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Targeted Therapy in Rectal Cancer

Targeted Therapy in Rectal Cancer

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.[8] 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.[9] 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.

Neoadjuvant Therapy

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.[10] 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.[14] 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.

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