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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.
At Mayo Clinic Cancer Center and many other institutions, there has been a paradigm shift in the sequencing of concurrent chemoradiation relative to surgical resection of rectal cancers, as noted by Willett et al. Previously, patients with mobile mid/upper-rectal cancers had surgical resection followed by postoperative chemoradiation if pathology evaluation indicated a moderate to high relapse risk after surgical treatment alone (T3, N0; T1–2, N1–2). The only patients referred for preoperative chemoradiation were those with decreased mobility (tethered T3/T4), disease fixation (T4), or distal cancers in which downstaging would potentially increase sphincter preservation. Given improvements in preoperative tumor-nodal staging (endoscopic ultrasound, pelvic computed tomography), a majority of patients with indications for adjuvant treatment are now treated with preoperative chemoradiation in many institutions.
The German phase III trial testing preoperative vs postoperative chemoradiation demonstrated an advantage to preoperative trimodality treatment for patients with T3–4 or node-positive cancers with regard to sphincter preservation, local control, and treatment tolerance. A pathologic complete response (pCR) was seen in 8% of patients randomized to receive preoperative chemoradiation, and the local relapse rate was 6% vs 13% (P < .006). In patients who were candidates for abdominoperineal resection, the sphincter preservation rate was 39% vs 19% with preoperative vs postoperative chemoradiation (P = .004). These improvements, however, did not lead to enhanced survival.
Strong Preclinical Rationale
In this issue of ONCOLOGY, Willett et al have presented a comprehensive review of the scientific justification and early clinical use of molecular-targeted agents in the treatment of rectal cancer, as an attempt to further enhance the results of current trimodality approaches. Although the majority of data supporting the use of epidermal growth factor (EGFR)- and vascular endothelial growth factor (VEGF)-directed therapy have been in conjunction with chemotherapy, the authors provide a strong preclinical rationale for using these agents in combination with pelvic chemoradiation for patients with locally advanced rectal cancer. In addition, they summarize early clinical experiences that support further investigation of this approach.
Of particular interest is the authors' reported experience of combining VEGF blockade with pelvic radiotherapy and chemotherapy in the neoadjuvant treatment of patients with rectal cancer. Not only is their clinical data on treatment toxicity and efficacy important, but the correlative research on tumor interstitial pressure, blood flow, and vascular density and metabolism will generate invaluable data to guide future hypothesis-driven clinical research. The authors are to be commended on their leadership in endeavoring to integrate the potential of molecular oncology with current cancer treatment paradigms.
While some of the initial work on combining biologic therapy with pelvic irradiation for rectal cancer suggests promise, other efficacy and toxicity results call for caution. As referenced in this review, trials of EGFR inhibition (mostly with cetuximab [Erbitux]) have generated the most clinical experience to date. Although the preclinical basis for combining EGFR inhibition with radiotherapy is sound, the two largest phase I/II studies of this approach reported a pCR rate of only 5% to 9%.[3,4] While the pCR rates were equivalent to that seen with the preoperative chemoradiation arm in the German phase III trial (8%), they do not approach the 15% to 30% pCR rates commonly seen with preoperative chemoradiation alone. These trials were modest in size, and the degree of pathologic response may to some degree depend on how aggressively a surgical specimen is examined. Nevertheless, the results warn of a possible negative interaction between cetuximab and pelvic chemoradiation-although the data do not preclude further investigation.
Perhaps with more promise, phase I data presented in this article describe encouraging pathologic responses among the initial patients treated with bevacizumab (Avastin) and pelvic chemoradiotherapy for rectal cancer.[2,6] Also of interest are the dose-limiting toxicities encountered in these trials (and others) with bevacizumab, as well as in a previously reported trial of gefitinib (Iressa) and pelvic chemoradiotherapy. Hopefully, one of the advantages of adding biologically targeted therapy to established cytotoxic therapies will be increased efficacy without overlapping or synergistic toxicity. These early clinical experiences, however, highlight our lack of clear understanding of the potential interactions among radiation, chemotherapy, and new biologic agents. Diligent monitoring of toxicity in these trials, particularly of unexpected side effects, is imperative.
Rectal cancer is not the only gastrointestinal malignancy for which bevacizumab has been employed with chemoradiation. Crane et al recently reported the results of a phase I study of 48 patients with locally advanced pancreatic cancer treated with radiotherapy, capecitabine (Xeloda), and bevacizumab. The tumor response rate and median patient survival (11.6 months) were encouraging; however, duodenal bleeding and ulceration were noted in patients with tumor invasion of the duodenum.
One of the greatest obstacles to the addition of targeted therapies to pelvic chemoradiation for rectal cancer may not be the establishment of better efficacy at the level of the primary tumor (eg, pCR), but rather, the demonstration of sufficient improvement in longer-term endpoints where outcomes are already quite good. With good, if not excellent, pelvic control among patients with locally advanced rectal cancers as a whole treated with pelvic chemoradiation, it may be difficult to demonstrate meaningful improvements in patient outcomes with the addition of targeted agents to standard therapy.
As previously noted, in the preoperative chemoradiation arm of the phase III German trial, the 5-year cumulative local relapse rate was only 6%. The published results of INT 0144, a randomized trial of various fluorouracil-based chemotherapy regimens and postoperative chemoradiation for rectal cancer, showed locoregional recurrence as an initial component of relapse in 4.6% to 8% of patients (2% to 5% when patients with T4 tumors were excluded). Although pCR rates with pelvic chemoradiation are modest (15% to 30%) and present an immediate and improvable endpoint for the study of targeted agents, translation into clinically significant gains that will justify their use may be formidable, in view of dose-limiting toxicities, as previously discussed.
Conceivably, we may discover greater potential application of EGFR and VEGF inhibition in the local treatment of rectal cancer as we try to address endpoints and goals other than the traditional benchmarks of local control and overall survival. The initial inclination is to add these agents to standard paradigms of surgery, radiation, and chemotherapy, but there may be greater opportunity in attempting to replace or reduce the standard components of therapy. Such strategies may reduce toxicity and morbidity of treatment for rectal cancer, while maintaining current levels of efficacy.
Willett et al review encouraging initial response data from the addition of VEGF blockade to chemoradiation for rectal cancer. Potential improvements in tumor response rates may afford the opportunity to expand the investigation of organ-preserving strategies in rectal cancer (eg, observation after local excision or complete clinical response, as seen in the series reported by Habr-Gama et al). As biologic agents are included in safe and effective combinations with chemoradiation, calculated efforts to improve the current standard of care for rectal cancer should involve strategies that not only add to current multimodality models of care, but that refine or transform those paradigms as well.
It has taken decades of clinical study to define the optimal sequencing, dose, and indications for pelvic chemoradiation in the treatment of rectal cancer. Doubtless, future gains could be made even with these well-studied tools as we continue to hone their use to improve patient outcomes. We now enjoy the fruition of years of basic science research identifying molecular targets for new cancer therapies and selective drugs with which to inhibit these targets. However, the optimal clinical use of these agents, particularly in combination with standard treatments, is largely unknown. As we embark and embrace the new possibilities of molecular oncology, may we do so with patience, careful methodology, and attention to goals that may improve all useful patient outcomes.
-Matthew Callister, MD
-Leonard L. Gunderson, MD
1. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004.
2. 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.
3. 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.
4. Rodel C, Hipp M, Liersch T, et al: Cetuximab, capecitabine, oxaliplatin, and radiation therapy as a preoperative treatment in rectal cancer. Presented at the annual meeting of the American Society for Therapeutic Radiology and Oncology. Philadelphia, November 5-9, 2006.
5. Rodel C, Valentini V, Minsky B: Rectal cancer, in Gunderson LL, Tepper JE (eds): Clinical Radiation Oncology, 2nd ed, pp 1113-1143. Philadelphia, Churchill Livingstone/Elsevier, 2007.
6. Czito BG, Bendell JC, Willett CG, et al: Prelimary results of a phase I study of external beam radiation therapy, oxaliplatin, bevacizumab, and capecitabine for locally advanced or metastatic adenocarcinoma of the rectum (abstract 3543). J Clin Oncol 24(18S):156s, 2006.
7. Lordick F, Geinitz H, Theisen J, et al: Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: Report of three cases. Int J Radiat Oncol Biol Phys 64:1295-1298, 2006.
8. 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.
9. Crane CH, Ellis LM, Abbruzzese JL, et al: Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 24:1145-1151, 2006.
10. Smalley SR, Benedetti J, Williamson SK, et al: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24:3542-3547, 2006.
11. Habr-Gama A, Perez RO, Nadalin W, et al: Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 240:711-718 (incl discussion), 2004.