Japanese Journal of Clinical Oncology 33:288-296 (2003)
© 2003 Foundation for Promotion of Cancer Research
Results of a Randomized Trial with or without 5-FU-based Preoperative Chemotherapy followed by Postoperative Chemotherapy in Resected Colon and Rectal Carcinoma
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Background: Our previous study confirmed the efficacy of postoperative treatment with mitomycin C (MMC) and oral 5-fluorouracil (5-FU) for colorectal cancer. The 2nd trial was designed to evaluate the effectiveness of additional preoperative chemotherapy to postoperative treatment with MMC and oral 5-FU for curatively resected colorectal cancer patients.
Patients and Methods: 1355 patients (colon 755; rectum 600) were enrolled in this study. The pre- and postoperative chemotherapy (PPC) group was treated preoperatively with 5-FU (320 mg/m2/day) by continuous intravenous infusion for 5 days beginning on day 6 before surgery and postoperatively with MMC (6 mg/m2) on days 7 and 14 and in months 2, 4 and 6, by bolus injection and oral 5-FU (200 mg/day) for 6 months. The postoperative chemotherapy (PC) group received postoperative chemotherapy only.
Results: In an intent-to-treat analysis, the 5-year survival rate in the PPC group and the PC group was 77.3% and 75.7% for colon cancer and 67.2% and 69.2% for rectal cancer, respectively. In a per-protocol analysis, the 5-year DFS rate in the PPC group and the PC group was 76.0% and 80.7% for colon cancer and 60.5% and 63.0% for rectal cancer, respectively, indicating no significant differences between the two groups. Adverse reactions were generally mild, confirming the safety of this preoperative chemotherapeutic regimen.
Conclusion: In the PC group, the 5-year survival rate was nearly identical with that seen in our earlier research using the same regimen, reaffirming the clinical effectiveness of postoperative MMC by protracted intravenous infusion and oral 5-FU. However, our findings did not support additional preoperative chemotherapy for curative resection in patients with colorectal cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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A number of randomized comparative studies have been performed in Japan to evaluate the effectiveness of postoperative chemotherapy in colorectal cancer (1). From 1984 through 1990, our group was among the first (2–4) to evaluate the effectiveness of postoperative chemotherapy. We selected patients who were scheduled to undergo a curative resection for colorectal cancer and then randomly allocated the patients into three groups: a group treated postoperatively with mitomycin C (MMC) by protracted intravenous infusion (6 mg/m2 x 5) + oral 5-FU (200 mg/day for 6 months), a group for whom this treatment was augmented by administration of MMC through the portal vein or intra-arterially during surgery and a group treated with surgery alone. Localized administration of MMC showed no clinically significant benefits, but statistical analysis confirmed the effectiveness of postoperative MMC by protracted intravenous infusion + oral 5-FU.
Preoperative chemotherapy is sometimes performed with the hope of down-staging before undertaking surgical intervention into the vasculature or lymph ducts, to reduce the likelihood of tumor recurrence by decreasing the viability of the tumor cells or to act against hypothesized metastatic micro-lesions (5). In cancers that are highly sensitive to anticancer drugs, such as cancers of the head and neck and osteosarcoma, preoperative chemotherapy is widely used in a multidisciplinary approach to surgery for functional preservation (6,7).
Preoperative chemotherapy is thus being applied in a variety of treatment modalities to various forms of solid cancer. However, in colorectal cancer patients scheduled for curative resection, preoperative therapy is contraindicated if the toxicity associated with this treatment will lead to increased surgical time and/or a higher rate of postoperative complications. There is also a risk that the use of long-term preoperative therapy may result in a loss of the option for curative resection.
In this study, we implemented preoperative chemotherapy during the waiting period before surgery in order to evaluate the efficacy of preoperative chemotherapy. Since we had already evaluated the effectiveness of postoperative MMC and 5-FU in our earlier research, we used those findings to evaluate potential advantages of adding preoperative chemotherapy to postoperative MMC and 5-FU in comparison with postoperative chemotherapy only. We did this to provide a basis for comparison of the effectiveness of additional preoperative chemotherapy and also to confirm the reproducibility of our earlier clinical study.
Before beginning this research, we performed a pilot study to confirm the safety of a preoperative chemotherapeutic regimen. Based on the results of the phase I study published by Lokich et al. (8) using 5-FU by continuous intravenous infusion (CIV), we established a preoperative chemotherapy schedule of 5-FU (320 mg/m2) CIV for 3–7 days or 5-FU (320 mg/m2) IV for 5 days (unpublished data). We found that 5-FU CIV for 5 days had a slight histological response and still maintained effective antineoplastic drug levels in the tumor and blood, so we adopted this regimen for the preoperative chemotherapy used in this study.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Eligibility
To be eligible for this study, a patient preoperatively had to meet the following criteria: a histologically proven colorectal cancer; a suitable candidate for surgery; no evidence of distant metastasis; tumor depth of at least SS (subserosal, tumor invasion through the muscularis propria into the subserosa) or A1 (tumor invasion into the muscularis propria without further penetration) or diagnostic imaging showing lymphatic metastasis; a curatively resectable tumor; age <70 years; no prior cancer; no double or multiple cancer present; laboratory test values generally within the range of WBC count
4000/µl, Hb 11.0 g/dl, PLT 100 000/µl, AST 
40 U and ALT 40 U, BUN 25 mg/dl and negative urinary protein; performance status of 0–1; no serious complications such as heart disease, hepatopathy, nephropathy, myelosuppression, infection, varicella, gastric ulcers or bleeding; patient not pregnant or potentially pregnant; at least 5 days remaining before the scheduled date of surgery; and informed consent obtained from the patient (or patient’s family). Patients were considered ineligible after enrollment if the histological findings after surgery were non-cancerous; double or multiple cancer was discovered within 6 months after surgery; or the case review committee judged that for some other reason the patient was not suitable for analysis.
Data on the patients who met the above criteria were analyzed by intent-to-treat. They were further analyzed by per-protocol analysis unless the disease was found to be Duke’s stage A after surgery; macroscopic or histological findings indicated that the tumor was non-resectable; or the patient died within 1 month after surgery.
All surgical and histopathological findings were described in accordance with the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (4th Edition) (9).
Stratification and Randomization
Patients who met the criteria for eligibility were enrolled with the central registry. The patient pool was stratified according to cancer site (colon or rectum) and preoperative carcinoembryonic antigen (CEA) level. The enrolled patients were then randomly allocated to receive either pre- and postoperative chemotherapy (PPC) or postoperative chemotherapy (PC) only. Patients were enrolled ~1 week before surgery.
Regimen
The PPC group was treated preoperatively with 5-FU (320 mg/m2/day) for 5 days CIV and postoperatively with bolus MMC (6 mg/m2) on days 7 and 14 and in months 2, 4 and 6, in conjunction with 6 months of oral 5-FU 200 mg/day beginning 14 days after surgery. The schedule called for preoperative 5-FU CIV administration to be completed on the day before surgery. The PC group received the same postoperative treatment, but the preoperative chemotherapy was omitted.
The dose was reduced or treatment suspended or discontinued on the judgment of the attending physician in the event of serious adverse drug reactions or complications. Use of any other drugs or agents with anticancer action, including anticancer drugs, radiation therapy and immunopotentiating agents, was not permitted, but the use of drugs for symptomatic treatment or for treatment following cancer recurrence was at the discretion of the attending physician.
Treatment Evaluation and Follow-up
The primary endpoint of this study was 5 year survival. Secondary endpoints were the 5-year disease-free survival rate (DFS) and adverse reactions. The evaluation of adverse drug reactions was based on published criteria from the Japan Society for Cancer Therapy (10,11).
Follow-up testing was performed yearly for 5 years after surgery in all patients. The primary laboratory tests were performed before surgery and at 2 and 4 weeks and 2, 3, 4 and 6 months after surgery. CEA was measured before enrollment and at 1 month intervals after surgery or each time the patient came to the hospital. The CEA cutoff line was the cutoff value for the method used at the relevant institution. Values below the cutoff line were defined as ‘CEA low’ and values above the cutoff line as ‘CEA high’.
Sample Size
The results of our earlier study showed a 5-year DFS of 64.6% in the chemotherapy group for Duke’s stage C colon cancer and rectal cancer patients. Calculations based on the Gehan table (12) indicated that the current study would require 260 patients (Duke’s stage C, 65%; 
= 0.05, ß = 0.20; detection of 10% difference).
Because it can be difficult to distinguish Duke’s stage B and C cancers preoperatively, we allowed both Duke’s stage B and C patients to be eligible for enrollment. Based on the above figures and assuming a 1:1 ratio of Duke’s stage B and C patients and an estimation that 10% of patients would be excluded from analysis, we calculated that 1144 patients would be required for this study.
Statistical Analysis
We used the 
2-test, the U-test and Student’s t-test to check for bias in patients’ characteristics. The Kaplan–Meier method was applied to calculations of survival (13). The overall survival rate was analyzed both on the basis of intent-to-treat (ITT) and per-protocol (PP). The disease-free survival rate was analyzed on the basis of PP. The log-rank test and the generalized Wilcoxon (g-Wilcoxon) test were applied to the duration of survival and disease-free survival. A level of significance was set at P < 0.05 (two-sided test). The statistical software used was the SAS System for Windows, Release 6.12 (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Patient Classification and Characteristics
A total of 1355 patients from 205 institutions across Japan were enrolled between February 1991 and December 1992. There were 755 cases of colon cancer (PPC 379; PC 376) and 600 cases of rectal cancer (PPC 289; PC 311). ITT analysis was performed on 1277 patients. For colon cancer, 46 patients were ineligible for ITT analysis (non-cancerous lesion, 14; double or multiple cancer, 9; enrollment violations, 8; age violations, 4; other, 11), leaving 709 eligible patients (93.9%). For rectal cancer, 32 patients were ineligible for ITT analysis (noncancerous lesion, 5; double or multiple cancer, 8; enrollment violations, 7; age violations, 5; other, 7), leaving 568 eligible patients (94.7%). PP analysis was performed on 937 patients. Of the patients included in the ITT analysis set for colon cancer, an additional 44 cases in which the tumor site classification at enrollment did not agree with the surgical findings and 135 cases who were ineligible for PP analysis (Duke’s stage A, 60; non-curative resection, 73; death, 2) were excluded, leaving 530 eligible patients (70.2%). Of the patients included in the ITT analysis set for rectal cancer, an additional 12 cases in which the tumor site classification at enrollment did not agree with the surgical findings and 149 cases who were ineligible for PP analysis (Duke’s stage A, 91; noncurative resection, 57; death, 1) were excluded, leaving 407 eligible patients (67.8%). The 5-year follow-up rate was 96.8% (1312/1355), with 43 patients lost to follow-up.
Table 1 summarizes the patients’ characteristics for the ITT analysis set. For colon cancer, bias was noted between the two groups with regard to both gross curability and histological typing (P < 0.05). No bias was noted with regard to any other patient characteristic. In the rectal cancer group, no significant bias was observed between the two groups.
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Five-year Survival
ITT analysis showed 5-year survival rates for colon cancer 77.3% in the PPC group and 75.7% in the PC group and for rectal cancer 67.2% and 69.2%, respectively, indicating no significant difference between the two treatment groups for either disease (Fig. 1). The ITT analysis set showed a significantly greater number of cases of non-curative resection among colon cancer patients in the PC group (P < 0.05), but even after adjusting for this factor, there was no significant difference in the 5-year survival rate.
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PP analysis showed 5-year survival rates for colon cancer 82.0% in the PPC group and 83.9% in the PC group and for rectal cancer 66.8% and 72.8%, respectively, again with no significant difference between the groups for either treatment regimen or disease. Results of the 5-year survival rate were nearly identical for ITT analysis and PP analysis.
Five-year DFS and Recurrence
PP analysis showed 5-year DFS for colon cancer 76.0% in the PPC group and 80.7% in the PC group and for rectal cancer 60.5% and 63.0%, respectively (Fig. 2), indicating no significant differences. Recurrent disease during the 5 years after surgery was confirmed for colon cancer in 72 patients in the PPC group and 59 patients in the PC group and for rectal cancer in 93 and 106 patients, respectively. Initial recurrence most commonly involved the liver in colon cancer (PPC 9.5%, PC 9.4%), followed by the lungs (PPC 6.4%, PC 4.1%). Local recurrence was more common in rectal cancer (PPC 13.3%, PC 16.4%), with a similar incidence of metastasis to the liver and lungs (PPC 12.8%, PC 11.0%). No bias was noted between the two groups regarding the incidence of these recurrences.
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Treatment Compliance
The 5-FU CIV treatment completion rate in the PPC group was high for patients with both colon cancer (97.0%) and rectal cancer (96.8%). The MMC completion rate for colon cancer was 75.8% in the PPC group and 67.3% in the PC group and for rectal cancer 72.3% and 71.2%, respectively. Full compliance (80% or better) of oral 5-FU was achieved in 81.8% of colon cancer patients in the PPC group and 84.6% in the PC group and in 84.6% of rectal cancer patients in the PPC group and 81.8% in the PC group. No statistically significant difference in postoperative chemotherapy compliance was noted between the two groups.
Adverse Reactions
Five out of 1355 enrolled patients (0.36%) died within one postoperative month and two of the dead patients were assessed as absolutely non-curative resection. All these five patients were analyzed by ITT. Three of them in the PC group all completed preoperative chemotherapy without adverse reactions, etc.
Table 2 shows a comparison of adverse reactions based on PP analysis between the PPC group and the PC group. The most common of these was leukopenia, which occurred at grade 2 or above in 24.1% (105/435) of the PPC group and 19.6% (90/460) of the PC group. Grade 4 adverse drug reactions developed in two patients in the PPC group (one case of thrombocytopenia and one case of diarrhea), but were ameliorated by withdrawal of treatment. No significant differences in the incidence of adverse drug reactions, including grade 4 reactions, were noted between these groups.
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The incidence of postoperative complications was 8.6% (39/452) in the PPC group and 8.0% (39/485) in the PC group. Of these, postoperative complications requiring treatment (grade G2 or above) occurred in 6.2% (28/452) of patients in the PPC group and in 7.0% (34/485) of patients in the PC group. No statistically significant difference was noted between these treatment groups and no effects of preoperative chemotherapy on postoperative complications were noted.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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We performed a multicenter randomized comparative study enrolling 1355 patients from 205 hospitals across Japan. This was not only a large pool of patients but also a highly reliable institutional group, since over half of the participating institutions are major hospitals at the cutting edge of colorectal cancer treatment in Japan.
The selection of participating patients was difficult because of the necessity to make the selection before surgery on the basis of limited information. As a result, only 70.2% of colon cancer patients and 67.8% of rectal cancer patients were actually eligible for PP analysis. PP analysis showed a 5-year survival rate in the PC group (active control) of 83.9% in colon cancer patients and 72.8% in rectal cancer patients, almost identical with our earlier findings under the same treatment regimen (colon cancer 82.1%, rectal cancer 73.6%) (2–4). These results demonstrated the reproducibility of our findings regarding the clinical effectiveness of postoperative MMC and oral 5-FU.
However, this study failed to prove the efficacy of preoperative chemotherapy, which was its primary objective. Overall analysis showed no improvement in therapeutic effectiveness or in DFS as a result of preoperative chemotherapy in either colon cancer or rectal cancer patients. A study of preoperative chemotherapy with carmoful (an oral 5-FU prodrug) in patients scheduled for curative colorectal resection was being performed in Japan at about the same time as the present study. In that study, similarly to our results, preoperative chemotherapy produced no improvement in either overall survival or DFS (14).
It is possible that these negative results occurred because the dose used in this protocol was too low and that we should reconsider the protocol structure. However, it should be possible to obtain satisfactory effects even when using a low-intensity dose protocol if the protocol is applied only to patients who are highly sensitive to the relevant anticancer drug. A recent report suggests that it may be possible actually to predict 5-FU responders in advance by measuring the mRNA for 5-FU-metabolizing enzymes within the tumor (15).
We investigated histological effects of preoperative chemotherapy in patients from the Department of Surgery II and the Department of Gastrointestinal Surgery of Tokyo Women’s Medical University who were enrolled in the present study (chemotherapy group, n = 15; non-chemotherapy group, n = 16; data not shown). We found slight histological degeneration in the chemotherapy group, although there was no clear evidence of down-staging. It is possible that in pronounced cases of such histological degeneration, there might be additional life-prolonging effects from postoperative chemotherapy. When Fujii and colleagues treated patients scheduled for colorectal cancer resection with 600 mg of oral UFT (tegafur and uracil) for 10 days before surgery, they found that survival was improved by postoperative chemotherapy in those patients who showed a histological response to the preoperative treatment (16). Nakajima et al. reported an insignificant increase in the general survival rate among histological responders in comparison with non-responders (17). These reports involved small numbers of patients and scant evidence. However, it appears that although preoperative chemotherapy does not produce an obvious down-staging effect, this treatment may damage tumor tissue to some extent and thus contribute to the effectiveness of postoperative chemotherapy.
Our research group is now exploring the potential benefits of a protocol that combines 5-FU CIV treatment immediately after surgery with basic postoperative MMC by protracted intravenous infusion and oral 5-FU. Some patients are now in their third year after surgery and we are able to provide an interim report. Our findings to date indicate a significantly higher 3-year survival rate in the group treated immediately after surgery with 5-FU CIV than in the active control group treated only with postoperative MMC by protracted intravenous infusion and oral 5-FU (92.4% vs 81.6%, P = 0.023) and we hope that this protocol will contribute to extending survival in cancer patients (18).
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APPENDIX |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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Cooperative Study Group Investigators
First Department of Surgery, Sapporo Medical University, Sapporo, Hokkaido; Department of Surgery, Sapporo City General Hospital, Sapporo, Hokkaido; Department of Surgery, National Sapporo Hospital, Hokkaido Cancer Center, Sapporo, Hokkaido; Department of Surgery, Hakodate Municipal Hospital, Hakodate, Hokkaido; Department of Surgery, Asahikawa Kosei Hospital, Asahikawa, Hokkaido; First Department of Surgery, Tohoku University School of Medicine, Sendai, Miyagi; Department of Surgery, Tohoku Rosai Hospital, Sendai, Miyagi; Department of Surgery, Sendai National Hospital, Sendai, Miyagi; Department of Surgery, Tohoku Kosei-Nenkin Hospital, Sendai, Miyagi; Department of Surgery, Miyagi Cancer Center, Natori, Miyagi; Department of Surgery, Sendai Red Cross Hospital, Sendai, Miyagi; Department of Surgery I, Iwate Medical University, Morioka, Iwate; Department of Gastroenterological Surgery, Iwate Prefectural Central Hospital, Morioka, Iwate; First Department of Surgery, Yamagata University School of Medicine, Yamagata, Yamagata; Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Yamagata; Department of Surgery II, Fukushima Medical University School of Medicine, Fukushima, Fukushima; Department of Surgery, Iwaki Kyoritsu General Hospital, Iwaki, Fukushima; First Department of Surgery, Akita University School of Medicine, Akita, Akita; Second Department of Surgery, Hirosaki University School of Medicine, Hirosaki, Aomori; First Department of Surgery, Faculty of Medicine, The University of Tokyo, Hongo, Tokyo; Third Department of Surgery, Faculty of Medicine, The University of Tokyo, Hongo, Tokyo; First Department of Surgery, Juntendo University School of Medicine, Hongo, Tokyo; First Department of Surgery, Nippon Medical School, Sendagi, Tokyo; Second Department of Surgery, First Hospital of Nippon Medical School, Fujimi, Tokyo; Department of Surgery, Tokyo Metropolitan Police Hospital, Koutoubashi, Tokyo; Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Sumida, Tokyo; Department of Surgery, The Jikei University School of Medicine, Shinbashi, Tokyo; Department of Surgery, Aoto Hospital, The Jikei University School of Medicine, Aoto, Tokyo; Department of Surgery, Keio University School of Medicine, Shinjuku, Tokyo; Second Department of Surgery, Showa University School of Medicine, Shinagawa, Tokyo; Third Department of Surgery, Ohashi Hospital, Toho University School of Medicine, Meguro, Tokyo; First Department of Surgery, Omori Hospital, Toho University School of Medicine, Ohmori, Tokyo; Department of Gastroenterological Surgery, Toranomon Hospital, Toranomon, Tokyo; Department of Surgery, National Tokyo Medical Center, Meguro, Tokyo; Department of Surgery, National Okura Hospital, Setagaya, Tokyo; Third Department of Surgery, Nihon University School of Medicine, Itabashi, Tokyo; Department of Surgery, Nihon University School of Medicine, Surugadai Hospital, Kanda, Tokyo; Department of Surgery II, Tokyo Women’s Medical University, Shinjuku, Tokyo; Department of Gastroenterological Surgery, Tokyo Women’s Medical University, Shinjuku, Tokyo; Department of Surgery, Tokyo Women’s Medical University School of Medicine Daini Hospital, Arakawa, Tokyo; Department of Surgery, Tokyo Medical University, Shinjuku, Tokyo; 1st Department of Surgery, Teikyo University School of Medicine, Itabashi, Tokyo; 2nd Department of Surgery, Teikyo University School of Medicine, Itabashi, Tokyo; Coloproctology Center, Social Insurance Central General Hospital, Shinjuku, Tokyo; Department of Gastroenterological Surgery, Japanese Foundation for Cancer Research, Ikebukuro, Tokyo; First Department of Surgery, Kyorin University School of Medicine, Mitaka, Tokyo; Department of Surgery, Daisan Hospital, The Jikei University School of Medicine, Komae, Tokyo; Department of Surgery, Tokyo Metropolitan Fuchu General Hospital, Fuchu, Tokyo; Department of Gastroenterological Surgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo; Second Department of Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa; Department of Surgery, Yokosuka Kyosai General Hospital, Yokosuka, Kanagawa; Department of Surgery, Yokohama General Hospital, Yokohama, Kanagawa; Department of Surgery, Showa University Fujigaoka Hospital, Yokohama, Kanagawa; Center for Digestive Diseases, Second Affiliated Hospital of Nippon Medical School, Kawasaki, Kanagawa; First Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa; Second Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa; Department of Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa; Department of Surgery, Kanto Rosai Hospital, Kawasaki, Kanagawa; Department of Surgery, Teikyo University School of Medicine, Mizonokuchi Hospital, Kawasaki, Kanagawa; Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kawasaki; Department of Surgery, Tokai University School of Medicine, Sagamihara, Kanagawa; Department of Surgery, Tokai University School of Medicine, Isehara, Kanagawa; Department of Surgery, Odawara Municipal Hospital, Odawara, Kanagawa; Department of Surgery, National Sagamihara Hospital, Sagamihara, Kanagawa; Department of Surgery, Hiratsuka City Hospital, Hiratsuka, Kanagawa; Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama; First Department of Surgery, Saitama Medical School, Iruma, Saitama; Department of Surgery, Saitama Medical Center, Kawagoe, Saitama; Department of Surgery, Saiseikai Kawaguchi General Hospital, Kawaguchi, Saitama; Department of Surgery, Social Insurance Saitama Chuo Hospital, Urawa, Saitama; Department of Surgery, Kasukabe Municipal Hospital, Yono, Saitama; Department of Surgery, Omiya Red Cross Hospital, Yono, Saitama; Department of Surgery, Dokkyo University School of Medicine, Koshigaya Hospital, Koshigaya, Saitama; Department of Abdominal Surgery, Saitama Cancer Center, Kita-adachi, Saitama; First Department of Surgery, School of Medicine, Chiba University, Chiba, Chiba; Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba, Chiba; Department of Surgery, Matsudo Municipal Hospital, Matsudo, Chiba; Department of Surgery, Kashiwa Hospital, The Jikei University School of Medicine, Kashiwa, Chiba; Department of Surgery, Juntendo University Urayasu Hospital, Urayasu, Chiba; First Department of Surgery, Yamanashi Medical University, Tamaho, Yamanashi; Department of Surgery, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi; Department of Surgery, Nagano Red Cross Hospital, Nagano, Nagano; Department of Surgery, Kofu Municipal Hospital, Kofu, Yamanashi; Department of Surgery, Okaya Municipal Hospital, Okaya, Nagano; Department of Surgery, National Kofu Hospital, Kofu, Yamanashi; First Department of Surgery, Niigata University School of Medicine, Niigata, Niigata; Department of Surgery, Niigata City General Hospital, Niigata, Niigata; Department of Surgery, Koseiren Nagaoka Chuo General Hospital, Nagaoka, Niigata; Department of Surgery, Ojiya General Hospital, Ojiya, Niigata; Department of Gastroenterological Surgery, Saiseikai Niigata Dai-ni Hospital, Kurosaki, Niigata; Department of Surgery, Tachikawa General Hospital, Nagaoka, Niigata; Department of Surgery, Niigata Rinko General Hospital, Niigata, Niigata; Department of Surgery, Mito National Hospital, Mito, Ibaraki; Department of Surgery, Mito Saiseikai General Hospital, Mito, Ibaraki; First Department of Surgery, Gunma University School of Medicine, Maebashi, Gunma; Department of Surgery, Takasaki National Hospital, Takasaki, Gunma; Department of Surgery, Kiryu Kousei General Hospital, Kiryu, Gunma; Department of Surgery, Isesaki Municipal Hospital, Isesaki, Gunma; Department of Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma; Department of Surgery, Isesaki Sawa Isikai Hospital, Isesaki, Gunma; Department of Gastroenterological and General Surgery, Jichi Medical School, Kawachi, Tochigi; First Department of Surgery, Dokkyo University School of Medicine, Mibu, Tochigi; Department of Surgery, Tochigi National Hospital, Utsunomiya, Tochigi; Department of Surgery, Ashikaga Red Cross Hospital, Ashikaga, Tochigi; Department of Surgery, Tochigi Cancer Center, Utsunomiya, Tochigi; Department of Surgery, Sano Kosei General Hospital, Sano, Tochigi; Department of Surgery II, Nagoya University School of Medicine, Department of Surgery II, Nagoya, Aichi; First Department of Surgery, Aichi Medical University, Nagakute, Aichi; Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Aichi; Department of Surgery, Red Cross Nagoya First Hospital, Nagoya, Aichi; Department of Surgery, Nagoya National Hospital, Nagoya, Aichi; Department of Surgery, Nagoya Ekisaikai Hospital, Nagoya, Aichi; Department of Surgery, Fujita Health University 2nd Teaching Hospital, Nagoya, Aichi; Department of Surgery, Fujita Health University School of Medicine, Toyoake, Aichi; Department of Surgery, Okazaki City Hospital, Okazaki, Aichi; Department of Surgery, Toyokawa City Hospital, Toyokawa, Aichi; Department of Surgery, Kariya General Hospital, Kariya, Aichi; First Department of Surgery, Gifu University School of Medicine, Gifu, Gifu; Second Department of Surgery, Gifu University School of Medicine, Gifu, Gifu; Department of Surgery, Ogaki Municipal Hospital, Ogaki, Gifu; Second Department of Surgery, Faculty of Medicine, Mie University, Tsu, Mie; Department of Surgery, Keio University School of Medicine, Ise, Mie; Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka; Department of Surgery, Shizuoka Red Cross Hospital, Shizuoka, Shizuoka; Department of Surgery, Hamamatsu Medical Center, Hamamatsu, Shizuoka; Department of Surgery, Seirei-Mikatabara General Hospital, Hamamatsu, Shizuoka; Department of Surgery II, Osaka University Medical School, Suita, Osaka; First Department of Surgery, Osaka City University Medical School, Abeno, Osaka; Department of Surgery, Osaka Kosei-Nenkin Hospital, Fukushima, Osaka; Department of Surgery, Osaka Red Cross Hospital, Tennoji, Osaka; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari, Osaka; Department of Surgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Osaka; Department of Surgery, Osaka National Hospital, Osaka, Osaka; Department of Surgery, Otemae Hospital, Osaka, Osaka; Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka; Second Department of Surgery, Kansai Medical University, Moriguchi, Osaka; Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka; Department of Surgery, Hoshigaoka Koseinenkin Hospital, Hirakata, Osaka; Department of Surgical Oncology, Osaka University Medical School, Suita, Osaka; Surgery I, Kinki University, Osaka-sayama, Osaka; Department of Surgery, Osaka Rosai Hospital, Sakai, Osaka; Department of Surgery, Sakai Municipal Hospital, Sakai, Osaka; Department of Surgery, Izumi Municipal Hospital, Izumi, Osaka; First Department of Surgery, Kobe University School of Medicine, Kobe, Hyogo; Second Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo; Department of Surgery, Kobe West City Hospital, Kobe, Hyogo; Department of Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo; Department of Surgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyogo; Department of Surgery, Nishinomiya Municipal Central Hospital, Nishinomiya, Hyogo; First Department of Surgery, Nara Medical University, Kashihara, Nara; Department of Abdomino-general Surgery, Tenri Hospital, Tenri, Nara; Department of Surgery, Nara National Hospital, Nara, Nara; Department of Surgery, Saiseikai Chuwa Hospital, Sakurai, Nara; Department of Surgery, Nara Prefectural Mimuro Hospital, Ikoma, Nara; Department of Surgery, Dongo Hospital, Yamato-takada, Nara; First Department of Surgery, Shiga University of Medical Science, Otsu, Shiga; First Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto; Second Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto; Department of Surgery & Surgical Basic Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto; Department of Surgery, Kyoto First Red Cross Hospital, Higashiyama, Kyoto; Department of General & Gastrointestinal Surgery, Kanazawa Medical University, Kahoku, Ishikawa; Department of Surgery, Kanazawa National Hospital, Kanazawa, Ishikawa; Department of General Gastroenterological Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa; The Second Department of Surgery, Toyama Medical and Pharmaceutical University Faculty of Medicine, Toyama, Toyama; Department of Surgery, Koseiren Takaoka Hospital, Takaoka, Toyama; Department of Surgery II, Hiroshima University, Faculty of Medicine, Hiroshima, Hiroshima; Department of Surgery, Saiseikai Hiroshima Hospital, Aki, Hiroshima; Department of Surgery, Hiroshima Prefectural Akitsu Hospital, Toyoda, Hiroshima; Department of Surgery, Hiroshima City Hospital, Nakaku, Hiroshima; Department of Surgery, Kure National Hospital, Kure, Hiroshima; Department of Surgery, Fukuyama National Hospital, Fukuyama, Hiroshima; First Department of Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi; Second Department of Surgery, Yamaguchi University, School of Medicine, Ube, Yamaguchi; First Department of Surgery, Okayama University Medical School, Okayama, Okayama; Second Department of Surgery, Okayama University Medical School, Okayama, Okayama; Department of Gastroenterological Surgery, Kawasaki Medical School, Kurashiki, Okayama; Department of Surgery, Okayama Saiseikai General Hospital, Okayama, Okayama; Department of Surgery, Kurashiki Central Hospital, Kurashiki, Okayama; Department of Surgery, Yonago National Hospital, Yonago, Tottori; Department of Surgery, National Shikoku Cancer Center, Matsuyama, Ehime; Department of Surgery, Matsuyama Simin Hospital, Matsuyama, Ehime; Department of Surgery, Saiseikai Imabari Hospital, Imabari, Ehime; Department of Surgery, Jyuzen General Hospital, Niihama, Ehime; First Department of Surgery, Kochi Medical School, Nankoku, Kochi; First Department of Surgery, School of Medicine, The University of Tokushima, Tokushima, Tokushima; Second Department of Surgery, School of Medicine, The University of Tokushima, Tokushima, Tokushima; First Department of Surgery, Kagawa Medical School, Kitagun, Kagawa; Department of Surgery, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa; Second Department of Surgery, Faculty of Medicine, Kyushu University, Fukuoka, Fukuoka; Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka; Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka, Fukuoka; Department of Surgery, Saga Medical School, Saga, Saga; First Department of Surgery, Nagasaki University, School of Medicine, Nagasaki, Nagasaki; Second Department of Surgery, Nagasaki University School of Medicine, Nagasaki, Nagasaki; Department of Surgery, Nagasaki Municipal Hospital, Nagasaki, Nagasaki; Department of Surgery, Sasebo City General Hospital, Sasebo, Nagasaki; Second Department of Surgery, Kumamoto University Medical School, Kumamoto, Kumamoto; Department of Surgery, Minamata City General Hospital & Medical Center, Minamata, Kumamoto; Department of Surgery II, Oita Medical University, Oita, Oita; Department of Surgery, Oita Prefectural Hospital, Oita, Oita; First Department of Surgery, Miyazaki Medical College, Miyazaki, Miyazaki; Department of Surgery, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Miyazaki; First Department of Surgery, Faculty of Medicine, Kagoshima University, Kagoshima, Kagoshima; Department of Surgery, Kagoshima City Hospital, Kagoshima, Kagoshima; First Department of Surgery, Faculty of Medicine, University of Ryukyus, Nishihara, Okinawa.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGMENTSREFERENCES |
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We thank the following doctors who contributed in the study: Main Adviser, Shuji Tsuchiya, MD, Emeritus Professor, Yokohama City University, School of Medicine, Kanazawa-Fukuura, Kanagawa; Representation Consultants, Kyoichi Hamano, MD, PhD, Emeritus Professor of Tokyo Women’s Medical University, Shinjuku, Tokyo; Masayuki Yasutomi, MD, PhD, Dean of Medical Department of Kinki University, Osaka-Sayama, Osaka; Consultants: the late Takashi Sakabe, MD, Emeritus Professor of Japan University, Itabashi, Tokyo; Yasuo Koyama, MD, Director of Tochigi Cancer Center, Utsunomiya, Tochigi; Takashi Takahashi, MD, Vice-President of Chiba Medical and Life Science General Hospital, Choshi, Chiba; Susumu Kodaira, MD, Professor of Department of Surgery, Teikyo University School of Medicine, Itabashi, Tokyo; Tetsuichiro Muto, MD, PhD, Director of Cancer Institute of Hospital, Japanese Foundation for Cancer Research, Ikebukuro, Tokyo; Tomoyuki Kato, MD, Vice Director and Head of Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi; Reviewer, Ken Tominaga, MD, Professor and Director of Breast Cancer Center, Toyosu Hospital, Showa University School of Medicine, Toyosu, Tokyo; Controller of this Trial, Nobuya Ogawa, MD, PhD, Emeritus Professor of Ehime University, Matsuyama, Ehime; Data Manager, Shin Akimoto, MD, Vice Director of Yokohama General Hospital, Yokohama, Kanagawa; Compliance Analysis, Toshihiko Uematsu, Professor of Department of Pharmacology, Gifu University School of Medicine, Gifu; Masashi Fujii, MD, Associate Professor of Third Department of Surgery, Nihon University School of Medicine, Itabashi, Tokyo.
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FOOTNOTES |
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+ For participating physicians and institutions, see Appendix.
For reprints and all correspondence: Shingo Kameoka, Department of Surgery II, Tokyo Women’s Medical University, 8–1 Kawada-chou, Sinjyuku-ku, Tokyo 162-0054, Japan.
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REFERENCES |
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Received October 7, 2002; accepted May 7, 2003
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