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Originally published as JCO Early Release 10.1200/JCO.2004.04.953 on June 21 2004 © 2004 American Society of Clinical Oncology.
Substitution of Oral Fluoropyrimidines for Infusional Fluorouracil With Radiotherapy: How Much Data Do We Need?1 Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2 Division of Biostatistics, Mayo Clinic Cancer Center, Rochester, MN In this issue of the Journal of Clinical Oncology, Fernandez-Martos et al1 report the results of a large phase II study that evaluated orally administered UFT, a combination of uracil and ftorafur (a fluoropyrimidine), given concurrently with preoperative radiotherapy in locally advanced rectal cancer. This was a well designed and well conducted multi-institutional trial with results showing low acute toxicity rates as well as pathologic tumor response, local tumor control, and overall survival rates comparable with the results from other studies evaluating preoperative chemoradiotherapy. On this basis, oral UFT is a good candidate for phase III study in combination with radiotherapy, as is its counterpart, capecitabine, approved in the United States for metastatic colorectal cancer when single-agent fluoropyrimidine therapy is indicated. The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial, a phase III study, was designed to compare an oral fluoropyrimidine with protracted venous infusional (PVI) fluorouracil (FU) in patients receiving preoperative radiotherapy for locally advanced rectal cancer. That study initially incorporated UFT, but when development of UFT was abandoned in the United States and capecitabine was approved, capecitabine replaced UFT in the design. The NSABP R-04 trial has been on hold for 2 years pending final approval by the National Cancer Institute for many reasons unrelated to the issue of capecitabine. PVI FU is the evidence-based standard chemotherapeutic agent used in conjunction with radiotherapy in postoperative concurrent chemoradiotherapy for rectal cancer. This standard was established by a randomized trial (North Central Cancer Treatment Group 86-47-51) in patients with resected rectal cancer who received either bolus FU (without leucovorin[LV]) or PVI FU plus postoperative radiotherapy.2 Although similar trials in patients with tumors at other gastrointestinal sites have not been conducted, the data derived from North Central Cancer Treatment Group 86-47-51 have been used to justify the use of PVI FU plus postoperative radiotherapy to treat other gastrointestinal malignancies. For example, PVI FU was incorporated as the standard chemotherapeutic agent in adjuvant concurrent chemoradiotherapy trials for pancreatic cancer (Radiation Therapy Oncology Group/Intergroup[INT]97-04) and gastric cancer (Cancer and Leukemia Group B/INT 80,101). Two subsequent postoperative rectal chemoradiotherapy trials conducted evaluated the biochemical modulation of FU with LV and/or levamisole (INT 0114), and the incorporation of PVI FU before and after chemoradiotherapy (INT 0144). The results from those two studies, which accrued a total of 3,600 patients, indicated that the various ways to administer and modulate FU were indistinguishable in terms of overall survival.3,4 In fact, the results of INT 0144 further complicated the picture because patients who received bolus FU with LV and levamisole concurrently with radiation had survival outcomes that were statistically identical to those who received PVI FU with radiation.3 On this basis, biochemically modulated FU appears to have efficacy similar to PVI FU with radiotherapy. Following in the footsteps of these studies is the thoughtfully designed NSABP R-04 trial. It addresses the very clinically relevant question of whether the PVI FU during radiation could be replaced by capecitabine. The combination of capecitabine and radiotherapy was very well tolerated in a phase I trial, with minimal gastrointestinal and no significant hematologic toxicity.5 In NSABP R-04, patients with locally advanced rectal cancer will be treated with preoperative chemoradiotherapy and either PVI FU or capecitabine. The use of postoperative adjuvant chemotherapy is left open to investigators or they may enter E3201. The primary end point of the study is pelvic tumor recurrence. Pelvic tumor recurrence after FU-based chemoradiotherapy followed by surgery has been reported in single arm studies to be between 2% and 10%1,6,7 and 2.4% at 2 years with radiation alone followed by surgery in a large phase III study.8 Because equally low pelvic recurrence rates are expected in the NSABP R-04 trial, and the difference in pelvic control rates due to PVI FU compared with capecitabine is likely to be small (if it exists at all), this study is appropriately statistically powered to include a small army of patients (N = 1,400). Ideally, important questions such as this should all be addressed in phase III trials, but even with this large sample size, the trial is underpowered to demonstrate noninferiority for overall survival, which would be impractical. During its lifetime, the NASBP R-04 trial will face several challenges. Although data from a randomized trial have established the superiority of preoperative chemoradiotherapy compared to postoperative chemoradiotherapy,9 and its use will probably increase, preoperative chemoradiotherapy is still less commonly used in the United States than postoperative chemoradiotherapy,10,11 which will impede patient accrual onto the study. On the other hand, conducting the trial could stimulate increased use of preoperative chemoradiotherapy in general. Conversely, clinicians may not find the question posed in NSABP R-04 interesting enough to motivate them to enroll their patients in the study, particularly if it means changing their practice from postoperative therapy to preoperative therapy. In contrast, studies evaluating other novel radiosensitizers will also be competing for this population of patients, and may be more appealing to both patients and clinicians than the question raised in the NSABP R-04 trial. All of the promising novel agents approved for use in colorectal cancer since 1996 (irinotecan, oxaliplatin, cetuximab, and bevacizumab) have radiosensitizing properties12-15 and are being combined with radiotherapy in clinical trials, and some have reported preliminary evidence of increased local tumor response.16,17 In addition, adjuvant oxaliplatin-based chemotherapy has been shown to improve disease-free survival in resected colon cancer.18 Because approximately twice as many patients with resected rectal cancer develop distant recurrence compared with local recurrence,19 trials that include novel systemic therapy in addition to novel radiosensitization are becoming more appealing. The desire to further decrease recurrence rates and improve patient survival with novel agents may prove more compelling than a demonstration of equivalence in local tumor control by the substitution of an oral drug for PVI FU. Multiple ongoing or planned trials (Eastern Cooperative Oncology Group 3201, RTOG 0247, and the SOCRATES) are integrating novel chemotherapeutic agents with radiation or as a component of adjuvant chemotherapy in an effort to improve local disease control, distant disease control, and overall survival in rectal cancer. Because of the availability of these novel agents and the large sample size necessary to conclude noninferiority, the chemoradiotherapy standard could change at least once during the time it will take to conduct the NSABP R-04 trial, possibly rendering the question of PVI FU versus capecitabine with radiotherapy obsolete, even before the trial's completion. Thus, the controversy will remain until we have mature results from the NSABP R-04 trial. In the meantime, would substituting capecitabine (or UFT) for PVI FU with radiotherapy outside the setting of a clinical trial be appropriate? As much as possible, medical decision-making should be evidence-based. Clearly, however, with limited patient and financial resources, every question cannot be studied with a phase III clinical trial. In postoperative adjuvant treatment of rectal cancer, many difficult or unanswerable questions have been sidestepped by rationally extrapolating information from available data sets without direct comparisons. For instance, the standard arm in INT 0144 (for resected stage II and III rectal cancer patients) consisted of bolus FU plus LV for two cycles, chemoradiotherapy with PVI FU, then two more cycles of bolus FU plus LV. Randomized trials have not directly established the benefit of the addition of adjuvant chemotherapy to chemoradiotherapy, the sequence of chemotherapy and chemoradiotherapy, or the number of cycles of chemotherapy. Furthermore, the benefit of adding chemotherapy to radiation preoperatively has not been demonstrated in a phase III trial. In fact, the only phase III trials demonstrating a benefit for any preoperative therapy (compared with surgery alone) used short-course preoperative radiotherapy alone (25 Gy in 1 week).8,20 Because the direct comparison of capecitabine with PVI FU in rectal cancer in the NSABP R-04 trial will be difficult, we must ask: what other level I evidence would support substituting oral fluoropyrimidines for PVI FU with radiotherapy? Data from studies of patients with colorectal cancer who do not undergo radiotherapy may help us decide. In patients with metastatic colon cancer, capecitabine has been shown to have an equivalent overall survival rate, with an increased response rate and less toxicity than FU/LV.21 The substitution of capecitabine for PVI FU in combination chemotherapy is the subject of multiple ongoing (SWOG 0303) and completed trials.22,23 The available data are less clear for patients with curable malignancies, but the efficacy data from two adjuvant colon cancer trials (Xeloda Adjuvant Colon Cancer trial [X-ACT] and NSABP C-06) addressing the role of oral fluoropyrimidines are maturing. Results from these trials, which are evaluating the effects of capecitabine (X-ACT) or UFT (NSABP C-06), compared with bolus FU plus LV, are presented at the 2004 American Society of Clinical Oncology Annual Meeting. Toxicity data from the X-ACT trial have already been reported, favoring capecitabine over the Mayo Clinic regimen of bolus FU and LV.24 The dose-intensity of the recommended capecitabine regimen given during radiation (825 mg/m2 bid every day, including weekends)5 is similar to that of the X-ACT trial (1250 mg/m2 bid given for 14 days, repeated every 21 days); the dose-limiting toxicity for both regimens is hand and foot syndrome. If the results of these trials indicate that that the effects of oral fluoropyrimidines are equivalent or superior to those of FU plus LV, then taken with the results of the INT-0144 trial, where rectal cancer patients treated with FU plus LV and levamisole plus radiotherapy had an identical overall survival to those who were treated with PVI FU plus radiotherapy, this trial would then support the substitution of oral fluoropyrimidines for PVI FU with radiotherapy for curable gastrointestinal malignancies. In summary, the results of the phase II clinical trial evaluating UFT with radiotherapy presented by Fernandez-Martos et al in this issue demonstrate what we want to achieve with chemoradiotherapy for rectal cancer: a low pelvic tumor–recurrence rate, a high 5-year-survival rate, and minimal acute toxicity. The NSABP R-04 trial is a phase III study that compares another oral fluoropyrimidine, capecitabine, with PVI FU in patients receiving preoperative chemoradiotherapy. The question it is addressing is important, but the NSABP R-04 trial will face obstacles to accrual. It runs the risk that clinicians and patients will chose other clinical trials evaluating promising combinations of cytotoxic or biologic agents with FU-based chemoradiotherapy, especially if the results of the X-ACT or NSABP C-06 trials show that oral fluoropyrimidines are equivalent or superior to FU plus LV in the adjuvant setting. If that happens, we will have additional evidence supporting the use of oral fluoropyrimidines with radiotherapy in curable gastrointestinal malignancies. Previous extrapolations have been made based on far less data before in rectal cancer therapy, even in the construction of the standard arm in clinical trials. Disclosures of Potential Conflicts of Interest The following individuals or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Axel F. Grothey, Sanofi-Synthelabo; Christopher H. Crane, Roche, Bristol-Myers Squibb, ImClone Systems, Sanofi-Synthelabo; Daniel J. Sargent, Sanofi-Synthelabo, Eli Lilly. Honoraria: Axel F. Grothey, Hoffmann-La Roche, Sanofi-Synthelabo; Christopher H. Crane, Roche, Bristol-Myers Squibb, ImClone Systems, Eli Lilly, Pfizer/Pharmacia; Daniel J. Sargent, Sanofi-Synthelabo. Research Funding: Axel F. Grothey, Sanofi-Synthelabo; Christopher H. Crane, Genentech, Pfizer/Pharmacia. For a detailed description of these categories or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue. Acknowledgment The authors acknowledge Axel Grothey for helpful discussions and comments. REFERENCES
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19. Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004
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21. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001 22. Grothey A, Jordan K, Keller O, et al: Randomized phase II trial of capecitabine plus irinotecan vs capecitabine plus oxaliplatin as first-line therapy of advanced colorectal cancer. Proc Am Soc Clin Oncol 22:255, 2003 (abstr 1022) 23. Van Cutsem E, Twelves C, Tabernero J, et al: XELOX: Mature results of a multinational, phase II trial of capecitabine plus oxaliplatin, an effective 1st line option for patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:255, 2003 (abstr 1023) 24. Twelves C, Wong A, Nowacki M, et al: Improved safety results of a phase III trial of capecitabine vs bolus 5-FU/leucovorin as adjuvant therapy for colon cancer (the X-ACT study). Proc Am Soc Clin Oncol 22:294, 2003 (abstr 1182) Related Article
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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