ABSTRACT: ABSTRACT: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.
Over the past 30 years, the clinical management of rectal cancer has undergone significant evolution. Until the 1970s and 1980s, surgery was often the only therapeutic modality employed in the treatment of rectal cancer patients. However, patterns-of-failure analyses by Gunderson and others documented that local recurrence was a common and clinically significant pattern of failure, resulting in significant patient morbidity and death.[1,2] To reduce these high failure rates, sentinel trials from the Gastrointestinal Tumor Study Group (GITSG), North Central Cancer Treatment Group (NCCTG), and National Surgical Adjuvant Breast and Bowel Project (NSABP) evaluated different strategies of adjuvant radiation therapy and fluorouracil (5-FU)-based chemotherapy.[3-5] Study results demonstrated that adjuvant radiation therapy and chemotherapy improved local control and surgery vs surgery alone, leading to the routine integration of these modalities into daily practice in the United States.
Total Mesorectal Excision
More recently, British investigators and others have described innovations in surgical techniques for rectal cancer.[6,7] These reports indicate that a more complete dissection of the mesorectum (total mesorectal excision, or TME) leads to lower local failure rates. Results from single-institution studies show that local failure rates < 10% could be achieved with TME. These impressive results with TME raised questions about the need for adjuvant radiation therapy and stimulated a Dutch study randomizing 1,805 eligible patients with operable (including stage I) rectal cancer to preoperative radiation therapy followed by TME vs TME alone. The results of this study demonstrated that patients receiving preoperative radiation therapy had improved local control vs patients undergoing TME only. Furthermore, the magnitude of improvement in local control with radiation therapy in this study may have been underestimated by the inclusion of stage I patients who have excellent outcomes with surgery only.
These findings have been supported by the preliminary results of a UK Medical Research Council (MRC) trial evaluating preoperative short-course radiation therapy vs selected postoperative combined-modality therapy. In this phase III study, 1,350 patients with clinically resectable rectal cancer were randomized to short-course preoperative radiation therapy (25 Gy in 5 fractions) plus TME vs TME followed by selective postoperative chemoradiation (45 Gy in 25 fractions with 5-FU) for patients with tumor involvement of the circumferential resection margin. In addition, patients with stage III disease received postoperative chemotherapy.
For patients undergoing preoperative radiation therapy compared to selective postoperative chemoradiation, the local recurrence rates were significantly reduced (4.7% vs 11.1%). In addition, the investigators found a significant improvement in 3-year disease-free survival of patients undergoing preoperative radiation therapy vs selective postoperative chemoradiation (79.5% vs 74.9%). These results suggest that even with TME and adjuvant chemotherapy, preoperative radiation therapy improves outcomes over selective adjuvant postoperative chemoradiation for patients with high-risk disease.
Because of the potential benefits of preoperative (vs postoperative) therapy, neoadjuvant trials have been pursued in rectal cancer patients. Two trials were initiated in the United States comparing these approaches. Both closed prematurely because of poor accrual. In contrast, German investigators successfully completed and published results of the CAO/ARO/AIO trial, comparing neoadjuvant chemoradiation to adjuvant chemoradiation. This landmark study demonstrated that by simply altering the sequence of chemoradiotherapy to surgery, improved rates of compliance, local control, sphincter preservation, and acute/late toxicity could be achieved, validating the advantages of preoperative therapy. These findings have led to a new standard of care in the United States in the treatment of rectal cancer.
Recently, European trials have further evaluated the role of concurrent 5-FU–based chemotherapy with radiation therapy in the neoadjuvant treatment of rectal cancer. Trial results from the European Organisation for Research and Treatment of Cancer (EORTC), Fdration Francophone de la Cancrologie Digestive (FFCD), and Poland demonstrated improved pathologic response rates and local control with the addition of chemotherapy. However, these reports have not verified a survival advantage with the addition of concurrent 5-FU.[11-13] Improved disease-free and overall survival rates have been shown with the addition of newer chemotherapeutic agents (capecitabine [Xeloda], oxaliplatin [Eloxatin], irinotecan [Camptosar]) to conventional chemotherapies in patients with metastatic and locally advanced colorectal cancer.
These agents have now been incorporated into the testing of new strategies for neoadjuvant therapy of rectal cancer. Capecitabine is an oral fluoropyrimidine prodrug that is readily absorbed in the gastrointestinal tract and mimics the efficacy of continuous-infusion 5-FU while avoiding that strategy's associated risk of side effects and complications. Other options being evaluated for neoadjuvant therapy include the addition of oxaliplatin or irinotecan to 5-FU and radiation therapy. Early data from phase I/II trials suggest that an oxaliplatin dose of 60 mg/m2 can be combined safely with 5-FU–based chemotherapy and radiation therapy approaches with acceptable grade 3 toxicity. In addition, promising rates of clinical and pathologic downstaging (25%–30%) have been reported. The NSABP R04 study is an ongoing phase III trial comparing preoperative radiation therapy and capecitabine with or without oxaliplatin with preoperative radiation therapy and continuous intravenous infusion of 5-FU with or without oxaliplatin in the treatment of patients with operable carcinoma of the rectum.
With increasing insight into the biochemical pathways within tumor cells that are related to tumor growth and spread, and the development of "targeted therapies" that block these pathways, much attention has turned to the use of these agents (in particular, cetuximab or gefitinib [Iressa] for EGFR and bevacizumab [Avastin] for VEGF) coupled with chemotherapy in the treatment of patients with advanced and metastatic rectal and colon cancer. For metastatic colorectal cancer patients, phase III trials have shown improved progression-free and overall survival rates with the use of these agents when combined with conventional chemotherapy. These agents are now being integrated in chemoradiotherapy protocols in phase I and II neoadjuvant studies of rectal cancer.
The goal of combining these agents with radiation therapy is to further enhance rates of tumor downstaging and sphincter preservation, local control, and survival. This review highlights the background, rationale, and results of combining cetuximab/gefitinib or bevacizumab with radiation therapy and chemotherapy in the treatment of localized rectal cancer.
1. Gunderson LL, Sosin H: Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum. Clinicopathologic correlation and implications for adjuvant therapy. Cancer 34:1278-1292, 1974.
2. Rich T, Gunderson LL, Lew R, et al: Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer 52:1317-1329, 1983.
3. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 312:1465-1472, 1985.
4. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991.
5. Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92:388-396, 2000.
6. Heald RJ: The 'Holy Plane' of rectal surgery. J R Soc Med 81:503-508, 1988.
7. Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133:894-899, 1998.
8. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001.
9. Sebag-Montefiore D, Steele R, Quirke P, et al: Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer: Preliminary results of the MRCX CR07 randomized trial (abstract 3511). J Clin Oncol 24(18S):148s, 2006.
10. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004.
11. Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006.
12. 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 72:15-24, 2004.
13. 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 24:4620-4625, 2006.
14. Rodel C, Liersch T, Hermann RM, et al: Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 25:110-117, 2007.
15. Saeki T, Salomon DS, Johnson GR, et al: Association of epidermal growth factor-related peptides and type I receptor tyrosine kinase receptors with prognosis of human colorectal carcinomas. Jpn J Clin Oncol 25:240-249, 1995.
16. Khorana A, Ryan C, Eberly S, et al: EGFR expression and survival in stage II, III and IV colon cancer (abstract 1272). Proc Am Soc Clin Oncol 22:317, 2003.
17. Nicholson RI, Gee JM, Harper ME: EGFR and cancer prognosis. Eur J Cancer 37(suppl 4):S9-15, 2001.
18. Raymond E, Faivre S, Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60(suppl 1):15-23; discussion 41-2, 2000.
19. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000.
20. Raben D, Helfrich BA, Chan D, et al: ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 29:37-46, 2002.
21. Raben D, Phistery M, Helfrich B, et al: ZD1839, a selective epidermal growth factor receptor trosine kinase inhibitor enhances radiation-induced cytotoxicity in human pancreatic and cholangiocarcinoma cell lines in vitro. Presented at Gastrointestinal Cancer Research Conference; Orlando, Fla; November 2000.
22. Williams KJ, Telfer BA, Stratford IJ, et al: ZD1839 ('Iressa'), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model. Br J Cancer 86:1157-1161, 2002.
23. Magne N, Fischel JL, Dubreuil A, et al: ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity: Rational basis for a new combination therapy with capecitabine. Clin Cancer Res 9:4735-4742, 2003.
24. Fisher G, Kuo T, Cho C, et al: A phase II study of gefitnib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer (abstract 3514). Proc Am Soc Clin Oncol 23:249, 2004.
25. Rothenberg ML, LaFleur B, Levy DE, et al: Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 23:9265-9274, 2005.
26. Zeuli M, Gelibter A, Nardoni C, et al: A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer (abstract 3748). Proc Am Soc Clin Oncol 22:306, 2004.
27. Zampino MG, Lorizzo K, Massacesi C, et al: First-line gefitinib combined with simplified FOLFOX-6 in patients with epidermal growth factor receptor-positive advanced colorectal cancer (abstract 3659). Proc Am Soc Clin Oncol 23(16S): 285s, 2005.
28. Townsley CA, Major P, Siu LL, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:1136-1143, 2006.
29. Meyerhardt JA, Zhu AX, Enzinger PC, et al: Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 24:1892-1897, 2006.
30. Czito BG, Willett CG, Bendell JC, et al: Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: Phase I trial results. J Clin Oncol 24:656-662, 2006.
31. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
32. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.
33. 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 5:62, 2005.
34. 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: A multicenter, retrospective analysis. Radiother Oncol 74:101-108, 2005.
35. Giralt J, Eraso A, Armengol M, et al: Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 54:1460-1465, 2002.
36. Kim JS, Kim JM, Li S, et al: Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 66:195-200, 2006.
37. Li S, Kim JS, Kim JM, et al: Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 65:705-712, 2006.
38. Spindler KL, Nielsen JN, Lindebjerg J, et al: Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys 66:500-504, 2006.
39. Zhang W, Park DJ, Lu B, et al: Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res 11:600-605, 2005.
40. Chung K, 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 3560). J Clin Oncol 24(18S):161s, 2006.
41. Hofheinz RD, 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 66:1384-1390, 2006.
42. 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 18:738-744, 2007.
43. Rodel C, Hipp M, Liersch T, et al: Cetuximab, capecitabine, oxaliplatin, and radiation therapy as preoperative treatment in rectal cancer. Presented at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology. Philadelphia, November 5-9, 2006.
44. Chin KF, Greenman J, Gardiner E, et al: Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer. Br J Cancer 83:1425-1431, 2000.
45. Hyodo I, Doi T, Endo H, et al: Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 34:2041-2045, 1998.
46. Nanashima A, Ito M, Sekine I, et al: Significance of angiogenic factors in liver metastatic tumors originating from colorectal cancers. Dig Dis Sci 43:2634-2640, 1998.
47. Cascinu S, Graziano F, Catalano V, et al: Vascular endothelial growth factor (VEGF), p53, and BAX expression in node positive rectal cancer (abstract 595). Proc Am Soc Clin Oncol 20:150a, 2001.
48. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003.
49. 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.
50. Giantonio BJ, Levy DE, O'Dwyer PJ, et al: A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 17:1399-1403, 2006.
51. National Cancer Institute: Bevacizumab (Avastinâ„¢) for metastatic colorectal cancer. Available at www.cancer.gov/newscenter/pressreleases/bevacizumab. Accessed June 18, 2007.
52. Kozin SV, Boucher Y, Hicklin DJ, et al: Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Res 61:39-44, 2001.
53. Lee CG, Heijn M, di Tomaso E, et al: Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565-5570, 2000.
54. Tong RT, Boucher Y, Kozin SV, et al: Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64:3731-3736, 2004.
55. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563, 2004.
56. Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 7:987-989, 2001.
57. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005.
58. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004.
59. Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136-8139, 2005.
60. Willett CG, Duda DG, di Tomaso E, et al: Complete pathological response to bevacizamab in advanced rectal cancer. Nat Clin Pract Oncol 4:316-321, 2007.
61. Czito BG, Bendell JC, Willett CG, et al: Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results. Int J Radiat Oncol Biol Phys 68:472-478, 2007.