Top

Drugs

Published in:

01-06-2011 | Review Article

Locally Advanced Rectal Cancer

A Comparison of Management Strategies

Authors: Dr Robert Glynne-Jones, Miranda Kronfli

Published in: Drugs | Issue 9/2011

Abstract

Traditionally, there has been a high local recurrence rate in rectal cancer and 10–40% of patients require a permanent stoma. Both short-course preoperative radiotherapy (SCPRT) and long-course preoperative chemoradiation (CRT) are used to reduce the risk of local recurrence and enable a curative 0resection. Total mesorectal excision has reduced the rate of local recurrence (even without radiotherapy) to below 10%, but has highlighted a high risk of metastatic disease in 30–40% of patients.

Current trials suggest that in resectable cancers, where the preoperative magnetic resonance imaging (MRI) suggests the circumferential resection margin (CRM) is not potentially involved, then SCPRT and CRT are equivalent in terms of outcomes such as local recurrence, disease-free survival (DFS) and overall survival (OS). For patients with more advanced disease, where the CRM is breached or threatened according to the MRI, the integration of more active chemotherapy and biological agents into chemoradiation is an attractive strategy because of the high risk of metastases. However, in none of the trials published in the last decade has chemoradiation impacted on DFS or OS.

We examine the strategies of neoadjuvant, concurrent, consolidation (after chemoradiation and before surgery) and postoperative adjuvant chemotherapy with cytotoxic agents, and the integration of biological agents for future potential strategies of treatment.

We also compare the trials and compare the different strategies of longcourse preoperative radiotherapy and SCPRT; the intensification of preoperative radiation and chemoradiation with dose escalation of external beam radiotherapy, using brachytherapy, intra-operative radiotherapy, hyperfractionation, and various available techniques such as intensity-modulated radiotherapy.

We recommend examining dose escalation of radiotherapy to the primary tumour where MRI predicts a threatened CRM. Of the potential treatment strategies involving cytotoxic agents, such as neoadjuvant, concurrent, consolidation and postoperative adjuvant chemotherapy, the most promising would appear to be consolidation chemotherapy following chemoradiation in locally advanced disease, and neoadjuvant chemotherapy in MRI-selected patients who do not require radiation. Improvement in the quality of surgery is also an important future goal.

Morris E, Quirke P, Thomas JD, et al. Unacceptable variation in abdominoperineal excision rates for rectal cancer: time to intervene? Gut 2008; 57(12): 1690–7PubMedCrossRef

Quirke P, Durdey P, Dixon MF, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumour spread and surgical excision. Lancet 1986; II: 996–9CrossRef

Hall NR, Finan PJ, al-Jaberi T, et al. Circumferential margin involvement after mesorectal excision of rectal cancer with curative intent: predictor of survival but not local recurrence? Dis Colon Rectum 1998; 41(8): 979–83PubMedCrossRef

Tekkis PP, Heriot AG, Smith J, et al. Association of Coloproctology of Great Britain and Ireland. Comparison of circumferential margin involvement between restorative and nonrestorative resections for rectal cancer. Colorectal Dis 2005; 7(4): 369–74

den Dulk M, Collette L, van de Velde CJ, et al., EORTC Radiation Oncology Group. Quality of surgery in T3-4 rectal cancer: involvement of circumferential resection margin not influenced by preoperative treatment: results from EORTC trial 22921. Eur J Cancer 2007; 43(12): 1821–8CrossRef

Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988; 80(1): 21–9PubMedCrossRef

Gastrointestinal Tumor Study Group. Prolongation of the disease-free survival in surgically treated rectal carcinoma. N Engl J Med 1985; 312: 1465–72CrossRef

Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324: 709–15PubMedCrossRef

Sauer R, Becker H, Hohenberger W, et al., German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–40PubMedCrossRef

10.

The Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable cancer. N Engl J Med 1997; 336(14): 980–7CrossRef

11.

Kapiteijn E, Marijnen CA, Nagtegaal ID, et al., Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345(9): 638–46PubMedCrossRef

12.

Peeters KC, Marijnen CA, Nagtegaal ID, et al., for the Dutch Colorectal Cancer Group. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg 2007; 246(5): 693–701PubMedCrossRef

13.

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 2009; 373(9666): 811–20PubMedCrossRef

14.

Quirke P, Steele R, Monson J, et al., MRC CR07/NCICCTG 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 2009; 373(9666): 821–8PubMedCrossRef

15.

Medical Research Council Rectal Cancer Working Party. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party. Lancet 1996; 348(9042): 1605–10CrossRef

16.

Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma: a prospective randomized trial. Cancer 1990; 66(1): 49–55CrossRef

17.

Dahl O, Horn A, Morild I, et al. Low-dose preoperative radiation postpones recurrences in operable rectal cancer: results of a randomized multicenter trial in western Norway. Cancer 1990; 66(11): 2286–94PubMedCrossRef

18.

Pahlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicenter trial. Ann Surg 1990; 211(2): 187–95PubMedCrossRef

19.

Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP-R 03. J Clin Oncol 2009; 27: 5124–30PubMedCrossRef

20.

Boulis-Wassif S, Gerrard A, Loygue J, et al. Final results of a randomised trial on the treatment of rectal cancer with pre-operative radiotherapy alone or in combination with 5 fluorouracil followed by radical surgery. Cancer 1984; 53: 1811–8PubMedCrossRef

21.

Bosset JF, Collette L, Calais G, et al. Chemoradiotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23PubMedCrossRef

22.

Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-T4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24: 4620–5PubMedCrossRef

23.

Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Sphincter preservation following preoperative radiotherapy for rectal cancer: report of a randomized trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol 2004; 72: 15–24

24.

Bujko K, Nowacki MP, Kepka L, et al. Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial. Comparing short-term radiotherapy vs chemoradiation. Colorect Dis 2005; 7: 410–6

25.

Ngan S, Fisher R, Goldstein D, et al. TROG, AGITG, CSSANZ, and RACS. A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) preoperative radiotherapy (RT) for clinical T3 rectal cancer: an intergroup trial (TROG, AGITG, CSSANZ, RACS) [abstract no. 3509]. J Clin Oncol 2010; 28 (15 Suppl.): 3509

26.

Siegel R, Burock S, Wernecke KD, et al. Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society. BMC Cancer 2009; 9: 50PubMedCrossRef

27.

Rouanet P, Rivoire M, Lelong B, et al. Sphincter preserving surgery after preoperative treatment for ultra-low rectal carcinoma: a French multicenter prospective trial: GRECCAR 1 [abstract]. J Clin Oncol 2006; 24 (18 Suppl.): 3527CrossRef

28.

Frykholm GJ, Pahlman L, Glimerlius B. Combined chemo- and radiotherapy vs. radiotherapy alone in the treatment of primary, nonresectable adenocarcinoma of the rectum. Int J Radiat Oncol Biol Phys 2001; 50(2): 427–34

29.

Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 2008; 26(22): 3687–94PubMedCrossRef

30.

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 2006; 93: 1215–23PubMedCrossRef

31.

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 2008; 70: 1081–6PubMedCrossRef

32.

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 Radiation Oncol Biol Phys 2005; 63: 745–52CrossRef

33.

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 2005; 93(9): 993–8PubMedCrossRef

34.

Bosset JF, Calais G, Mineur L, et al. Enhanced tumoricidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results of EORTC 22921. J Clin Oncol 2005; 23: 5620–7PubMedCrossRef

35.

Ceelen W, Fierens K, Van Nieuwenhove Y, et al. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: a systematic review and meta-analysis. Int J Cancer 2009; 124(12): 2966–72PubMedCrossRef

36.

Moertel CG, Childs Jr DS, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1996; II: 865–7

37.

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 2007; 25(16): 2198–204PubMedCrossRef

38.

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 2009; 27(19): 3109–16PubMedCrossRef

39.

Mohiuddin M, Winter K, Mitchell E, et al. Randomised phase II study of neoadjuvant combined modality chemoradiation in distal rectal cancer. Radiation Oncology Group Trials 0012. J Clin Oncol 2006; 24: 650–5

40.

Aschele C, Pinto C, Rosati G, et al. Preoperative (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 [abstract no. CRA 4008]. J Clin Oncol 2009; 27: 18S (part II of II): 804sCrossRef

41.

Gérard 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(10): 1638–44PubMedCrossRef

42.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–42PubMedCrossRef

43.

Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11(1): 38–47PubMedCrossRef

44.

Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360(14): 1408–17PubMedCrossRef

45.

Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360: 563–72PubMedCrossRef

46.

Papillon J. Rectal and anal cancers: conservative treatment by radiation — an alternative to surgery. New York: Springer Verlag, 1982

47.

Wang Y, Cummings B, Catton P, et al. Primary radical external beam radiotherapy of rectal adenocarcinoma: long term outcome of 271 patients. Radiother Oncol 2005; 77(2): 126–32PubMedCrossRef

48.

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 2003; 21: 1119–24PubMedCrossRef

49.

Dahlberg M, Glimerlius B, Graf W, et al. Preoperative radiation affect functional results after surgery for rectal cancer: results from a randomised study. Dis Colon Rectum 1998; 41: 543–9PubMedCrossRef

50.

Tepper JE, O’Connell M, Niedzwiecki D, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex and local control: final report of intergroup 0114. J Clin Oncol 2002; 20: 1744–50PubMedCrossRef

51.

Gallagher MJ, Brereton HD, Rostock RA. A prospective study of treatment techniques to minimise the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 1986; 12: 1565–73PubMedCrossRef

52.

Marijnen CA, van de Velde CJ, Putter H, et al. Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2005; 23(9): 1847–58PubMedCrossRef

53.

Pollack J, Holm T, Cedermark B, et al. Long-term effect of preoperative radiation therapy on anorectal function. Dis Colon Rectum 2006; 49(3): 345–52PubMedCrossRef

54.

Peeters K, van de Velde C, Leer J, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients. Dutch Colorectal Cancer Group study. J Clin Oncol 2005; 23: 6199–206

55.

Lange MM, den Dulk M, Bossema ER, et al., Cooperative Clinical Investigators of the Dutch Total Mesorectal Excision Trial. Risk factors for faecal incontinence after rectal cancer treatment. Br J Surg 2007; 94(10): 1278–84PubMedCrossRef

56.

Frykholm GJ, Sintorn K, Montelius A, et al. Acute lumbosacral plexopathy during and after preoperative radiotherapy of rectal adenocarcinoma. Radiother Oncol 1996; 38(2): 121–30PubMedCrossRef

57.

Birgisson H, Pahlman L, Glimelius B. Adverse effects of preoperative radiation therapy for rectal cancer: longterm follow-up of the Swedish rectal Cancer Trial. J Clin Oncol 2006; 23: 8697–705CrossRef

58.

Birgisson H, Pahlman L, Gunnarsson U, et al. Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 2005; 23: 6126–31PubMedCrossRef

59.

Baxter NN, Habermann EB, Tepper JE, et al. Risk of pelvic fractures in older women following pelvic irradiation. JAMA 2005; 294(20): 2587–93PubMedCrossRef

60.

Herman MP, Kopetz S, Bhosale PR, et al. Sacral insufficiency fractures after preoperative chemoradiation for rectal cancer: incidence, risk factors, and clinical course. Int J Radiat Oncol Biol Phys 2009; 74(3): 818–23PubMedCrossRef

61.

Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumors by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34: 1274–81PubMedCrossRef

62.

Ishikawa T, Sekiguchi F, Fukase Y, et al. Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumours in human tumour xenografts. Cancer Res 1998; 58: 685–90PubMed

63.

Schüller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45: 291–7PubMedCrossRef

64.

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 2008; 23(2): 139–45PubMedCrossRef

65.

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 Radiation Oncol Biol Phys 2008; 17: 102–10CrossRef

66.

Hofheinz R, Wenz F, Post S, et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo-)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Safety results of a randomized, phase III trial [abstract]. J Clin Oncol 2009; 27: 15S (May 20 Suppl.): 4014CrossRef

67.

Gollins S. Radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal cancer. Colorectal Dis 2010; 12 Suppl. 2: 2–24PubMedCrossRef

68.

Wong SJ, Winter K, Meropol NJ, et al. RTOG 0247: A randomized phase II study of neoadjuvant capecitabine and irinotecan versus capecitabine and oxaliplatin with concurrent radiation therapy for locally advanced rectal cancer [abstract no. 4021]. J Clin Oncol 2008 May 20; 26 Suppl.: 183sCrossRef

69.

Dworak O, Keilholz L, Hoffman A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997; 12: 19–23PubMedCrossRef

70.

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 2006; 17(1): 50–6PubMedCrossRef

71.

Horisberger K, Hofheinz RD, Palma P, et al. Tumor response to neoadjuvant chemoradiation in rectal cancer: predictor for surgical morbidity? Int J Colorectal Dis 2008; 23(3): 257–64PubMedCrossRef

72.

Stelzmueller I, Zitt M, Aigner F, et al. Postoperative morbidity following chemoradiation for locally advanced low rectal cancer. J Gastrointest Surg 2009; 13: 657–67PubMedCrossRef

73.

Douillard JY, Siena S, Cassidy J, et al. Randomized phase II trial of panitumumab with infusional fluorouracil, leucovorin and oxaliplatin (FOLFOX 4) versus FOLFOX4 alone as first line treatment in patients with previously untreated metastatic colorectal cancer. The PRIME study. J Clin Oncol 2010; 28(31): 4697–705CrossRef

74.

Allegra CJ, Yothers G, O’Connell MJ, et al. 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(1): 11–6PubMedCrossRef

75.

Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147 [abstract no. 3508]. J Clin Oncol 2010; 28 Suppl.: 262s

76.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11(1): 21–8PubMedCrossRef

77.

Nyati MK, Morgan MA, Feng FY, et al. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 2006; 6: 876–85PubMedCrossRef

78.

Kim SY, Hong YS, Kim DY, et al. Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with locally advanced resectable rectal cancer: a multicenter phase II study. Int J Radiat Oncol Biol Phys. Epub 2010 Sep 30

79.

Velenik V, Ocvirk J, Oblak I, et al. A phase II study of cetuximab, capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer. Eur J Surg Oncol 2010; 36(3): 244–50PubMedCrossRef

80.

Eisterer WM, De Vries A, Oefner D, et al. Neoadjuvant chemoradiation therapy with capecitabine plus cetuximab and external beam radiotherapy in locally advanced rectal cancer (LARC) ABCSG trial R03 [abstract 4109]. J Clin Oncol 2009; 27 (15S pt I of II): 195s

81.

Horisberger K, Treschl A, Mai S, et al. MARGIT (Mannheimer Arbeitsgruppe für Gastrointestinale Tumoren). Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a phase II MARGIT trial. Int J Radiation Oncol Biol Phys 2009; 74(5): 1487–93CrossRef

82.

Cabebe EC, Kuo T, Koong A, et al. Phase I trial of preoperative cetuximab in combination with oxaliplatin, capecitabine, and radiation therapy for locally advanced rectal cancer [abstract]. J Clin Oncol 2008; 26 (May 20 Suppl.): 15019

83.

Bertolini F, Chiara S, Bengala C, et al. Neoadjuvant treatment with single agent cetuximab followed by 5-FU, cetuximab and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiation Oncol Biol Phys 2009; 73(2): 466–72CrossRef

84.

Hong YS, Kim DY, Lee KS, et al. Phase II study of preoperative chemoradiation (CRT) with cetuximab, irinotecan and capecitabine in patients with locally advanced resectable rectal cancer [abstract]. J Clin Oncol 2007; 25(18S): 4045

85.

Machiels JP, Sempoux C, Scalliet P, et al. Phase I/II study of preoperative cetuximab, capecitabine and external beam radiotherapy in patients with rectal cancer. Ann Oncol 2007; 18: 738–44PubMedCrossRef

86.

Chung KY, Minsky B, Schrag D, et al. Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer [abstract]. J Clin Oncol 2006; 24: 18S: 3560CrossRef

87.

Hoffheinz R-D, Horisberger K, Woernle C, et al. Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 2006; 66: 1384–90CrossRef

88.

Dewdney A, Cunningham D, Tabernero J, et al. EXPERTC: a randomized phase II European multicenter trial of neoadjuvant chemotherapy (capecitabine/oxaliplatin) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined high-risk rectal cancer [abstract no. 360]. J Clin Oncol 2011; 29 Suppl. 4: 360

89.

Debucquoy A, Haustermanns K, Daemen A, et al. Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol 2009; 27(17): 2751–7PubMedCrossRef

90.

Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med 2006; 354(6): 567–78PubMedCrossRef

91.

Lorenzen S, Schuster T, Porschen R, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2009; 20(10): 1667–73PubMedCrossRef

92.

de Gramont A, Van Cutsem E, Tabernero J, et al. AVANT: results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer [abstract no. 362]. J Clin Oncol 2011; 29 Suppl. 4: 362CrossRef

93.

Willett C, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10: 145–7PubMedCrossRef

94.

Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 2009; 27(18): 3020–6PubMedCrossRef

95.

Czito B, Bendell J, Willett C, et al. Bevacizamab, oxaliplatin and capecitabine with radiation therapy and rectal cancer: phase I trial results. Int J Radiat Oncol Biol Phys 2007; 68: 472–8PubMedCrossRef

96.

Crane CH, Eng C, Feig BW, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2010; 76(3): 824–30PubMedCrossRef

97.

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. Epub 2010 Oct 13

98.

Martinez Villacampa M, Santos C, Garcia M, et al. Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally advanced rectal cancer [abstract no. 516]. J Clin Oncol 2011; 29 Suppl. 4: 516

99.

Liang JT, Lai HS, Cheng KW. Technical feasibility of laparoscopic total mesorectal excision for patients with low rectal cancer after concurrent radiation and chemotherapy with bevacizumab plus FOLFOX. Surg Endosc 2011; 25(1): 305–8PubMedCrossRef

100.

Chau I, Brown G, Cunningham D, et al. Role of neoadjuvant chemotherapy in rectal cancer: interpretation of the EXPERT study [author reply]. J Clin Oncol 2006; 24(28): 4665–6CrossRef

101.

Fernández-Martos C, Pericay C, Aparicio J, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo Cancer de Recto 3 study. J Clin Oncol 2010; 28(5): 859–65PubMedCrossRef

102.

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 trial. Lancet Oncol 2010; 11(3): 241–8PubMedCrossRef

103.

Habr-Gama A, Perez RO, Sabbaga J, et al. Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: results of a prospective study using additional chemotherapy during the resting period. Dis Colon Rectum 2009; 52(12): 1927–34PubMedCrossRef

104.

Schrag MR, Weiser KA, Goodman KA, et al. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer [abstract no. 3511]. J Clin Oncol 2010; 28 (15 Suppl.): 3511

105.

Schrag D, Weiser MR, Goodman KA, et al. Neoadjuvant FOLFOX-bev, without radiation for locally advanced rectal cancer [abstract no. 434]. 2010 Gastrointestinal Cancers Symposium. Cancers of the Colon and Rectum Proceedings; 2010 Jan; San Francisco (CA): 166

106.

Cercek A, Weiser MR, Goodman KA, et al., Complete pathological response in the primary of rectal or colon cancer treated with FOLFOX without radiation [abstract no. 3649]. J Clin Oncol 2010; 28 Suppl.: 15s

107.

Taylor FG, Quirke P, Heald RJ, et al., for the MERCURY study group. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study that recruited consecutive patients with rectal cancer. Ann Surg. Epub 2011 Jan 13

108.

Frasson M, Garcia-Granero E, Roda D, et al. Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer. Cancer. Epub 2011 Jan 24

109.

Belizon A, Balik E, Feingold DL. Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods. Ann Surg 2006; 244(5): 792–8PubMedCrossRef

110.

Mohiuddin M, Mohiuddin MM, Marks J, et al. Future directions in neoadjuvant therapy of rectal cancer: maximizing pathological complete response rates. Cancer Treat Rev 2009; 35(7): 547–52PubMedCrossRef

111.

Milas L, Fang FM, Mason KA, et al. Importance of maintenance therapy in C225-induced enhancement of tumor control by fractionated radiation. Int J Radiat Oncol Biol Phys 2007; 67: 568–72PubMedCrossRef

112.

Andersson U, Johansson D, Benham-Motlagh P, et al. Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro. Acta Oncol 2007; 46(7): 951–60PubMedCrossRef

113.

Pueyo G, Mesia R, Figueras A, et al. Cetuximab may inhibit tumor growth and angiogenesis induced by ionising radiation: a preclinical rationale for maintenance treatment after radiotherapy. Oncologist 2010; 15(9): 976–86PubMedCrossRef

114.

Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil as adjuvant treatment for colon cancer. N Engl J Med 2004; 23: 2343–51CrossRef

115.

Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009; 27(19): 3117–25PubMedCrossRef

116.

Quasar Collaborative Group, Gray R, Barn well J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007; 370(9604): 2020–9CrossRef

117.

Collette L, Bosset JF, den Dulk M, et al., 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 Oncol 2007; 25(28): 4379–86PubMedCrossRef

118.

Cionini L, Sainato A, De Paoli A, et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer [abstract]. Radiother Oncol 2010; 96 Suppl. 1: S113–4

119.

Gray R, McConkey C, on behalf of the Quasar Investigators. Adjuvant chemotherapy for rectal cancer [letter]. Lancet 2008; 371(9623): 1502–3; author reply 1503CrossRef

120.

Glynne-Jones R, Meadows H, Wood W. Chemotherapy or no chemotherapy in clear margins after neoadjuvant chemoradiation in locally advanced rectal cancer: CHRONICLE — a randomised phase III trial of control vs capecitabine plus oxaliplatin. Clin Oncol (R Coll Radiol) 2007; 19(5): 327–9CrossRef

121.

Piedbois P, Ychou M, Zawadi A, et al., for AERO, GERCOR, FFCD and FNCLCC. Safety analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan in resected stages II-III rectal cancers [abstract no. 4088]. J Clin Oncol 2008; 26 Suppl.: 4088

122.

Minsky BD. Adjuvant management of rectal cancer: the more we learn, the less we know. J Clin Oncol 2007; 25(28): 4339–40PubMedCrossRef

123.

Benson AB, Catalano PJ, Meropol NJ et al., ECOG E3201:Intergroup randomized phase III study of postoperative irinotecan, 5-fluorouracil (FU), leucovorin (LV) (FOLFIRI) versus oxaliplatin FU/LV (FOLFOX) vs FU/LV for patients with stage II/III rectal cancer receiving either pre- or postoperative radiation (RT)/FU [abstract]. J Clin Oncol Proc ASCO; 2006: 24,18S (Jun 20 Suppl.): 3526

124.

Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010; 21(9): 1743–50PubMedCrossRef

125.

Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358: 1291–304CrossRef

126.

Fortier GA, Constable WC, Meyers H, et al. Preoperative radiation therapy for rectal cancer. Arch Surg 1986; 121: 1380–4PubMedCrossRef

127.

Chan AK, Wong AO, Langevin J, et al. Preoperative chemoradiotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Int J Radiat Oncol Biol Phys 2000; 48(3): 843–56PubMedCrossRef

128.

Ahmad NR, Marks G, Mohiuddin M. High-dose preoperative radiation for cancer of the rectum: impact of radiation dose on patterns of failure and survival. Int J Radiat Oncol Biol Phys 1993; 27: 773–8PubMedCrossRef

129.

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 2006; 24(4): 650–5PubMedCrossRef

130.

Wiltshire KL, Ward IG, Swallow C, et al. Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, diseasefree survival, and overall survival. Int J Radiat Oncol Biol Phys 2006; 64(3): 709–16PubMedCrossRef

131.

Marsh PH, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma: results of a prospective randomized trial. Dis Colon Rectum 1994; 37(12): 1205–14PubMedCrossRef

132.

Liang K, Ang KK, Milas L, et al. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 2003; 57: 246–54PubMedCrossRef

133.

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 2005; 92: 1209–14PubMedCrossRef

134.

Brooks S, Glynne-Jones R, Novell R, et al. Short course continuous hyperfractionated accelerated radiotherapy (CHART) as pre-operative treatment for rectal cancer. Acta Oncol 2006; 45: 1079–85PubMedCrossRef

135.

Coucke PA, Notter M, Matter M, et al. Effective timing of surgery on survival after preoperative hyperfractionated accelerated radiotherapy (HART) for locally advanced rectal cancer (LARC). Is it a matter of days? Acta Oncol 2006; 45: 1086–93PubMedCrossRef

136.

Guckenberger M, Wulf J, Thalheimer A, et al. Prospective phase II study of preoperative short-course radiotherapy for rectal cancer with twice daily fractions of 2.9 Gy to a total dose of 29 Gy-long-term results. Radiat Oncol 2009; 4: 67PubMedCrossRef

137.

Kamikonya N, Hishikawa Y, Kurisu K, et al. Primary rectal cancer treated with high-dose-rate intraluminal brachytherapy following external radiotherapy. Radiat Med 1991; 9: 85–7PubMed

138.

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 2002; 45: 1486–93PubMedCrossRef

139.

Kaufman N, Nori D, Shank B, et al. Remote afterloading intraluminal brachytherapy in the treatment of rectal, rectosigmoid, and anal cancer: a feasibility study. Int J Radiat Oncol Biol Phys 1989; 17: 663–8PubMedCrossRef

140.

Jakobsen A, Mortensen JP, Bisgaard C, et al. Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost. Int J Radiat Oncol Biol Phys 2006; 64: 461–5PubMedCrossRef

141.

Corner C, Bryant L, Chapman C, et al. High-dose-rate afterloading intraluminal brachytherapy for advanced inoperable rectal carcinoma. Brachytherapy 2010; 9: 66–70PubMedCrossRef

142.

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 2004; 22: 2402–9CrossRef

143.

Pettersson D, Cedermark B, Holm T, et al. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg 2010; 97(4): 580–7PubMedCrossRef

144.

Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter sparing surgery for rectal cancer: the Lyon R90-01 randomised trial. J Clin Oncol 1999; 17: 2396–402PubMed

145.

Sun Myint A, Mukhopadhyay T, Ramani VS, et al. Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes? Colorectal Dis 2010; 12 Suppl. 2: 30–6CrossRef

146.

Tanum G, Wiig J, Andersen OK. Endoluminal radiotherapy for rectal tumors. Oncology 1998; 55(6): 521–4PubMedCrossRef

147.

Birnbaum EH, Ogunbiyi OA, Gagliardi G, et al. Selection criteria for treatment of rectal cancer with combined external beam and endocavitary radiation. Dis Colon Rectum 1999; 42: 727–33PubMedCrossRef

148.

Janjan NA, Crane CN, Feig BW, et al. Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2000; 47(3): 713–8PubMedCrossRef

149.

Krishnan S, Janjan NA, Skibber JM, et al. Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2006; 66(3): 762–71PubMedCrossRef

150.

Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiation after palliative surgery for locally recurrent rectal cancer. Cancer 1995; 75: 939–52PubMedCrossRef

151.

Hashiguchi Y, Sekine T, Sakamoto H, et al. Intraoperative irradiation after surgery for locally recurrent rectal cancer. Dis Colon Rectum 1999; 42: 886–93PubMedCrossRef

152.

Kusters M, Valentini V, Calvo FA, et al. Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases. Ann Oncol 2010; 21(6): 1279–84PubMedCrossRef

153.

Papillon J. The future of external beam radiotherapy irradiation as initial treatment of rectal cancer. Br J Surg 1987; 74: 449–54PubMedCrossRef

154.

Gerard A, Berrod JL, Pene F, et al. Interim analysis of a phase III study on preoperative radiation therapy in resectable rectal carcinoma: trial of the Gastrointestinal Tract Cancer Cooperative Group of the European Organization for Research on Treatment of Cancer (EORTC). Cancer 1985; 55(10): 2373–9PubMedCrossRef

155.

Kligerman MM, Urdaneta N, Knowlton A, et al. Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes. Am J Roentgenol Radium Ther Nucl Med 1972; 114(3): 498–503PubMed

156.

Stevens Jr KR, Allen CV, Fletcher WS. Preoperative radiotherapy for adenocarcinoma of the rectosigmoid. Cancer 1976; 37(6): 2866–74PubMedCrossRef

157.

Cummings BJ. A critical review of adjuvant preoperative radiation therapy for adenocarcinoma of the rectum. Br J Surg 1986; 73(5): 332–8PubMedCrossRef

158.

Glehen O, Chapet O, Adham M. Long-term results of the Lyon R90-01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter-saving surgery in rectal cancer. Br J Surg 2003; 90: 996–8PubMedCrossRef

159.

Kerr SF, Norton S, Glynne-Jones R. Delaying surgery after neoadjuvant chemoradiotherapy for rectal cancer may reduce postoperative morbidity without compromising prognosis. Br J Surg 2008; 95: 1534–40PubMedCrossRef

160.

Moore HG, Gittleman AE, Minsky BD, et al. Rate of pathological complete response with increased interval between preoperative combined modality therapy and rectal cancer resection. Dis Colon Rectum 2004; 47: 279–86PubMedCrossRef

161.

Supiot S, Bennouna J, Rio E, et al. Negative influence of delayed surgery on survival after preoperative radiotherapy in rectal cancer. Colorectal Dis 2006; 8: 430–5PubMedCrossRef

162.

Mercury Group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333(7572): 779–84CrossRef

163.

Nagtegaal ID, van de Velde CJH, Marijnen CAM, et al. Low rectal cancer: a call for a change of approach in abdominoperineal resection. J Clin Oncol 2005; 23(36): 9257–64PubMedCrossRef

164.

Kim IL, Lim SB, Kang HC. Microarray gene expression profiling for predicting complete response to preoperative chemoradiotherapy in patients with advanced rectal cancer. Dis Colon Rectum 2007; 50: 1342–53PubMedCrossRef

165.

Bengala C, Patelli S, Bertolini F, et al. Epidermal Growth Factor Receptor gene copy number KRAS mutation and pathological response to preoperative Cetuximab, 5FU and radiation therapy in locally advanced rectal cancer. Ann Oncol 2009; 20: 469–74PubMedCrossRef

166.

Zlobec I, Vuong T, Compton CC, et al. Combined analysis of VEGF and EGFR predicts complete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 2008; 98: 450–6PubMedCrossRef

167.

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 locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery. Int J Radiat Oncol Biol Phys 2009; 74(5): 1461–9PubMedCrossRef

168.

Mak D, Joon DL, Chao M, et al. The use of PET in assessing tumor response after neoadjuvant chemoradiation for rectal cancer. Radiother Oncol 2010; 97(2): 205–11PubMedCrossRef

169.

Janssen MH, Ollers MC, van Stiphout RG, et al. Evaluation of early metabolic responses in rectal cancer during combined radiochemotherapy or radiotherapy alone: sequential FDG-PET-CT findings. Radiother Oncol 2010; 94(2): 151–5PubMedCrossRef

170.

Patterson DM, Padhani AR, Collins DJ. Technology insight: water diffusion MRI — a potential new biomarker of response to cancer therapy. Nat Clin Pract Oncol 2008; 5(4): 220–33PubMedCrossRef

171.

Sun YS, Zhang XP, Tang L, et al. Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusionweighted MR imaging for early detection of tumor histopathologic downstaging. Radiology 2010; 254(1): 170–8PubMedCrossRef

172.

Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002; 8: 994–1003PubMed

173.

Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59: 1935–40PubMed

Title: Locally Advanced Rectal Cancer
A Comparison of Management Strategies
Authors: Dr Robert Glynne-Jones
Miranda Kronfli
Publication date: 01-06-2011
Publisher: Springer International Publishing
Published in: Drugs / Issue 9/2011
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI: https://doi.org/10.2165/11591330-000000000-00000

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Locally Advanced Rectal Cancer

A Comparison of Management Strategies

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2011

Rivastigmine Transdermal Patch

Tuberculosis and HIV Co-Infection

Vascular Endothelial Growth Factor-Targeted Therapy for the Treatment of Renal Cell Carcinoma

Use of Nicorandil in Cardiovascular Disease and Its Optimization

Current Concepts in the Pharmacotherapy of Pseudobulbar Affect

Role of Spleen Tyrosine Kinase Inhibitors in the Management of Rheumatoid Arthritis