#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The Combination of Neoadjuvant Chemoradiotherapy and Epidermal Growth Factor Receptor Inhibitors in the Treatment of Rectal Adenocarcinoma


Authors: I. Richter 1;  J. Dvořák 2;  J. Bartoš 1
Authors‘ workplace: Onkologické oddělení, Krajská nemocnice Liberec, a.  s. 1;  Onkologická klinika 1. LF UK a Thomayerova nemocnice, Praha 2
Published in: Klin Onkol 2014; 27(3): 166-172
Category: Review

Overview

Rectal adenocarcinoma, in contrast to colorectal carcinoma, is typical of its high local rec­curence rate. Radiotherapy is proved to reduce the incidence of recurrences. Neoadjuvant chemoradiotherapy demonstrated better treatment results than adjuvant chemoradiotherapy. Standard cytotoxic agents involved in combination therapy are 5- flurouracil or capecitabin. Epidermal growth factor receptor (EGFR) is supposed to play an important role in cell- cycle regulation, proliferation, differentiation, and surviving of normal epithelial tissues. EGFR overexpression in patients with rectal adenocarcinoma is associated with radioresistance of malignant tissues, lower rates of patological complete response after neoadjuvant chemoradiation and generally poor survival. There are many clinical studies describing combination of neoadjuvant chemoradiotherapy with EGFR inhibitors, however, this regimen has not gained an acceptance as a standard of treatmentment.

Key words:
rectal cancer – chemoradiotherapy – monoclonal antibodies – epidermal growth factor receptor

This work was supported by te Scientific Council of the Regional Hospital Liberec, plc.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
5. 1. 2014

Accepted:
6. 5. 2014


Sources

1. Doleželová- Horová H, Ondrová B, Šlampa P et al. Karcinom konečníku. In: Šlampa P, Petera J et al (eds). Radiační onkologie. 1. vyd. Praha: Galén 2007: 153– 162.

2. Kocáková I, Soumarová R. Chemoradioterapie karcinomu konečníku. In: Šlampa P, Soumarová R, Kocáková Iet al. Konkomitantní chemoradioterapie solidních nádorů. Praha: Galén 2005: 62– 72.

3. Gray R, Hills R, Stowe R et al. Adjuvant radiotherapy for rectal cancer: a systemic overview of 8507 patients from 22 randomised trials. Lancet 2001; 358(9290): 1291– 1304.

4. Šlampa P, Lovas P, Lovasová Z et al. Karcinomy konečníku. In: Šlampa P et al (eds). Radiační onkologie v praxi. 3. vyd. Brno: Masarykův onkologický ústav 2011: 70– 78.

5. Bujko K, Kepka L, Michalski W et al. Does rectal cancer shrinkage by preoperative radiochemotherapy increase the likelihood of anterior resection? A systemic review of randomised trilas. Radiother Oncol 2006; 80(1): 4– 12.

6. Wong RK, Tandan V, De Silva S et al. Pre‑operative radiotherapy and curative surgery for the management of lacalized rectal carcinoma. Cochrane Database Syst Rev 2007; CD002102.

7. Horsman MR, Wouters BG, Joiner MC et al (eds). The oxygen effect and fractionated radiotherapy. In: Joiner M, van der Kogel A. Basic clinical radiobio­logy. 4th ed. London: Edward Arnold 2009: 207– 216.

8. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351(17): 1731– 1740.

9. Sauer R, Liersch T, Merkel S et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer: results of the German CAO/ ARO/ AIO- 94 randomized phase IIItrial after a median follow‑up of 11 years. J Clin Oncol 2012; 30(16): 1926– 1933. doi: 10.1200/ JCO.2011.40.1836.

10. Bosset JF, Calais G, Mineur L et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results EORTC 22921. J Clin Oncol 2005; 23(24): 5620– 5627.

11. Collette L, Bosset JF, den Dulk M et al. Patients with curative resection of cT3– 4 rectal cancer after preoperative radiotherapy or chemoradiotherapy: does anybody benefit from adjuvant fluorouracil‑based chemotherapy? A trial of the EORTC. J Clin Oncol 2007; 25(28): 4379– 4386.

12. Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorine in T3– 4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24(28): 4620– 4625.

13. Ceelen WP, Van Nieuwenhove Y, Fierens K. Preoperative chemoradiation versus radiation alone for stage II and IIIresectable rectal cancer. Cochrane Database Syst Rev 2009: CD006041. doi: 10.1002/ 14651858.CD006041.pub2.

14. 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 2012; 13(6): 579– 588. doi: 10.1016/ S1470‑ 2045(12)70116‑ X.

15. 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 rektum: NSABP R- 04 (abstrakt). J Clin Oncol 2011; 29 (Suppl 15):3503.

16. Aschele C, Cionini L, Lonardi S et al. Primary tumor response to preoperative chemoradiotion with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR- 01 randomized phase III trial. J Clin Oncol 2011; 29(20): 2773– 2780. doi: 10.1200/ JCO.2010.34.4911.

17. Gérard JP, Azria D, Gourgou- Bourgade S et al. Comparison of two neoadjuvant chemoradiotherapy regiment for locally advanced rectal cancer: results of the phase IIItrial ACCORD 12/ 0405 –  prodige 2. J Clin Oncol 2010; 28(10): 1638– 1644. doi: 10.1200/ JCO.2009.25.8376.

18. Rodel C, Liersch T, Becker H et al. Preoperative chemoradiotherapy and post postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of German CAO/ ARO/ AIO- 04 randomised phase 3 trial. Lancet Oncol 2012.

19. Mohiuddin M, Winter K, Mitchell E et al. Randomized phase II study of neoadjuvant combined- modality chemoradiation for distal rectal cancer: Radiation Therapy Oncol Group Trial 0012. J Clin Oncol 2006; 20(4): 650– 655.

20. Sirák I, Hartlová J, Petera J et al. Receptor pro epidermální růstový faktor a jeho úloha v radioterapii. Klin Okol 2008; 21(6): 338– 347.

21. Willett CG, Duda DG, Czito BG et al. Targeted therapy in rectal cancer. Oncology (Williston Park) 2007; 21(9): 1055– 1065.

22. Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanism and therapeutic opportunities. Eur J Cancer 2001; 37 (Suppl 4): S3– S8.

23. Uberall I, Kolár Z, Trojanec R et al. The status and role of ErbB receptors in human cancer. Exp Mol Pathol 2008; 84(2): 79– 89. doi: 10.1016/ j.yexmp.2007.12.002.

24. Akimoto T, Hunter NR, Buchmiller L et al. Inverse relationship between epidermal growth factor expression and radiocurability of murine carcinomas. Clin Cancer Res 1999; 5(10): 2884– 2890.

25. Liang K, Ang KK, Milas L et al. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Biol Phys 2003; 57(1): 246– 254.

26. Verbeek BS, Andriaansen- Slot SS, Vroom TM et al.Overexpression of EGFR and c- erbB2 causes enhanced cell migration in human breast cancer cells and NIH3T3 fibroblasts. FEBS Lett 1998; 425(1): 145– 150.

27. Steele RJ, Kelly P, Ellul B et al. Epidermal growth factor receptor expression in colorectal cancer. Br J Surg 1990; 77(12): 1352– 1354.

28. Mayer A, Takimoto M, Fritz E et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and MDR gene expression in colorectal cancer. Cancer 1993; 71(8): 2454– 2460.

29. Khorana AA, Ryan CK, Cox et al. Vascular enndothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with stage II and stage III colon carcinoma: a role for the host response in prognosis. Cancer 2003; 97(4): 960– 968.

30. Kopp R, Rothbauer E, Ruge M et al. Clinical implications of the EGF receptor ligand system for tumour progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options. Recent Results Cancer Res 2003; 162: 115– 132.

31. Giralt J, de las Heras M, Cerezo L et al. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy. Radiother Oncol 2005; 74(2): 101– 108.

32. Bandyopathy D, Mandal M, Adam L et al. Physical interaction between epidermal growth factor receptor and DNA- dependent protein kinase in mammalian cells. J Biol Chem 1998; 273(3): 1568– 1573.

33. Meyn RE, Munshi A, Haymach JV et al. Receptor signalling as a regulatory mechanism of DNA repair. Radiother Oncol 2009; 92(3): 316– 322. doi: 10.1016/ j.radonc.2009.06.031.

34. Lammering G, Valerie K, Lin PS et al. Radiosensitization of malignant glioma cells through overexpression of dominant negative epidermal growth factor receptor. Clin Cancer Res 2001; 7(3): 682– 690.

35. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27(2): 131– 146.

36. Baumann M, Petersen C, Eichler W et al. Mechanism of repopulation in experimental squamos cell carcinoma. In: Kogelnik HD, Lukas P, Sedlmayer F (eds). Progress in radiation- oncology, vol. 7. Bologna: Monduzzi 2002: 417– 422.

37. Begg AC. Prediction of repopulation rates and radiosensitivity in human tumours. Int J Radiat Biol 1994; 65(1): 103– 108.

38. Fowler JF. Rapid repopulation in radiotherapy: a debate on mechanism. The phantom of tumor treatment –  continually rapid proliferation inmasked. Radiother Oncol 1991; 22(3): 156– 158.

39. Schmitdt- Ullrich RK, Contessa JN, Dent P et al. Molecular mechanism of radiation‑induced accelerated repopulation. Radiat Oncol Investig 1999; 7(6): 321– 330.

40. Li S, Kim JS, Kim JM et al. Epidermal growth factor receptor as a prognostic factor in locally advanced rectal cancer patiens treated with preoperative chemoradiotion. Int J Radiat Oncol Biol Phys 2006; 65(3): 1019– 1028.

41. Kim JS, Kim JM, Li S et al. Epidermal growth factor receptor as a predictor of tumour downstaging in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiation Oncol Bio­l Phys 2006; 66(1): 195– 200.

42. Bertolini F, Bengala C, Losi L et al. Prognostic and predictive value of baseline and post‑treatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007; 68(5): 1455– 1468.

43. Zlobec I, Vuong T, Compton CC et al. Combined analysis of VEGF and EGFR predicts komplete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 2008; 98(2): 450– 456. doi: 10.1038/ sj.bjc.6604172.

44. Azria D, Bibeau F, Barbier N et al. Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco- regional recurrence after preoperative radiotherapy in rectal cancer. BMC Cancer 2005; 5: 62.

45. Dvořák J, Sitorová V, Ryška A et al. The prognostic significance of changes of tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma. Strahlenter Onkol 2012; 10: 145– 147.

46. Shepherd FA, Pereira JR, Ciuleanu T et al. Erlotinib in previously treated non‑small‑cell lung cancer. N Engl J Med 2005; 353(2): 123– 132.

47. Williams KJ, Telfer BA, Stratford IJ et al. ZD1839 (Iressa), a specific oral epidermal growth factor receptor tyrosine kinase inhibitor potentiates radiohterapy in a human colorectal cancer xenograft model. Br J Cancer 2002; 86(7): 1157– 1161.

48. Valentini V, De Paoli A, Gambacorta MA et al. Infusional 5- fluorouracil and ZD 1839 (gefitinib- Iressa) in combination with preoperative radiotherapy in patiens with locally advanced rectal cancer: a phase I and II trial (1839IL/ 0092). Int J Radiat Oncol Biol Phys 2008; 72(3): 644– 649. doi: 10.1016/ j.ijrobp.2008.01.046.

49. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan- refractory metastatic colorectal cancer. N Engl J Med 2004; 351(4): 337– 345.

50. Finocchiaro G, Capuzzo F, Janne PA et al. EGFR HER2, and K- ras as predictive factors for cetuximab sensitivity in colorectal cancer. J Clin Oncol 2007; 25: 168.

51. Van Cutsem E, Köhne CH, Láng I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorine as fist‑line treatment for metastatic colorectal cancer: update analysis of overall survival according to tumor KRAS and BRAF station status. J Clin Oncol 2011; 29(15): 2011– 2019. doi: 10.1200/ JCO.2010.33.5091.

52. Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first‑line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27(5): 663– 671. doi: 10.1200/ JCO.2008.20.8397.

53. Maugham TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatine‑based first‑line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2013– 2114.

54. Tveit KM, Guren T, Glimelius B et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorine and oxaliplatine (Nordic FLOX) versus FLOX alone in first‑line treatment of metstatic colorectal cancer: the NORDIC- VII study. J Clin Oncol 2012; 30(15): 1755– 1762. doi: 10.1200/ JCO.2011.38.0915.

55. Van Cutsem E, Peeters M, Siena S et al. Open- label phase III trial of panitumumab plus bets supportive care compared with best supportive care alone in patiens with chemotherapy- refractory metastatic colorectal cancer. J Clin Oncol 2007; 25(13): 1658– 1664.

56. Oliner KS, Douillard JY, Siena S et al. Analysis of KRAS/ NRAS and BRAF station in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first‑line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol 2013; 31 (Suppl): abstr. 3511.

57. Ince WL, Jubb AM, Holden SN et al. Association of k- ras, b- raf, and p53 status with the treatment effect of bevacizumab. J Nat Cancer Inst 2005; 97(13): 981– 989.

58. Richman SD, Seymour MT, Cahmbers P et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 2009; 27(35): 5931– 5937. doi: 10.1200/ JCO.2009.22.4295.

59. Rödel C, Martus P, Papadoupolos T et al. Prosnostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005; 23(24): 8688– 8696.

60. Janjan NA, Crane C, Feig BW et al. Improvede overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001; 24(2): 107– 112.

61. Janjan NA, Abbruzzese J, Pazdur R et al. Prognostic implications of response to preoperative infusionla chemoradiation in locally advanced rectal cancer. Radiother Oncol 1999; 51(2): 153– 160.

62. Maas M, Nelemans PJ, Valentini V et al. Long‑term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of indivudual patient data. Lancet Oncol 2010; 11(9): 835– 844. doi: 10.1016/ S1470‑ 2045(10)70172‑ 8.

63. Hartley A, Ho KF, McConkey C et al. Pathological complete response following preoperative chemoradiotheraoy in rectal cancer: analysis of phase II/ III trials. Br J Radiol 2005; 78(934): 934– 938.

64. 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. J Clin Oncol 2006; 24 (Suppl 18): 161.

65. 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(4): 738– 744.

66. Rödel 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(4): 1081– 1086.

67. Hofheinz RD, Horisberger K, Woernle C et al. Phase Itrial of cetuximab in combination with capecitabine, weekly irinotecan and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 2006; 66(5): 1384– 1390.

68. Horisberger K, Treschl A, Mai S et al. Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a Phase II MARGIT trial. Int J Radiat Oncol Biol Phys 2009; 74(5): 1487– 1493. doi: 10.1016/ j.ijrobp.2008.10.014.

69. 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 Radiat Oncol Biol Phys 2009; 73(2): 466– 472. doi: 10.1016/ j.ijrobp.2008.04.065.

70. 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. J Clin Oncol 2007; 25 (Suppl 18): abstr. 4045.

71. Cabebe EC, Kuo T, Koong M et al. Phase I trial of pre­operative cetuximab in combination with oxaliplatine, capecitabine, and radiation therapy for locally advanced rectal cancer. J Clin Oncol 2008; 26 (Suppl): 15019.

72. 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. J Clin Oncol 2009; 27 (Suppl): 4109.

73. Velenik V, Ocvirk J, Oblak I et al. Neoadjuvant cetuximab, capecitabine, and radiotherapy (RT) in locally advanced resectable rectal cancer: results of a phase II trial. J Clin Oncol 2009; 27 (Suppl): e15029.

74. 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 2011; 81(3): 677– 683. doi: 10.1016/ j.ijrobp.2010.06.035.

75. Pinto C, Di Fabio­ F, Maiello E et al. Phase II study of panitumumab, oxaliplatin, 5- fluorouracil, and concurrent radiotherapy as preoperative treatment in high‑risk locally advanced rectal cancer patients (StarPan/ STAR- 02 Study). Ann Oncol 2011; 22(11): 2424– 2430. doi: 10.1093/ annonc/ mdq782.

76. Debucquoy A, Haustermans K, Daemen A et al. Moleculary response to cetuximab and efficacy of pre­operative cetuximab‑based chemoradiation in rec­tal cancer. J Clin Oncol 2009; 27(14): 2751– 2757. doi: 10.1200/ JCO.2008.18.5033.

77. Bengala C, Bettelli S, Bertolini F et al. Epidermal growth factor receptor gene copy number, K- ras station and pathological response to preoperative cetuximab, 5- FU and radiation therapy in locally advanced rectal cancer. Ann Oncol 2009; 20(3): 469– 474. doi: 10.1093/ annonc/ mdn647.

78. Luna- Pérez P, Segura J, Alvarado I et al. Specific c- K- ras gene mutations as a tumor- response marker in locally advanced rectal cancer trated with preoperative chemoradiotherapy. Ann Surg Oncol 2000; 7(10): 727– 731.

79. Hirvikoski P, Auvinen A, Cummings B et al. K- ras and p53 mutations and overexpressions as prognostic factors in fiale rectal carcinoma. Anticancer Res 1999; 19(1B): 685– 691.

80. Alberts SR, Sargent DJ, Nair S et al. Effect of oxaliplatine, fluorouracil, and leucovorine with or without cetuximab on survival among patients with resected stage IIIcolon cancer: a randomised trial. JAMA 2012; 307(13): 1383– 1393. doi: 10.1001/ jama.2012.385.

81. Mishani E, Abourbeh G. Cancer molecular imaging: radionuclide‑based bio­markers of the epidermal growth factor receptor (EGFR). Curr Top Med Chem 2007; 7(18): 1755– 1772.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#