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.
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.