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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 933-934 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.214
Update on Design of the National Surgical Adjuvant Breast and Bowel Project Trial R-04Allegheny General Hospital, Pittsburgh, PA
University of Southern California, Los Angeles, CA
Helen F. Graham Cancer Center, Christiana Care, Newark, DE To the Editor: We were somewhat perplexed in reading the Editorial by Crane and Sargent titled "Substitution of Oral Fluoropyrimidine for Infusional Fluorouracil With Radiotherapy: How Much Data Do We Need?" in the August 1, 2004, edition of the Journal of Clinical Oncology.1 The Editorial ostensibly reviewed the article by Fernandez-Martos et al, which reported a phase II trial of uracil, tegafur, and radiotherapy in operable rectal cancer2 in the same issue. Yet, inexplicably, the majority of the comments and critique were directed at the National Surgical Adjuvant Breast and Bowel Project (NSABP) phase III neoadjuvant trial (protocol R-04) that was in development at the time of writing. We feel compelled, therefore, to provide readers of the Journal with additional information regarding protocol R-04 from those responsible for its development. First, we do not agree that pelvic tumor recurrence rates as low as 2.4% following preoperative chemoradiotherapy would be expected in protocol R-04 based on our own experience. In a similar population of patients in NSABP protocol R-03, local tumor recurrence was seen in 9% of patients treated with preoperative fluorouracil (FU) + leucovorin chemotherapy combined with pelvic radiation therapy.3 There would seem to be room for improvement in this clinically important end point. Furthermore, complete tumor response (CR) rates following neoadjuvant therapy have been shown by the NSABP3 and others, to correlate with long-term disease-free survival. The use of CR rate to evaluate novel systemic and radiosensitizing agents is appealing as a research strategy and holds the potential to significantly hasten drug development. The neoadjuvant setting in protocol R-04 also affords a unique opportunity to evaluate molecular markers that may predict for high complete tumor response rates following treatment with specific regimens. Such molecular profiles portend the possibility of individualized therapy for patients in the future. Neither are we as confident as Crane and Sargent that oral capecitabine would produce only small (if any) improvement in pelvic tumor control rates. Capecitabine is a prodrug that is selectively activated in tumor tissue, providing a theoretical basis for thinking that it could be more effective and/or less toxic than infusional FU combined with radiation. Additional interest in capecitabine in the adjuvant therapy of colorectal cancer has also been stimulated by the recent report of the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study at the 2004 American Society of Clinical Oncology meeting.4 This study demonstrated convincingly that oral capecitabine was not inferior to intravenous FU + leucovorin in the surgical adjuvant setting for patients with stage III colon cancer. In fact, there was a strong trend (P = .053) suggesting superiority in disease-free survival with capecitabine. We really do need a phase III trial to adequately compare capecitabine and infusion FU in rectal cancer; this remains a highly clinically relevant question to the colorectal surgeons participating in the NSABP. Crane and Sargent also point out that despite recruiting a "small army" of patients (N = 1,400 eligible patients), the trial is underpowered to demonstrate noninferiority for overall survival. Here we fully agree, since the study was never designed to address a survival end point. R-04 was intentionally powered to address local control end points and was designed in concert with protocol E3201, which will compare three different approaches to postoperative systemic chemotherapy. Patients from R-04 are eligible to participate in protocol E3201. In the latter study survival and disease-free survival are the primary study end points. Although we appreciate the concern expressed about our ability to accrue patients to R-04, we believe the Editorial statement that in the United States preoperative chemoradiotherapy is still less commonly used than postoperative chemoradiotherapy, is anachronistic. The references cited were published in 1997 and 1998 on data collected between 1988 and 1994. In fact, several authors of the cited references have themselves recently emphasized in oral presentations at national and international medical meetings the movement toward preoperative chemoradiotherapy for rectal cancer in the United States. This change in clinical practice has been accelerated by the landmark study performed by the German Rectal Cancer Group demonstrating significant improvements in local tumor control and less toxicity with preoperative chemoradiotherapy compared with postoperative chemoradiotherapy in a prospectively randomized clinical trial.5 Of more substance is the observation that new opportunities have emerged to enhance protocol R-04 since it was originally conceived more than 3 years ago. The trajectory of clinical trials research is not linear and is unpredictable for a number of scientific and regulatory reasons. We are grateful to have pilot data from phase II studies performed by the Eastern Cooperative Oncology Group, the Cancer and Leukemia Group B, and the German Rectal Cancer Group, now available, which would support the addition of oxaliplatin to protocol R-04 in a 2 x 2 factorial design with the intent of further increasing complete tumor response rates, sphincter-sparing surgery, and local tumor control. We are currently in discussions with the National Cancer Institute, members of the NSABP Colorectal Committee, and leadership of the GI Intergroup to appropriately amend protocol R-04. In the meantime, we have activated R-04 across the North American continent with the full support of the National Cancer Institute and hope for a much more enthusiastic endorsement from members of the oncology community at large. We hope that our comments will shed some light on the ongoing development of the NSABP rectal cancer program, but wonder whether the Editorial pages of the Journal of Clinical Oncology are the best forum to explain and defend such clinical trials when they are still in development. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Crane CH, Sargent DJ: Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: How much data do we need? J Clin Oncol 22:2978-2981, 2004
2. Fernández-Martos C, Aparicio J, Bosch C, et al: Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: A phase II multicenter study with 3 years' follow-up. J Clin Oncol 22:3016-3022, 2004 3. Roh MS, Colangelo L, Wieand S, et al: Response to preoperative multimodality therapy predicts survival in patients with carcinoma of the rectum. Proc Am Soc Clin Oncol 22:246s, 2004 (abstr 3505) 4. Cassidy J, Scheithauer W, McKendrick J, et al: Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial. Proc Am Soc Clin Oncol 22:247s, 2004 (abstr 3509) 5. Sauer R: German Rectal Cancer Group: Adjuvant versus neoadjuvant combined modality treatment for locally advanced rectal cancer—First results of the German Rectal Cancer Study (CAO/ARO/AIO-94). Int J Radiat Oncol Biol Phys 57:S124-S125, 2003 (suppl 2)[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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