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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3542-3547 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9544 Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144
From the Kansas City Community Clinical Oncology Program (CCOP), Kansas City, KS; Southwest Oncology Group Statistical Center, Seattle, WA; University of Kansas Medical Center, Kansas City, MO; William Beaumont Hospital, Royal Oak, MI; University of Illinois College of Medicine at Peoria; Illinois Oncology Research Association CCOP, Peoria; Northwestern University, Chicago, IL; London Regional Cancer Centre, London, Ontario; Ottawa Health Research Institute, Ottawa, Ontario; Cross Cancer Institute, Edmonton, Alberta, Canada; University of Virginia Health Sciences Center, Charlottesville, VA; Mayo Clinic, Rochester, MN; University of Pennsylvania Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; Wake Forest/Southeast Cancer Control Consortium, Winston-Salem, NC; University of Texas Health, Science Center, San Antonio, TX; University of California, Davis, Sacramento; University of Southern California School of Medicine, Los Angeles, CA; and St Vincent's Comprehensive Cancer Center, New York, NY Address reprint requests to Southwest Oncology Group (SWOG-9304), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org
PURPOSE: Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens. PATIENTS AND METHODS: After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery. RESULTS: Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3. CONCLUSION: All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.
Postoperative chemoradiotherapy for rectal cancer has improved overall survival (OS) and pelvic control.1-4 Recently, postoperative trials have addressed chemotherapy radiosensitization to reduce distant relapse and locoregional failure (LRF). The use of protracted venous infusion (PVI) of fluorouracil (FU) developed for several reasons. Seven phase III trials comparing PVI versus bolus indicated improved response rates in metastatic disease.5-12 These improved response rates raised the possibility that PVI might more effectively eradicate subclinical distant metastasis in the adjuvant setting. Second, radiobiologic data13-17 suggested PVI improved radiosensitization. Finally, Intergroup (INT) 864751 compared PVI versus bolus FU. Bolus FU was administered before, during, and after pelvic radiotherapy (XRT) versus the same pre- and post-XRT bolus schedule, but with PVI administered with XRT. Improved OS and disease-free survival (DFS) was observed.4 Chau et al18 randomly assigned resected colorectal cancer patients to 6 months of bolus FU/leucovorin (LV) versus 12 weeks of PVI FU. PVI FU improved DFS and OS (statistically nonsignificant) with less toxicity. Biochemical modulation of FU also generated interest. Improvement in OS was observed in several adjuvant extrapelvic colon trials using FU modulated by LV19-21 or levamisole.22-24 In addition, reports suggested that biochemically modulated FU improved survival in advanced disease.25-27 INT 0114 tested bolus FU alone, FU plus LV, FU plus levamisole, and FU plus LV plus levamisole all with pelvic XRT.28,29 No OS or DFS difference was observed. Outcome was similar to the PVI arm of INT 864751, raising the possibility that a bolus-alone FU schedule might obviate the requirement for a central venous catheter. The purpose of this study was to determine whether consistent administration of FU via PVI could further improve outcome by more efficient eradication of distant metastatic disease, and to evaluate the need for use of central venous catheters and PVI versus a bolus FU regimen.
Eligibility Criteria Patients were required to have had curatively resected nonmetastatic rectal adenocarcinoma. Extension through the muscularis propria and/or nodal spread (T3-4, N0 or T1-4, N1-3) was required. Patients with involved radial margins were ineligible with the exception of the extraperitoneal serosal margin (T4a). Rectal cancer was defined as tumor noted intraoperatively below the peritoneal reflection or  12 cm from the anal verge. Patients with dentate involvement were eligible. Patients were older than 18 years, had 0 to 2 performance score, and were not pregnant or lactating. No prior chemotherapy or radiation therapy for rectal cancer, or prior history of rectal cancer (with the exception of previously resected T1-2, N0, M0 tumors) was allowed. Satisfactory pretreatment laboratory parameters and the absence of serious illness were required. Chest x-ray and abdominopelvic computed tomography scans were required within 56 days of registration. Computed tomography scans were mandatory, unless bilirubin, AST, and alkaline phosphatase were within institutional normal limits, and the operative report specifically described the liver as normal. Registration was between days 20 to 70, and institutional review board approval and written informed consent were obtained.
Treatment Summary Arm 1 comprised preradiotherapy FU was intravenous bolus FU only 500 mg/m2/d on days 1 to 5 and 29 to 33. Combined FU with XRT was FU via continuous PVI 225 mg/m2/d to begin on day 57. After completion of radiation, patients were to have received a 28-day interruption of therapy. FU was then administered for two postradiation cycles at 450 mg/m2/d on days 1 to 5 every 28 days for two cycles. Arm 2 comprised FU 300 mg/m2/d for 42 consecutive days before radiation therapy and chemotherapy, followed by a 2-week interruption of treatment before initiation of combined-modality therapy. Beginning on day 57 through the duration of pelvic radiation, patients received FU 225 mg/m2/d via PVI. Twenty-eight days after completion of radiation, patients received FU 300 mg/m2/d via PVI for 56 consecutive days. Arm 3 comprised bolus FU administered at 425 mg/m2/d on days 1 to 5 and 29 to 33. LV 20 mg/m2/d was administered immediately before FU on each day. Levamisole was administered orally 50 mg tid on days 1 to 3 and 14 to 16 of each 28-day cycle. Radiation and FU plus LV were initiated on day 57. Bolus FU 400 mg/m2/d was administered after LV 20 mg/m2/d on days 1 to 4 every 28 days during radiation. Ideally, this was administered days 57 to 60, 85 to 88. After XRT, treatment was interrupted for 28 days. Patients then received FU 380 mg/m2/d, with LV 20 mg/m2/d administered immediately before the FU. Therapy was delivered days 1 to 5 every 28 days of two postradiation cycles. Levamisole 50 mg tid was administered every 14 days for 3 consecutive days.
XRT Parameters
Statistical Considerations The study was monitored by the Southwest Oncology Group Data and Safety Monitoring Committee. The protocol specified a formal interim analysis after 2 years of accrual, and then annually thereafter. In August 2000, the Data and Safety Monitoring Committee approved a modification of the accrual goal to 1,800 eligible patients, based on slower than expected accrual and the fact that the necessary number of events could be attained with fewer patients. This decision was based solely on accrual patterns, and not on interim study results. The four stratification factors (type of surgery [two levels], T stage [three levels: T1-2 v T3-4a v T4b], N stage [three levels], and time from surgery [two levels]) were included in a stratified Cox regression analysis. This model allowed for assessment of other covariates, such as race, sex, and age. All eligible patients were included in the analysis of OS and DFS by their assigned treatment according to the intent-to-treat principle. Patients who refused treatment were not included in toxicity analyses.
Patients A total of 1,917 patients registered from March 1994 to August 2000. Sixty-one patients were ineligible (14 due to insufficient prestudy documentation). Four ineligible patients are included in the study summary and tables: one patient was registered 2 days earlier than the required 20 days after surgery; one patient had a missing eligibility checklist; and two patients had a missing surgical checklist but otherwise seemed fully eligible for study. Patient characteristics by treatment arm are listed in Table 1. Arms were well balanced for age, sex, race, performance status, and the stratification variables of surgery type, nodal status, T stage, and time from surgery to registration. Median follow-up for living patients was 5.7 years. Quartiles of lymph nodes examined for the group overall are as follows: first quartile, one to six nodes; second quartile, seven to 10 nodes; third quartile, 11 to 16 nodes; fourth quartile 17 or more nodes.
Major protocol deviations occurred in 44 (2%) patients. Twenty-five patients never initiated protocol therapy, and three received the wrong treatment arm. These 28 patients are analyzed according to assigned treatment arm, but not toxicity. Sixteen additional patients received various major deviations.
Toxicity Evaluation
Disease Outcome OS and DFS are shown in Figures 1A and 1B, respectively. Three and 5-year OS is 81% and 68%, 83% and 71%, and 82% and 68% for arms 1, 2, and 3, respectively. The overall test of differences in these values is not significant (P = .5). DFS (Fig 1B) shows similar outcome among the three treatment arms (P = .25). Estimates of 3- and 5-year DFS are 68% and 62%, 69% and 62%, and 67% and 57% for arms 1, 2, and 3, respectively. The primary study comparison was an assessment of the possible benefit of administering FU by PVI throughout therapy (arm 2) as opposed to only during radiation (arm 1), which was the best arm of INT 864751. OS and DFS comparisons were not statistically different between the two arms (one-sided P = .17 for OS and .21 for DFS). The corresponding hazard ratio for OS is 0.91 (95% CI, 0.75 to 1.11) and for DFS is 0.95 (95% CI, 0.80 to 1.13). The second primary aim was to assess whether a bolus FU-based regimen would yield similar results to the two PVI-based arms. The results of that comparison likewise showed no statistical significance (P = .57 for OS and .11 for DFS). The corresponding hazard ratios are 1.05 (95% CI, 0.89 to 1.24) and 1.13 (95% CI, 0.97 to 1.31), respectively. We were unable to detect any survival differences by race or sex. Similarly, there were no treatment interactions with either race or sex.
We were concerned that some treatment effect may have been obscured by inclusion of a significant number (n = 485) of favorable T3, N0 patients (3- and 5-year OS estimates of 91% and 82%, respectively). However, the estimates of the hazard ratios were virtually unchanged with the exclusion of these patients.
Relapse Patterns
INT 864751 tested PVI versus bolus FU with radiation. PVI improved DFS and OS (P = .005) primarily by reducing extrapelvic relapse.4 This suggested that PVI improved systemic control of micrometastatic disease. Accordingly, we adopted arm 1 (the best arm of INT 864751) as the standard control arm. In addition, multiple phase III studies reported improved response rates with PVI versus bolus schedules in advanced disease.5-12 The reduction in distant metastatic relapse in INT 864751 and the improvement in objective response with PVI in advanced disease suggested that a more uniform approach of PVI may further reduce the emergence of micrometastatic disease. Therefore, arm 2 adopted PVI throughout therapy. Interest in biochemical modulation of FU and practical concerns regarding central venous catheters prompted adoption of arm 3. During the course of this study, INT 0114 results became available.28,29 This study compared three biochemically modulated FU regimens (including arm 3) versus bolus FU alone (which was the control arm of INT 864751). No benefit to biochemical modulation was observed. Our study suggests there is no clinically meaningful difference in outcome based on FU-only dose schedule. Whether FU is biochemically modulated or administered as PVI during part of or the entirety of treatment, outcomes were equivalent. Three- and 5-year DFS and OS were essentially identical in all three arms of the trial. Predefined study end points testing PVI throughout therapy versus PVI only during radiation did not reach significance. Comparison of the two infusion FU arms versus the biochemically modulated bolus FU arm likewise showed similar results. Toxicity showed important clinical differences, but none of these three arms were clearly superior to the others with regard to toxicity. Lethal toxicity was identical and uncommon in all three arms. Grade 3/4 GI toxicity occurred in 40% to 41% of these arms. Hematologic toxicity, similar to other experiences comparing PVI versus bolus regimens,12 was markedly diminished in arm 2 (PVI only). However, most of these toxicities were expressions of laboratory values and did not result in harm to patients. Grade 3/4 infection rates were 6% in the PVI-only arm versus 9% to 10% in arms 1 and 3. Several studies demonstrated increased toxicity in females receiving FU.30-33 Females had increased grade 3 to 4 GI and hematologic toxicities. This translated into more clinically significant infections (grade 3 to 4 infections in 11% to 12% of females in the two bolus arms versus 4% in arm 2). We were encouraged that there was no significant interaction of sex or race with treatment effect on DFS and OS. LRF is uncommon at the time of first treatment failure. Therefore, additional improvements in rectal cancer outcome will likely come from improved control of distant metastatic disease. The capecitabine versus bolus FU/LV as adjuvant therapy for colon cancer (X-ACT) trial has compared oral capecitabine versus bolus FU/LV in node-positive extrapelvic colon cancer.35 DFS showed a trend toward superiority with capecitabine, which neared statistical significance (P = .053). Improved safety profile was also evident with this approach. The dose of capecitabine (800 to 825 mg/m2/bid daily) administered during radiation for rectal cancer in several reports36-42 is similar to that of the X-ACT trial (1,250 mg/m2 bid daily for 14 days every 21 days). Several trials have now incorporated oxaliplatin or other agents, which could also be tested formally.34 The LRF information provides reassurance to those who advocate initial surgery for selected rectal cancer patients. The recent German Rectal Cancer study43,44 randomized stages II or III rectal cancer to either pre- or postoperative radiochemotherapy. Survival, distant relapse, and abdominoperineal resection rate was similar in both arms. LRF was 6% with neoadjuvant versus 13% with postoperative adjuvant therapy (P = .006). Interpretation is complicated by the fact that only 54% of the postoperative group versus 92% of the preoperative group received the full XRT dose, undoubtably contributing to the increased LRF observed in this arm. However, it is hoped that these data will lead to more widespread use of neoadjuvant XRT and chemotherapy for appropriately selected rectal cancer. The German data support the use of neoadjuvant radiochemotherapy, particularly for patients requiring abdominoperineal resection or with T4 lesions. However, clearly there are situations more judiciously managed by initial surgery. Improvements in surgical technique have included both total mesorectal excision (TME) and an improved understanding of nerve-sparing to reduce long-term toxicity. TME seems to improve LRF45-52 and thorough nodal evaluation is associated with improved outcome.53-57 Patients with T3, N0 tumors have less than 10% incidence of pelvic relapse with this approach. The Dutch trial randomly assigned 1,861 patients with TME to surgery alone versus preoperative radiation.58,59 LRF at 2 years was 8.2% v 2.4% with preoperative radiation. Of note, LRF clearly was a function of the distance of the tumor from the anal verge. T3, N0 disease had only a 5.7% incidence of 2-year LRF and primary lesions 10 to 15 cm from the anal verge had only a 4% incidence of 2-year LRF with TME alone. Therefore, T3 primary cancers requiring low anterior resection may be considered appropriately for initial surgery. Patients with T1-2, N0 disease should be managed with surgery alone. Selected patients (meaning those with satisfactory radial margins and good nodal surgery) with T1-3 and minimal nodal disease or T3, N0 patients should be counseled carefully regarding the risks and benefits of adjuvant radiation. It is not uncommon to encounter this subset of patients. Eighteen percent of the patients in the German study had stage I tumors only, and 30% had stage 0-I tumors in the Dutch trial. Patients with these favorable presentations may forego XRT and often all adjuvant treatment. Anal, rectal, and small bowel function all are adversely influenced by preoperative and postoperative adjuvant therapy.60-64 In addition, the Dutch study observed that XRT before TME increased impotence (31% v 21%; P = .03) and ejaculatory difficulties (a three-fold increase).65 Others have documented sexual dysfunction with adjuvant rectal cancer therapy66-68 and female sexual dysfunction, including anorgasmia.66,67 Clearly, avoidance of these problems is best accomplished by avoiding adjuvant therapy in those not likely to benefit. Initial surgery in selected patients allows individualization of therapy and reserves radiochemotherapy only for those most likely to benefit. We suggest initial surgery is appropriate for those without extensive local disease (T1-2 and early T3) who are candidates for low anterior resection. We observed a 3% to 5% initial LRF in these patients with the addition of postoperative chemoradiotherapy. Although this LRF may seem low compared with that in other adjuvant trials, this is the only report that has evaluated LRF in this subset of patients, and we have mature follow-up. Our patients overwhelmingly did not receive TME and had nodal evaluation inferior to current recommendations. However, even with suboptimal surgery and nodal evaluation, we observed acceptable LRF.
Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
Supported by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA35176, CA12644, CA21661, CA25224, CA17145, CA32291, CA03927, CA22433, CA46441, CA35113, CA58882, CA67575, CA20319, CA35090, CA14028, CA58861, CA12644, CA35119, CA45377, CA45807, CA35176, CA67663, CA42777, CA63844, CA45450, CA27057, CA58348, CA46282, CA35192, CA049*19, CA37981, CA35178, CA58686, CA58416, CA76429, CA35261, CA12213, CA04920, CA76447, CA03096, CA35262, CA58658, CA52654, CA58415, CA46136, CA63845, CA16385, CA63850, CA28862, CA68183, CA35281, CA45560, CA35996, CA35128, CA46368, CA52772, CA46113, CA13612, CA45461, CA52757, CA74647, and CA76462. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .025). This sample size was sufficient to detect a hazard ratio of 1.39 for DFS with 95% power (corresponding to a 67% v 75% rate at 3 years). A secondary hypothesis was that OS and relapse-free survival were similar between the non-PVI regimen (arm 3) and the two PVI regimens (arms 1 and 2). 
