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Journal of Clinical Oncology, Vol 22, No 3 (February 1), 2004: pp. 484-492 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.065 Efficacy of Oral Adjuvant Therapy After Resection of Colorectal Cancer: 5-Year Results From Three Randomized TrialsMeta-Analysis Group of the Japanese Society for Cancer of the Colon and Rectum and the Meta-Analysis Group in CancerFrom the Meta-Analysis Group of the Japanese Society for Cancer of the Colon and Rectum, and the Meta-Analysis Group in Cancer Address reprint requests to Junichi Sakamoto, MD, Department of Epidemiological and Clinical Research Information Management, Kyoto University, Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; e-mail: sakamoto{at}pbh.med.kyoto-u.ac.jp
PURPOSE: Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. PATIENTS AND METHODS: This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. RESULTS: The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P = .04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P < .001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. CONCLUSION: Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.
Colorectal cancer is the second most common malignant disease in developed countries, causing approximately half a million deaths worldwide each year [1]. In Japan, more than 55,000 new cases are diagnosed and more than 35,000 deaths are caused by colorectal cancer each year [2]. Surgery is the treatment of choice for approximately three quarters of colorectal cancer patients [3]. However, even if resection is considered curative, up to half will subsequently develop an incurable recurrence, and the overall 5-year survival rate is only 50% [4]. Major advances in adjuvant therapy for colorectal cancer have been achieved since the 1980s. Large-scale randomized trials [5-10] as well as the pooled analysis of several randomized trials [11] firmly established the efficacy of adjuvant chemotherapy for colorectal cancer by intravenous (IV) fluorouracil (FU) plus levamisole or by FU plus leucovorin (LV). The latter regimen is now considered a standard for the treatment of curatively resected colorectal cancers with lymph node involvement (Dukes’ C, or stage III, tumors). In Japan, adjuvant therapy after curative resection of a colorectal tumor was developed primarily using oral fluorinated pyrimidines, such as oral FU; tegafur; tegafur, uracil, and FU (UFT); 1-hexylcarbomoyl-5-fluorouracil (HCFU; carmofur); and 5'-deoxy-5-fluorouridine. In Western countries, skepticism has prevailed on the use of oral fluorinated pyrimidines as adjuvant therapy for resectable tumors of the colon and rectum. Such skepticism may be based in part on a small, double-blind, randomized trial performed in the United States during the late 1970s [12]. In this clinical trial, oral FU was compared with IV FU in 100 patients with advanced colorectal cancer, and the results, although based on too few patients to be conclusive, seemed to favor IV administration in terms of duration of response. Other reasons for the reluctance of using oral anticancer drugs in Western countries may have included the poor bioavailability of oral fluoropyrimidines and the difficulty of ensuring compliance of treatments that are administered on an outpatient basis. In contrast, oral treatments have been used extensively in Japan, both in clinical trials of adjuvant therapy for colorectal cancers and outside of such trials. A preliminary appraisal of the effect of oral adjuvant therapy was performed using individual patient data from clinical trials performed in the 1980s to compare patients treated with oral fluorinated pyrimidines with a control group of untreated patients [13]. In this meta-analysis, a significant benefit of oral fluorinated pyrimidines was shown in terms of disease-free survival (DFS), but no significant benefit could be identified in terms of survival. Furthermore, the results of the meta-analysis were not entirely convincing, because patients had been randomly assigned in these early trials using sealed envelopes, and a large proportion of patients had been excluded from the trials or were lost to follow-up. Therefore, the true benefit of oral fluorinated pyrimidines and their impact on the survival of patients with nonmetastatic stages of colorectal cancer (Dukes’ A through C, or stages I to III, tumors) still needed to be established reliably. In this article, we present an individual patient data meta-analysis of three centrally randomized trials performed in Japan to compare patients treated with oral fluorinated pyrimidines with a control group of untreated patients. This meta-analysis, which was carried out in collaboration with the Meta-Analysis Group in Cancer, includes more than 5,000 patients and therefore provides a more reliable assessment of the effects of oral adjuvant therapy on the survival and DFS of patients with colorectal cancer than is available from any of the individual studies.
Selection of Trials Trials that randomly assigned patients to either long-term (12 months) administration of oral fluorinated pyrimidines or no further treatment after curative resection of colorectal tumors were eligible for the meta-analysis, providing that the trial was initiated before 1990 and the randomization technique used was one that precluded the possibility of prior knowledge of the treatment to be allocated. Thus trials using centralized randomization were included, but those using sealed envelopes were not (a separate meta-analysis based on individual patient data of the latter trials is available elsewhere [13]). Three trials, all conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer (JFMTC) and identified as 7-1, 7-2, and 15, were included in the meta-analysis (Table 1). They involved a total of 5,233 patients. Parts of these trials had been previously published [14,15]. All three trials had separate randomizations for patients with colon cancer (referred to as 7-1-C, 7-2-C, and 15-C, respectively) and those with rectal cancer (referred to as 7-1-R, 7-2-R, and 15-R, respectively). In colon cancer, two trials (7-2-C and 15-C) tested HCFU (carmofur) and one (7-1-C) tested oral FU. In rectal cancer, two trials tested UFT (7-1-R and 15-R) and one trial tested HCFU (7-2-R). One trial (trial 15) had a third treatment arm consisting of the nonspecific immunopotentiator OK-432, which was discontinued by the Ministry of Health and Welfare of Japan at the end of 1989. As of January 1990, random assignment in this study was performed on a 2:1 ratio (two treatments to one control). For the purposes of this meta-analysis, the JFMTC-15 trial was therefore considered as two separate trials, labeled 15-1 (three-arm study) or 15-2 (two-arm study). In all three trials, patients who were randomly assigned to the experimental group received mitomycin during surgery. In trials 7-1 and 15, patients who were randomly assigned to the experimental group also received IV mitomycin (6 mg/m2) at 1 week and once monthly for 6 months. In trial 15, patients who were randomly assigned to the experimental group additionally received an induction course of IV FU (250 mg daily) during 7 postoperative days (Table 1).
Protocol for the Meta-Analysis In February 2000, a protocol for the meta-analysis describing its rationale, statistical methodology, and rules for publication were distributed to the principal investigators of the three trials. Investigators were asked to provide individual data for every randomized patient, whether eligible or not, assessable or not, and properly followed up or not. Items requested for every patient were as follows: patient identification, date of surgery, eligibility, treatment assigned by random assignment, age, sex, primary tumor site, Dukes’ stage, induction chemotherapy, date of recurrence, death or last visit, and cause of death. DFS was calculated from the date of surgery to the date of recurrence or death, whichever occurred first. Survival was calculated from the date of surgery to the date of death, regardless of the cause of death. All patients had been followed up through 5 years in all trials, and therefore DFS and survival data were not available beyond 5 years. Toxicity data were not collected, because detailed analyses of side effects can be found in the published reports of the individual trials [14,15].
Data Collection
Pretreatment Patient Characteristics
Statistical Analysis
Survival Survival hazard ratios are presented in Figure 1 for all the trials by tumor site and overall. The overall hazard ratio was 0.89 (95% CI, 0.80 to 0.99; P = .04), with no significant heterogeneity between the treatment effects in different trials (  27 for heterogeneity = 2.11; P = .95). The benefit of oral fluorinated pyrimidines was seen both in rectal locations (hazard ratio = 0.92; 95% CI, 0.79 to 1.07) and colon locations (hazard ratio = 0.86; 95% CI, 0.73 to 1.00).
Figure 2 shows the breakdown of the survival hazard ratio by various patient characteristics. There was a trend toward larger treatment benefits in earlier Dukes’ stages ( 21 for trend = 3.1; P = .077). A trend toward smaller benefits in older age groups could also be seen (with a negative effect among patients older than 70 years), but this trend was not consistent among younger patients, and overall the observed pattern in treatment effect was far from statistical significance (21 for trend = 0.8, P = .4). There was no statistically significant difference between the benefits of the various oral fluoropyrimidines (22 for interaction = 0.5; P = .8), but the trials used different agents depending on tumor site, and so this comparison may be confounded by other differences in trial characteristics.
Figure 3 shows survival curves by treatment and disease stage. These curves confirm the hazard ratio analysis shown in Figure 2 and point to a benefit of oral fluorinated pyrimidines in all Dukes stages. The (nonsignificant) trend toward larger benefits in stages with better prognosis resulted in absolute benefits of roughly similar magnitude across all Dukes’ stages: the survival benefits at 5 years were 3.7%, 4.3%, and 2.4%, respectively, for patients with Dukes’ A, B, and C tumors.
A proportional hazard regression model of survival confirmed the benefit of treatment and the lack of significant treatment by covariate interactions, except for a trend toward larger benefit in earlier Dukes’ stages, which almost reached statistical significance. The best survival model excluded sex, site, or type of oral fluoropyrimidine, and included Dukes’ stage ( 2 = 165; P < .0001), age (2 = 10.2; P = .001), treatment (2 = 4.94; P = .026), and the interaction between treatment and Dukes’ stage (2 = 3.49; P = .066).
DFS
Figure 5 lists the DFS hazard ratios by various patient and treatment characteristics. Just as for survival, a trend toward a larger benefit in earlier Dukes’ stages was noted but failed to reach statistical significance (P = .1), whereas the trend toward a larger benefit in younger age groups was unconvincing (P = .4).
Figure 6 shows survival curves by treatment and disease stage. These curves again point to a benefit of oral fluorinated pyrimidines in all Dukes’ stages. The absolute benefits were of similar magnitude in all Dukes’ stages: the DFS benefits at 5 years were 5.2%, 4.7%, and 4.4%, respectively, for patients with Dukes’ A, B, and C tumors.
The best DFS model retained the same covariates as the survival model: Dukes’ stage ( 2 = 194; P < .0001), age (2 = 6.25; P = .012), treatment (2 = 5.34; P = .021), and the interaction between treatment and Dukes’ stage (2 = 2.80; P = .095).
The potential of fluorinated pyrimidines to reduce the risk of tumor recurrence and thereby increase survival in patients with colorectal cancer was suspected more than 20 years ago. Extensive preclinical and clinical research led to the optimization of FU administration, with FU bolus in combination with LV emerging as standard therapy both in metastatic disease [17] and after curative resection of Dukes’ C (stage III) colon cancer [9-11]. However, the toxicity of the FU/LV regimen, especially the risk of hematologic toxicity and mucositis, is not negligible. In advanced disease, continuous-infusion FU or regimens that combine bolus FU modulated by LV with continuous-infusion FU (the LV5FU2 regimen in France, and the Arbeitsgemeinschaft Internistische Onkologie regimen in Germany) were shown to have better efficacy and better tolerance than bolus FU [18-21]. In the adjuvant setting, the LV5FU2 regimen was shown to have lower toxicity than FU/LV, but no difference was demonstrated in terms of survival [22]. The need for an implanted venous access and the delivery of chemotherapy through a portable pump limit the wide availability of continuous-infusion treatments. The recent development of oral fluoropyrimidines has therefore opened new perspectives. Oral fluoropyrimidines may mimic continuous-infusion FU without its technical inconvenience. In patients with advanced colorectal cancer, the efficacy of UFT plus oral folinic acid [23,24] or of capecitabine alone [25,26] seems comparable to the efficacy of IV FU/LV, with less than 3% neutropenia and grade 3 to 4 stomatitis. The risks of severe stomatitis and of hand-foot syndrome are lower with oral fluoropyrimidines than with FU/LV (4% v 13% to 21%), but the risks of severe diarrhea and severe nausea/vomiting are higher with oral fluoropyrimidines than with continuous-infusion FU (4% to 10% v 3%). Oral fluoropyrimidines have been administered for many years in Japan, both to patients with advanced colorectal cancer and to patients in whom the tumor could be curatively resected. Several Japanese groups conducted randomized clinical trials comparing oral fluoropyrimidines with control after surgery. Six such trials were identified, three of which were combined in a previously reported meta-analysis, whereas the three other trials are included in the present meta-analysis [13]. The present meta-analysis was restricted to trials that had been randomized centrally and from which no patients had been excluded for any reason. It represents the largest series of properly randomly assigned patients in which patients receiving oral adjuvant therapy were compared with patients receiving no therapy after tumor resection. This meta-analysis found a statistically significant benefit of oral fluoropyrimidines on overall survival (hazard ratio = 0.89; P = .04) and DFS (hazard ratio = 0.85; P < .001). These benefits may be more pronounced with HCFU and UFT than with oral FU, although the statistical test for interaction failed to reach significance. Interestingly, the treatment benefits were about the same in rectal and colon tumors, with tests for interaction between treatment effect and tumor location being quite far from statistical significance despite the large number of patients available. Although adjuvant chemotherapy has been primarily investigated in large trials restricted to patients with colon cancer, there is much indirect evidence that supports our findings of a benefit of adjuvant chemotherapy in both rectal and colon locations. Tests of interaction between the effect of treatment and tumor location were not significant in any of the previous meta-analyses carried out with patients suffering from both types of tumor, again despite the large number of patients available in these meta-analyses [27-29]. Therefore, all the evidence available justifies use of adjuvant chemotherapy for both locations, whether in the context of randomized trials or in clinical practice. There is also a lack of consensus on the utility of adjuvant chemotherapy for early-stage colorectal cancer (Dukes’ A and B, or stage I and II, tumors) [30]. If anything, the present meta-analysis showed a trend toward a larger relative effect in earlier tumors, resulting in absolute benefits of about the same magnitude in all Dukes’ stages: a 5-year survival benefit of approximately 3% and a 5-year DFS benefit of approximately 5.5% for all tumor stages. In terms of numbers needed to treat, these benefits imply that approximately 33 patients need to be treated for one fewer patient to die within 5 years, and approximately 18 patients need to be treated for one fewer patient to suffer a disease recurrence within 5 years, regardless of disease stage. Many of the earlier trials of adjuvant therapy for colorectal cancer had either excluded patients without lymph node involvement or had included too few of them to reach a reliable conclusion about possible treatment benefits in that subset. Our results show that the benefit of therapy is not confined to patients with nodal involvement (Dukes’ C, or stage III, tumors) and thereby confirm previously published claims that chemotherapy may also be beneficial in stage II (Dukes’ B) patients [31]. The limited number of patients with stage I disease (Dukes’ A) calls for caution in interpreting any observed benefit in this subset. Whether the magnitude of the benefit among stage I and II patients justifies routine use of chemotherapy in these patients is still a matter of debate [11]. In view of the excellent tolerability of oral fluoropyrimidines, these may constitute a treatment of choice for patients with early-stage tumors in whom IV therapy would not be routinely recommended. In patients with nodal involvement (Dukes’ C, or stage III, tumors), IV FU-based regimens have consistently been shown to reduce the risks of recurrence and death by up to 30% [9-11], which may represent larger benefits than the reduction of 15% in the risk of recurrence and 11% in the risk of death found in the present meta-analysis. Although such indirect comparisons are to be taken with caution, IV therapy should remain the treatment of choice in patients with nodal involvement who are at high risk of disease progression until more effective treatments become available. Some of these patients, however, are too frail to tolerate long-term IV chemotherapy or may decline such therapy for personal convenience. Some older patients may fall in this category. A recent meta-analysis of seven randomized clinical trials comparing chemotherapy with control in Dukes’ B and C (stage II and III) colon cancers found no interaction between age and treatment efficacy and no increase of toxicity in older patients [32]. However, older patients included in these trials may not be representative of the general population of aging patients. Here again, the good tolerability of oral fluoropyrimidines may make them an attractive treatment option. Finally, regardless of disease site or stage and patient age or general condition, there is a need for further trials on the combination of oral fluoropyrimidines and new agents with activity in advanced disease, such as irinotecan or oxaliplatin.
Writing Committee: Junichi Sakamoto (Kyoto University, Kyoto, Japan), Yasuo Ohashi (Tokyo University, Tokyo, Japan), and Chikuma Hamada (Science University of Tokyo, Tokyo, Japan) on behalf of the Japanese Society for Cancer of the Colon and Rectum, and Marc Buyse (International Drug Development Institute, Cambridge, MA; Center for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium), Tomasz Burzykowski (Center for Statistics, Limburgs Universitair Centrum, Diepenbeek, Belgium), and Pascal Piedbois (Assistance Publique Hopitaux de Paris, Hopital Henri Mondor, Créteil, France) on behalf of the Meta-Analysis Group in Cancer.
The authors indicated no potential conflicts of interest.
We acknowledge Susumo Kodaira (Teikyo University, Tokyo, Japan), Masayuki Yasutomi (Kinki University, Osaka, Japan), and Hiroaki Nakazato (Japanese Foundation for Multidisciplinary Treatment of Cancer, Nagoya, Japan) for their participation in the conception and design of this study, and Emmanuel Quinaux (International Drug Development Institute, Brussels, Belgium), who provided statistical expertise. We are grateful to the trialists for providing data on individual patients randomized in the trials used in the meta-analysis, and especially to Dr Kiyoshi Inokuchi, Chairman of the Board of Directors of the Japanese Foundation for Multidisciplinary Treatment for Cancer, for his generous cooperation.
Authors’ disclosures of potential conflicts of interest are found at the end of this 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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ABSTRACT
INTRODUCTION
