Japanese Journal of Clinical Oncology Advance Access originally published online on May 4, 2006
Japanese Journal of Clinical Oncology 2006 36(4):237-244; doi:10.1093/jjco/hyl014
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© 2006 Foundation for Promotion of Cancer Research
Adjuvant Chemotherapy with Uracil–Tegafur for Pathological Stage III Rectal Cancer after Mesorectal Excision with Selective Lateral Pelvic Lymphadenectomy: A Multicenter Randomized Controlled Trial*
1 Colorectal Surgery Division, 2 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, 3 Department of Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo, Tokyo, 4 National Cancer Center Hospital East, Kashiwa, Chiba and 5 Department of Surgery, Teikyo University, Tokyo, Japan
For reprints and all correspondence: Takayuki Akasu, Colorectal Surgery Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: takasu{at}ncc.go.jp
Received December 28, 2005; accepted February 22, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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Background: Although adjuvant radiotherapy was proved to be effective for local control of rectal cancer even after standardized mesorectal excision, the role of adjuvant chemotherapy after such standardized surgery remains to be clarified. We aimed to assess the efficacy of a combination of uracil and tegafur for pathological stage III rectal cancer treated by standardized mesorectal excision with selective lateral pelvic lymphadenectomy.
Methods: We randomly assigned patients with completely resected stage III rectal cancer, who underwent standardized mesorectal excision with selective lateral pelvic lymphadenectomy, to receive either oral uracil–tegafur (400 mg/m2 tegafur per day) for one year or no treatment. Standardization and quality control of the surgery and pathological techniques were ensured by use of the guidelines of the Japanese Society for Cancer of the Colon and Rectum. The primary endpoint was relapse-free survival. The secondary endpoint was overall survival.
Results: We enrolled and randomized 276 patients. Excluding two ineligible patients, 274 were included in the analysis. Planned interim analysis 2 years after accrual termination revealed significant prolongation of relapse-free survival (P = 0.001) and overall survival (P = 0.005) in the uracil–tegafur group. The 3-year relapse-free survival and overall survival rates were 78 and 91% in the chemotherapy group and 60 and 81% in the surgery-alone group, respectively. Local recurrence rates were low in both groups. Grade 3 events occurred in 17% of the chemotherapy patients, but no grade 4 or more events occurred.
Conclusion: Adjuvant chemotherapy with uracil–tegafur improves survival of patients with stage III rectal cancer after standardized mesorectal excision with selective lateral pelvic lymphadenectomy.
Key Words: adjuvant chemotherapy • uracil–tegafur • rectal cancer • surgery
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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The quality of surgical procedures has prognostic significance for local control and survival in rectal cancer (1,2). However, the lack of standardization for surgery and limitations of surgical information in previous adjuvant trials is well documented (3). The Dutch Colorectal Cancer Group was the first to adopt standardized mesorectal excision (4,5) in a rectal cancer adjuvant study (6). Mesorectal excision involves complete resection of the mesorectum by precise, sharp dissection under direct visualization (4,5) and is recommended in the Guidelines 2000 for Colon and Rectal Cancer Surgery (5).
The Dutch group clearly showed that preoperative radiotherapy is effective for local control even when standardized mesorectal excision is performed (6). Previous studies evaluating adjuvant radiotherapy, but not using standardized surgery, also showed its advantages in local control and survival (7,8). Therefore adjuvant radiotherapy has been recommended as the standard treatment. However, this approach was challenged by the results of a randomized trial which revealed no additional survival benefit from radiotherapy when chemotherapy was administered (9). Furthermore, radiotherapy entails risks of morbidity and mortality (6,7,10–12).
We started the National Surgical Adjuvant Study of Colorectal Cancer 01 randomized trial at the same time as the Dutch trial started (6). The aim of our trial was to evaluate the efficacy of postoperative adjuvant chemotherapy with a combination of uracil and tegafur (a prodrug of fluorouracil) taken orally after standardized mesorectal excision with selective lateral pelvic lymphadenectomy in stage III rectal cancer. Selective lateral pelvic lymphadenectomy is defined as selective application of extended lateral pelvic lymph node dissection, to resect the iliac and obturator lymph nodes when lateral pelvic lymph node involvement is clinically suspected (5,13–15).
We adopted mesorectal excision with selective lateral pelvic lymphadenectomy alone as the control treatment because it was the standard for stage III rectal cancer in Japan (13–15). We did not choose adjuvant radiotherapy because, in addition to the reasons mentioned above, local recurrence rate after mesorectal excision with selective lateral pelvic lymphadenectomy in Japan had been 7–15% in high-volume centers (14,15). Instead, we used oral uracil–tegafur, which was reported to be effective as adjuvant therapy for lung cancer in recent studies (16), because previous studies suggested efficacy of uracil–tegafur for prolonging disease-free survival in rectal cancer (17,18). Bolus fluorouracil and folinic acid, the present world standard for stage III colon cancer, was not used, because folinic acid was not approved in Japan until 1999. We present the results of the planned interim analysis at a median follow-up of 3 years.
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METHODS |
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TOPAbstractINTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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PATIENTS AND STUDY DESIGN
Enrollment began in October 1996. Eligible patients had undergone a microscopically verified complete resection of pathological stage III adenocarcinoma of the rectum according to the 1992 Tumour Node Metastasis (TNM) Classification of Malignant Tumours (International Union Against Cancer) (19), by standardized mesorectal excision with selective lateral pelvic lymphadenectomy. Other inclusion criteria were the center of the tumor being located between the levels of the first sacral bone and the anal canal; an age of 20–75 years; the absence of preoperative anticancer treatment, previous cancer and synchronous multiple cancers; an Eastern Cooperative Oncology Group performance status of 0, 1 or 2; a leukocyte count of at least 4000/mm3; a platelet count of at least 100 000/mm3; serum aspartate aminotransferase and alanine aminotransferase levels that were no more than twice the upper limit of the normal range; a serum total bilirubin level of at most 1.2 mg/dl; a blood urea nitrogen level of at most 25 mg/dl; a serum creatinine level of at most 1.5 mg/dl; normal electrocardiogram; and an absence of severe postoperative complications uncontrolled by the time of registration.
An open-label study design was used. After written informed consent had been obtained, we randomly assigned the patients to postoperative adjuvant treatment with uracil–tegafur or to surgery alone. Randomization was performed by telephone or fax at the central trial office within 42 days after operation. Patients were allocated by the minimization method with Zelen's adjustment for inter-institutional imbalance. The factors used for balancing were the site of the primary tumor (above versus below the rectovesical fossa or rectouterine fossa), primary tumor stage (pT1 or pT2 versus pT3 or pT4) and N stage (pN1 or pN2 versus pN3). The primary endpoint was relapse-free survival and the secondary endpoint was overall survival. The trial was approved by the institutional review board of each participating center.
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TREATMENT |
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TOPAbstractINTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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QUALITY CONTROL FOR SURGERY AND PATHOLOGY
All of the 28 participating centers are the high-volume centers which treated more than 100 colorectal cancer patients per year and institutional members of the Japanese Society for Cancer of the Colon and Rectum (JSCCR) (13). The JSCCR has held a general assembly and sessions intended to improve treatment of colorectal cancer twice every year, and has standardized treatment. The JSCCR has provided guidelines for standardized surgical treatment and pathological evaluation (13). All procedures and pathological evaluations were in accordance with the fifth edition of the guidelines published in 1994 (13).
Mesorectal excision was the baseline procedure for all patients. The definitions of the mesorectum and mesorectal excision were the same as those from the Guidelines 2000 (5,13–15). In addition, extended lateral pelvic lymph node dissection (5,13–15) was performed in cases with clinically suspected lateral lymph node disease, as recommended by the JSCCR guidelines (13–15).
The quality of surgery was monitored by the surgeon's report on the location and clinical stage; extent of the resection of the bowel; mesorectum; and lymph nodes, and the pathologist's documentation of the pathological stage; number of resected and positive lymph nodes in each lymph node group; extent of bowel resection; and anal, oral and radial margin status (13).
ADJUVANT CHEMOTHERAPY
In the treatment group, uracil–tegafur (UFT®, Taiho Pharmaceutical Co., Tokyo, Japan; 400 mg/m2 tegafur per day) in the form of 100 mg units (100 mg of tegafur plus 224 mg of uracil) was given orally twice daily for 5 consecutive days every weekday for 1 year, starting 6 weeks postoperatively. The dose was rounded up or down to the nearest 100 mg. All patients but one received 3 units of uracil–tegafur (300 mg of tegafur and 672 mg of uracil) twice daily. The patients were asked at each follow-up visit whether they had taken the units as prescribed.
Adverse events were graded according to the toxicity grading criteria of the Japan Clinical Oncology Group, which consist of the Common Toxicity Criteria of the National Cancer Institute with minor modifications (20). Grades range from 0 (none) to 5 (fatal) (20). If a moderate (grade 2) adverse event occurred, the dose of uracil–tegafur was reduced to 250 mg/m2 per day of tegafur. Treatment was stopped if, despite dose reduction, there was anything of the following: a grade 2 or higher adverse event, a leukocyte count of <3000/mm3, an aspartate aminotransferase or alanine aminotransferase level of more than 2.6 times the upper limit of the normal range, a total bilirubin level of more than two times the upper limit of the normal range, moderate or severe anorexia, one or more vomitings per day or four or more bowel movements per day.
FOLLOW-UP
All the patients were evaluated every 4 months for the first 2 years after surgery and every 6 months for the next 3 years. The evaluation included a physical examination, a complete blood count, blood chemical tests, serum tumor markers, chest roentgenography, and abdominal ultrasonography or computed tomography. A pelvic computed tomography was performed every 6 months. In addition, patients receiving uracil–tegafur had a physical examination, a complete blood count and blood chemical tests every month during the first year.
STATISTICAL ANALYSIS
The sample size was calculated by the method of Schoenfeld and Richter. The study was designed to detect a hazard ratio for relapse or death of 0.67 in the uracil–tegafur group compared with the control group with 80% power at a two-sided 
-level of 0.05. Assuming a 5-year relapse-free survival rate of 50% in the surgery-alone group, a 2-year accrual period and a 5-year follow-up, the targeted sample size was 400. In April 2000, the accrual period was extended to 5 years based on the actual accrual rate.
Interim analysis was planned 2 years after accrual termination. Early termination would be considered at the time of the interim analysis if the one-sided P-value of the log-rank test for the primary endpoint was below 0.005, according to the Lan-DeMets spending function method.
Relapse-free survival was defined as the time from surgery until the appearance of the first recurrence of cancer, or death from any cause, and overall survival was defined as the time from surgery until death from any cause. All comparisons between the treatment groups were made on the intention-to-treat principle. Survival curves were estimated by the Kaplan–Meier method, and differences in survival were evaluated with the log-rank test.
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RESULTS |
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TOPAbstractINTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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ACCRUAL AND INTERIM ANALYSIS
From October 1996 to April 2001, 276 patients were enrolled and randomly assigned to one of the two treatment groups (Fig. 1). The study group decided to stop recruitment in April 2001, because a rapid, further enrollment could not be expected and evaluation of the treatment would be possible through a meta-analysis including the data obtained from this study and existing data (17,18,21). Planned interim analysis was conducted by the data and safety monitoring committee on 13 December 2003. Sufficient results favoring the treatment arm caused the committee to recommend a prompt disclosure of the results. This report is based on the results presented to the data and safety monitoring committee.
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PATIENT POPULATION
Of the 276 enrolled patients 2 (one in each group) proved to be ineligible so that data from 274 patients (139 in the uracil–tegafur group and 135 in the surgery-alone group) were included in the analysis (Fig. 1). The characteristics of the patients are shown in Table 1 and were well balanced in the two groups.
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QUALITY OF SURGERY
The quality of the surgical procedures (Table 2) was similar in both groups. All patients underwent at least mesorectal excision. Extended lateral pelvic lymph node dissection was added in 38% of the patients, most of whom had a tumor locating below the rectovesical fossa or rectouterine fossa. Distal margins of the mesorectum and rectum were sufficient in both groups. Anal, oral and radial margins were microscopically negative in all the patients. More than 12 lymph nodes were resected in 80% of the patients. The rate of positive lateral pelvic lymph node metastasis was 17% (18/104) in the patients who underwent extended lateral pelvic lymph node dissection.
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ADVERSEEVENTS ANDCOMPLIANCE
Of the 139 patients assigned to the uracil–tegafur group, 137 actually took uracil–tegafur and two withdrew from the trial before drug administration (Fig. 1). Moderate (grade 2) and severe (grade 3) events were observed in 65 and 17% of the patients in the uracil–tegafur group and in 39 and 4% of the patients in the surgery-alone group, respectively. Observed adverse events are listed in Table 3. A life-threatening (grade 4) event occurred only in one patient in the surgery-alone group. There was no fatal event.
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Compliance with instructions to take uracil–tegafur was calculated on the basis of the number of patients who actually took uracil–tegafur and the number of patients who were assigned to it, excluding those with a recurrence and those who died. The rate of compliance, with or without dose reduction, was 93% at 3 months, 88% at 6 months, 83% at 9 months and 80% at 12 months. The reasons for discontinuation of uracil–tegafur were a cancer recurrence (18 patients), an adverse event (8 patients), patient withdrawal due to adverse events (10 patients) and patient withdrawal due to other causes (4 patients).
RELAPSE-FREESURVIVAL
The median follow-up among surviving patients was 3.0 years. At the last follow-up, 32 patients in the uracil–tegafur group and 53 in the surgery-alone group had recurrence or had died (Table 4). The 3-year estimate of relapse-free survival for the uracil–tegafur group was 78% (95% CI 71–86%). That for the surgery-alone group was 60% (95% CI 51–69%) (Fig. 2). Patients receiving uracil–tegafur had significantly better relapse-free survival than those undergoing surgery alone (P = 0.0014). The hazard ratio for any recurrence in the uracil–tegafur group as compared with the surgery-alone group was 0. 52 (95% CI 0. 33–0. 81).
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OVERALL SURVIVAL
At the last follow-up, 12 patients in the uracil–tegafur group and 27 in the surgery-alone group had died. The 3-year estimate of overall survival for the uracil–tegafur group was 91% (95% CI 86–97%). That for the surgery-alone group was 81% (95% CI 73–88%) (Fig. 2). Thus patients with uracil–tegafur had significantly better overall survival than those with surgery alone (P = 0.0048). The hazard ratio for death in the uracil–tegafur group compared with the control group was 0.42 (95% CI 0. 21–0.83).
PATTERN OF RECURRENCE
Details of the pattern of first recurrence are shown in Table 4. At the last follow-up, the rates of overall local recurrence were 5.8% (8/139) for the uracil–tegafur group and 9.6% (13/135) for the surgery-alone group. Adjuvant uracil–tegafur reduced the rates of distant metastases. The rates of overall distant metastases were 18% (25/139) for the uracil–tegafur group and 32% (43/135) for the surgery-alone group. Liver and/or lung metastases composed the majority of distant metastases in both treatment groups.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMETHODSTREATMENTRESULTSDISCUSSIONMembers of the National...References |
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This trial demonstrated the efficacy of postoperative adjuvant chemotherapy with uracil–tegafur after standardized mesorectal excision with selective lateral pelvic lymphadenectomy in pathological stage III rectal cancer. At the planned interim analysis, we found that the 3-year estimate of both relapse-free survival (78%) and overall survival (91%) of the uracil–tegafur group were significantly better than the surgery-alone group (60 and 81%, respectively). The data and safety monitoring committee concluded that the results confirmed the findings of previous studies (17,18) and a recent meta-analysis (21) which showed the effectiveness of uracil–tegafur for rectal cancer.
Rates of local recurrence have been reported to be 20–36% in series of non-standardized, conventional surgery for stage III rectal cancer, with a follow-up of 5 years (3,7,8). For experienced surgeons in mesorectal excision, however, they are 7.5–12% (22,23). At a median follow-up of 3 years, the local recurrence rate was 9.6% in the surgery-alone group of our trial. Although comparisons of such figures should be interpreted cautiously, this shows that a standardized mesorectal excision with selective lateral pelvic lymphadenectomy may achieve good results even in a multicenter setting. Moreover, it may possibly be better than the 2-year local recurrence rate of 8.2% in the mesorectal-excision-alone group of the Dutch trial (6), considering that 56% of patients of the Dutch trial had stage 0–II tumors (6).
Lateral pelvic lymph node metastases from rectal cancer occur outside the mesorectum and appear to account for a major cause of local recurrence. The incidence of lateral pelvic lymph node metastases was reported to be 9–14% (14,15). If the patients have such metastases and undergo only mesorectal excision, the patients have apparent residual tumor in case of recognizable metastases or develop local recurrence after seemingly curative surgery in unrecognizable metastasis cases. Extended lateral pelvic lymph node dissection is a surgical procedure to resect such macroscopic or microscopic metastases (5,14,15). Therefore, this procedure potentially has a similar local-control effect to adjuvant radiotherapy. Whether lateral dissection can be an alternative to radiotherapy should be tested in a randomized controlled trial assessing local control, survival, mortality and morbidity. To conduct such trials, accuracy for detection of lateral pelvic metastases may be a problem. Indeed, in our trial, only 17% of the patients who underwent lateral dissection actually had lateral metastases. To avoid such over-treatment, an accurate diagnostic modality detecting metastasis is necessary.
Between 1990 and 1994, the JSCCR registered 25 224 patients with colorectal cancer. (24) Among them, 2789 patients had curative resection of stage III rectal cancer and their 3-year overall survival rate was 75% (24). In the surgery-alone group of our trial, the 3-year overall survival was 81%. Introduction of revised guidelines, standardized surgical procedures assured by precise documentation and participation of colorectal specialists from high-volume centers may have contributed to this improvement. Quality of surgery is already known as an independent prognostic factor for survival in rectal cancer (1,2), and case volume per surgeon also influences the outcome (3,25).
However, the quality of surgery has no influence on the initial occurrence of distant metastases (1). Even when better-quality surgery reduces local recurrence, occult distant metastases necessitate further treatment to improve survival. We found that, in addition to the efficacy of mesorectal excision with selective lateral pelvic lymphadenectomy, uracil–tegafur further decreased the rate of local recurrence from 9.6 to 5.8%. The rate of distant metastasis was almost halved from 32 to 18%, including a substantial reduction in the rates of liver and lung metastases. Uracil–tegafur appears to improve survival mainly through reduction of distant metastases when applied along with such operations.
The recent meta-analysis assessing randomized controlled trials using oral fluorouracil-based adjuvant chemotherapy for stage I–III colorectal cancer revealed that 1-year chemotherapy reduced the risk of death by 11% (P = 0.04) and the risk of recurrence or death by 15% (P < 0.001) as compared with surgery alone (21). However, of the three previous randomized trials that compared uracil–tegafur adjuvant therapy with surgery alone in rectal cancer, two revealed significantly improved relapse-free survivals, but none demonstrated an advantage in overall survival (17,18). In these trials, eligible stages were I–III, the dosage of tegafur was 400 mg per day, the compliance was 48–70% and local recurrence rates in surgery-alone group were 19–34% (17,18,21). The significantly better relapse-free and overall survivals in our uracil–tegafur group may be attributable to a selection of stage III patients, a higher dosage of 600 mg per day, better compliance and better quality of surgery. In the meta-analysis, hazard reduction was more marked in early-stage disease (21). In contrast, our results show that a higher dosage may also be effective for advanced-stage disease.
We found that 1-year treatment with uracil–tegafur was safe and well tolerated. Grade 3 events occurred in 16.5% of the patients and consisted mainly of increases in bilirubin and aminotransferases. No grade 4 or grade 5 events were observed. Previous colon cancer adjuvant trials showed that the overall incidences of grade 3 or more events in patients treated with different regimens were 38% or more for fluorouracil plus folinic acid (26,27), 38% for uracil–tegafur plus folinic acid (27), 30% for capecitabine (26) and more than 41% for oxaliplatin with fluorouracil plus folinic acid (28). The most frequent events included neutropenia, diarrhea, vomiting and hand-foot syndrome. Therefore, the safety profile of uracil–tegafur compares favorably with those of the previous regimens. Consequently, 80% of our patients completed 1 year of treatment, including dose modification. A study using a therapy preference questionnaire demonstrated that, after having experienced both oral and intravenous fluorouracil regimens, most patients preferred an oral regimen (29). The most important reasons for their preference included the convenience of taking the medication at home, less stomatitis and diarrhea, and preference of pills over injections (29). In addition, we should mention that uracil–tegafur is less expensive than the other regimens in this country, where medical costs are becoming an increasingly important issue.
Thus the most significant findings of our trial can be summarized as follows. Peroral monotherapy using uracil–tegafur achieved survival prolongation of stage III rectal cancer patients, without an addition of any other active agents, including folinic acid. This makes it possible to provide less toxic, yet effective, and convenient adjuvant chemotherapy for such patients.
However, several issues may limit the wider applicability of our findings. The numbers of patients recruited were smaller than those of recent rectal cancer adjuvant trials (6,7), although our trial was aimed solely at stage III tumor. The median follow-up time of our study was only 3 years, though disease-free survival with 3-year follow-up is suggested to be an appropriate primary endpoint to replace overall survival with 5-year follow-up (30). We used mesorectal excision with selective lateral pelvic lymphadenectomy that is a standard treatment only in Japan, and did not use mesorectal excision with radiotherapy, a world-standard combination. We could not use fluorouracil plus folinic acid, a standard adjuvant chemotherapy for stage III colon cancer, and neither the recently reported effective regimens including capecitabine and oxaliplatin (26–28). While the standard adjuvant chemotherapy course for colorectal cancer is 6 months (26–28), we opted for chemotherapy of 1 year. Therefore, the appropriateness of our approach should be tested further through comparison with recent standard adjuvant radiotherapy and chemotherapy.
In conclusion, radiotherapy has been considered to be standard adjuvant therapy worldwide for stage III rectal cancer. The present study indicates that uracil–tegafur treatment improves relapse-free survival and overall survival after mesorectal excision with selective lateral pelvic lymphadenectomy. This approach may become one of the treatment options for stage III rectal cancer and may deserve comparison with other treatment approaches.
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Members of the National Surgical Adjuvant Study of Colorectal Cancer |
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Study Chairpersons––S. Yoshida (National Cancer Center Hospital East, Chiba) and S. Kodaira (Teikyo University, Tokyo); Study coordinators––K. Shirao (National Cancer Center Hospital, Tokyo); Y. Shimada (National Cancer enter Hospital, Tokyo); Statistical Analyst––Y. Ohashi (The University of Tokyo, Tokyo); Evaluation Committee––Y. Moriya (National Cancer Center Hospital, Tokyo); S. Imaoka (Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka); T. Kato (Aichi Cancer Center Hospital, Aichi); S. Kodaira (Teikyo University, Tokyo); E. Ikeda (Yamagata Prefectural Central Hospital, Yamagata); T. Takahashi (Cancer Institute Hospital, Tokyo); Independent Data and Safety Monitoring Committee––N. Saijo (National Cancer Center Hospital East, Chiba); Y. Ariyoshi (Aichi Prefectural Hospital, Aichi); S. Ebihara (National Cancer Center Hospital East, Chiba); H. Origasa (Toyama Medical and Pharmaceutical University, Toyama); M. Fukuoka (Kinki University, Osaka); T. Mitsuishi (Mitsuishi Law & Patent Office, Tokyo); T. Tsuruo (The University of Tokyo, Tokyo); Participating Centers and Investigators––Keiyukai Sapporo Hospital, Hokkaido (M. Hosokawa); Sapporo Kosei General Hospital, Hokkaido (Y. Kondo); National Hospital Organization Sendai Medical Center, Miyagi (T. Saito); Miyagi Cancer Center, Miyagi (Y. Kamiyama, S. Goto); Yamagata Prefectural Central Hospital, Yamagata (E. Ikeda); Ibaraki Prefectural Central Hospital, Ibaraki (F. Yoshimi, Y. Miyata, M. Ohkuwa, H. Ohkura); Tochigi Cancer Center, Tochigi (K. Kotake); Gunma Prefectural Cancer Center, Gunma (S. Sakaue, M. Takahashi); National Cancer Center Hospital East, Chiba (M. Ono, M. Sugito); Cancer Institute Hospital, Tokyo (T. Takahashi, H. Ohta, M. Ueno); National Cancer Center Hospital, Tokyo (Y. Moriya, T. Akasu); International Medical Center of Japan, Tokyo (Y. Saito); Teikyo University Hospital, Tokyo (S. Kodaira, M. Adachi); Tokyo Metropolitan Komagome Hospital, Tokyo (T. Mori, K. Takahashi); Toranomon Hospital, Tokyo (M. Tsurumaru, T. Sawada); Social Insurance Central General Hospital, Tokyo (J. Iwadare); Kanagawa Cancer Center, Kanagawa (S. Takemiya); Niigata Cancer Center Hospital, Niigata (Y. Takii); Aichi Cancer Center Hospital, Aichi (T. Kato); Aichi Prefectural Hospital, Aichi (J. Sakamoto, H. Kojima); Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (S. Imaoka, M. Kameyama, K. Murata); National Hospital Organization Osaka National Hospital, Osaka (N. Kikkawa, I. Nishisho, H. Mishima); Hyogo Medical Center for Adults, Hyogo (S. Nakaya, K. Kawaguchi); Okayama Saiseikai General Hospital, Okayama (H. Kimura); Kagawa University Hospital, Kagawa (H. Usuki); National Hospital Organization Shikoku Cancer Center, Ehime (M. Tanada); National Hospital Organization Kyushu Cancer Center, Fukuoka (H. Tomoda, S. Kohnoe, T. Okamura); Kurume University Medical Center, Fukuoka (H. Isomoto).
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Acknowledgments |
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The authors are indebted to Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript. This study was supported by the Japan Health Sciences Foundation and by Taiho Pharmaceutical Company, Tokyo, Japan.
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Notes |
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* This work was presented at the 40th American Society of Clinical Oncology annual meeting, New Orleans, USA, June 5–8, 2004.
The investigators and institutions participating in the National Surgical Adjuvant Study of Colorectal Cancer are listed at end of report.
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References |
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