline CASGoogle Scholar
• 100 Feng H Y, Li D C, Lou R C et al. Preoperative chemoradiotherapy as neoadjuvant therapy for 35 patients with locally advanced lower rectal carcinoma. Zhonghua Wei Chang Wai Ke Za Zhi 8(2), 125–128 (2005).
  MedlineGoogle Scholar
• 101 Turitto G, Panelli G, Frattolillo A et al. Phase II study of neoadjuvant concurrent chemoradiotherapy with oxaliplatin-containing regimen in locally advanced rectal cancer. Front. Biosci. 11, 1275–1279 (2006).
  Medline CASGoogle Scholar
• 102 Gerard JP, Chapet O, Nemoz C et al. 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. Oncol. 21, 1119–1124 (2003).
  MedlineGoogle Scholar
• 103 Glynne-Jones R, Sebag-Montefiore D, Samuel L et al. Socrates Phase II study results: capecitabine (CAP) combined with oxaliplatin (OX) and preoperative radiation (RT) in patients (pts) with locally advanced rectal cancer (LARC). J. Clin. Oncol. 23(16s), 252 (Abstract 3527) (2005).
  Google Scholar
• 104 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. 28(10), 1638–1644 (2010).
  Medline CASGoogle Scholar
• 105 Aschele C, Cionini L, Lonardi S et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized Phase III trial. J. Clin. Oncol. 29(20), 2773–2780 (2011).
  Medline CASGoogle Scholar
• 106 Roh MS, Yothers GA, O'Connell MJ et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. NSABP R-04. J. Clin. Oncol. 29(Suppl.; Abstract 3503) (2011).
  Google Scholar
• 107 Rödel C, Liersch T, Becker H et al. German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised Phase 3 trial. Lancet Oncol. 13(7), 679–687 (2012).
  MedlineGoogle Scholar
• 108 Schmoll H-J, Haustermans K, Price TJ et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: first results of the PETACC-6 randomized trial (abstract). J. Clin. Oncol. 31(Suppl.; Abstract 3531) (2013).
  Google Scholar
• 109 Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation trials. J. Clin. Oncol. 25, 4096–4103 (2007).
  Medline CASGoogle Scholar
• 110 Machtay M, Moughan J, Trotti A et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J. Clin. Oncol. 26, 3582–3589 (2008).
  Medline CASGoogle Scholar
• 111 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
  Medline CASGoogle Scholar
• 112 Van Cutsem E, Köhne CH, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).
  Medline CASGoogle Scholar
• 113 Van Cutsem E, Tabernero J, Lakomy R et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a Phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30(28), 3499–3506 (2012).
  Medline CASGoogle Scholar
• 114 Douillard JY, Siena S, Cassidy J et al. Final results from PRIME: randomized Phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann. Oncol. 25(7), 1346–1355 (2014).
  Medline CASGoogle Scholar
• 115 Dipetrillo T, Pricolo V, Lagares-Garcia J et al. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 82, 124–129 (2012).
  Medline CASGoogle Scholar
• 116 Nogue M, Salud A, Vicente P et al. On behalf of the AVACROSS Study Group. Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging-defined poor-prognosis locally advanced rectal cancer: the AVACROSS Study. Oncologist 16(5), 614–620 (2011).
  Medline CASGoogle Scholar
• 117 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. 30(14), 1620–1627 (2012).
  Medline CASGoogle Scholar
• 118 Glynne-Jones R, Hadaki M, Harrison MT. The status of targeted agents in the setting of neoadjuvant radiation therapy in locally advanced rectal cancers. J. Gastrointest. Oncol. 4(3), 264–284 (2013).
  Medline CASGoogle Scholar
• 119 Sclafani F, Gonzalez D, Cunningham et al. RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial. Eur. J. Cancer. 50(8), 1430–1436 (2014).
  Medline CASGoogle Scholar
• 120 Budach W, Hehr T, Budach V, Belka C, Dietz K. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 8, 28 (2006).
  Google Scholar
• 121 Brierley JD, Keane TJ, Cummings B, Hao Y. The absence of an adverse effect of prolongation of radiation treatment of primary rectal adenocarcinoma. Clin. Oncol. (R. Coll. Radiol.) 8(2), 97–101 (1996).
  Medline CASGoogle Scholar
• 122 Guckenberger M, Wulf J, Thalheimer A et al. Prospective Phase II study of preoperativeshort-course radiotherapy for rectal cancer with twice daily fractions of 2.9Gy to a total dose of 29 Gy – long-term results. Radiat. Oncol. 4, 67 (2009).
  MedlineGoogle Scholar
• 123 Ceelen W, Boterberg T, Pattyn P et al. Neoadjuvant chemoradiation versus hyperfractionated accelerated radiotherapy in locally advanced rectal cancer. Ann. Surg. Oncol. 14, 424–431 (2007).
  MedlineGoogle Scholar
• 124 Marsh RW, George TJ, Siddiqui T et al. A Phase II trial of neoadjuvant capecitabine combined with hyperfractionated accelerated radiation therapy in locally advanced rectal cancer. Am. J. Clin. Oncol. 33, 251–256 (2010).
  Medline CASGoogle Scholar
• 125 Liszka L, Zielinska-Pajak E, Pajak J et al. Usefulness of two independent histopathological classifications of tumor regression in patients with rectal cancer submitted to hyperfractionated pre-operative radiotherapy. World J. Gastroenterol. 13, 515–524 (2007).
  MedlineGoogle Scholar
• 126 Widder J, Herbst F, Dobrowsky W et al. Preoperative short-term radiation therapy (25 Gy, 2.5 Gy twice daily) for primary resectable rectal cancer (Phase II). Br. J. Cancer 92, 1209–1214 (2005).
  Medline CASGoogle Scholar
• 127 Brooks S, Glynne-Jones R, Novell R et al. Short-course continuous, hyperfractionated, accelerated radiation therapy (CHART) as preoperative treatment for rectal cancer. Acta Oncol. 45, 1079–1085 (2006).
  Medline CASGoogle Scholar
• 128 Doi H, Beppu N, Odawara S et al. Neoadjuvant short-course hyperfractionated accelerated radiotherapy (SC-HART) combined with S-1 for locally advanced rectal cancer. J. Radiat. Res. 54(6), 1118–1124 (2013).
  MedlineGoogle Scholar
• 129 Yeo SG, Oh JH, Kim DY et al. Preoperative short-course concurrent chemoradiation therapy followed by delayed surgery for locally advanced rectal cancer: a Phase 2 multicenter study (KROG 10-01). Int. J. Radiat. Oncol. Biol. Phys. 86(1), 34–39 (2013).
  Medline CASGoogle Scholar
• 130 Papillon J. Rectal and Anal Cancers: Conservative Treatment by Radiation- An Alternative to Surgery. Springer Verlag, NY, USA (1982).
  Google Scholar
• 131 Jakobsen A, Ploen J, Vuong T, Appelt A, Lindebjerg J, Rafaelsen SR. Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses. Int. J. Radiat. Oncol. Biol. Phys. 84(4), 949–954 (2012).
  MedlineGoogle Scholar
• 132 Appelt AL, Pløen J, Vogelius IR, Bentzen SM, Jakobsen A. Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 85(1), 74–80 (2013).
  MedlineGoogle Scholar
• 133 Gerard JP, Chapet O, Nemoz C et al. Improved sphincter preservation in low rectal cancer with high dose preoperative radiotherapy: the Lyon R96–02 randomised trial. J. Clin. Oncol. 22, 2402–2409 (2004).
  Google Scholar
• 134 Vuong T, Belliveau PJ, Michel RP et al. Conformal preoperative endorectal brachytherapy treatment for locally advanced rectal cancer: early results of a Phase I/II study. Dis. Colon Rectum 45, 1486–1493 (2002).
  MedlineGoogle Scholar
• 135 Sanghera P, Wong DW, McConkey CC et al. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin. Oncol. (R. Coll. Radiol.) 20(2), 176–183 (2008).
  Medline CASGoogle Scholar
• 136 Gerard JP, Chapet O, Ramaioli A et al. Long-term control of T2-T3 rectal adenocarcinoma with radiotherapy alone. Int. J. Radiat. Oncol. Biol. Phys. 54, 142–149 (2002).
  MedlineGoogle Scholar