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Cohort Analysis of Etiological Factors for Colorectal Cancer following Endoscopic Resection of Colorectal Tumors

HIDEKI ISHIKAWA,a,c KENICHIRO MITANI,a IKUKO AKEDO,a

KAZUSHIGE ISEKI,a TAKAICHIRO SUZUKI,a TATSUYA IOKA,a ITARU KAJI,b

HIROYUKI NARAHARA,b AND TORU OTANIb aDepartment of Cancer Epidemiology, Research Institute, and bDepartment of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

INTRODUCTION

In Japan, it is estimated that colorectal cancer is the second most commonly di-agnosed cancer in both men and women.1 Therefore we planned a randomized con-trolled trial (RCT) in a high-risk group of colorectal cancer to study preventivemethods against cancer and formulated a practical protocol.2 This protocol has beenin progress as scheduled for six years since its beginning. In this report, the protocolthat we formulated is explained, as is the cohort analysis of etiological factors forcolorectal cancer following endoscopic resection of colorectal tumors, usingcolonoscopy results at two years in our intervention trial subjects.

METHODS

The subjects are patients with multiple colorectal tumors, who are in a high-riskgroup for colorectal cancer. They are limited to those in whom two or more colorec-tal lesions have been diagnosed histologically by endoscopic examination to be car-cinoma or adenoma; all these tumors have been resected radically by endoscopicprocedures. They are 40–65 years of age; have no history of intestinal resection, ex-cept appendectomy; are presently free of malignant diseases; and have no seriouscomplications.

Two regimens were established for prevention of colorectal tumors based on di-etary guidance and regular intake of wheat bran (WB) biscuits. The first regimen(regimen I) is dietary guidance alone, and the second regimen (regimen II) consistsof dietary guidance and intake of WB biscuits. A regimen is assigned at random foreach week in advance. All patients who have received endoscopic treatment, havebeen examined by a doctor of our group, and have fulfilled the entry criteria are re-cruited. Consent to participate in the trial must be obtained by the patient’s free will,and the record of the consent is on a informed consent form.

cAddress for communication: Hideki Ishikawa, M.D., Department of Cancer Epidemiology,Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3-3, Nakamichi 1-chome, Higashinari-ku, Osaka 537-8511, Japan. Voice: +81-6-6972-1181; fax: +81-6-6981-3000.

e-mail: cancer@gol.com

245ISHIKAWA et al.: COHORT ANALYSIS

The core of the dietary guidance is to restrict energy intake from oil and fat to 18–22% of the total energy intake. The contents of meals for three consecutive days be-fore the examination are recorded on diet record forms, a nutritionist interviews thepatient on the basis of this record, and the total energy intake and the intake of fatand oil are estimated. For nutritional guidance, the patient is requested to visit thehospital with the family, and instructions about the intake of oil and fat are given in-dividually for about one hour by a nutritionist assigned exclusively to this project,using a “Pamphlet for Guidance of Oil and Fat Intake” prepared especially for thistrial. On a later day, the mean daily intake of each nutrient from the date of the di-etary investigation is calculated using a computer, and the results are returned bymail to the patients with comments by the nutritionist. Follow-up dietary investiga-tions are made after three months and one year to examine the effects of the dietaryguidance, and, if necessary, guidance is given again.

The WB biscuits that we developed have a wheat bran content of about 30% byweight. The patients are instructed to eat 25 g of WB biscuits (7.5 g as wheat bran)daily before each meal. The regimen is continued for four years.

The main end point of the trial is examination of the presence or absence, or re-currence of colorectal tumors. Colorectal endoscopy is performed two and four yearsafter the beginning of the regimen to examine for the recurrence of colorectal tu-mors. A video colonoscope system (Olympus EIVS 200), which shows real-time en-doscopic images on cathode ray tubes, so that two or more doctors can study theimages simultaneously, is used for the examination. Examination is always done bytwo or more doctors to detect new lesions. All lesions observed are biopsied and ex-amined histologically without the knowledge of which group the patient belongs to.The cell proliferation in ascending and sigmoid color biopsy specimens is also stud-ied by the immunohistochemical technique, and this examination is also done with-out the knowledge of which group the patient belongs to.

The tolerability of the biscuits is assessed by examining compliance through aquestionnaire. The compliance with the dietary guidance is evaluated according tothe percentage of oil and fat in the total energy intake at follow-up dietary investiga-tions three months and one year after the beginning of the regimen.

The target number of patients is 200, namely 100 for each group. How to estimatethe necessary number of subjects was as follows. We expect that the recurrence ratefor colorectal tumors that has been determined by endoscopic examination after twoyears in regimen I (dietary guidance alone) is 60%; the recurrence rate for colorectaltumors in regimen II (dietary guidance plus eating wheat bran biscuits) is 40 percent.To establish a significant difference in the number of subjects who have been recruit-ed between the two regimens, to fix for α error to be 5% and for β error to be 80%,97 patients are needed for each group. The necessary number of subjects is 100 foreach group.

This plan was approved by the Ethics Committee, Osaka Medical Center for Can-cer and Cardiovascular Diseases in March1993, and entry of subjects was started inJune 1993.

RESULTS

Recruiting of subjects was started in June 1993 and was finished in September1997; 100 (90%) of 115 patients recruited for regimen I and 100 (88%) of 116 pa-

246 ANNALS NEW YORK ACADEMY OF SCIENCES

tients recruited for regimen II consented to participate in the trial. No severe adverseeffects have been reported, and the trial is progressing well. The trial will be com-pleted in September 2001, when the four-year follow-up of the last patient will becomplete.

At the time of writing, 115 subjects are due for their two-year colonoscopy, ofwhom 113 (98%) have undergone examination of the entire colon. At the two-yearcolonoscopy, no colorectal tumor was seen in 42 subjects (37%), a single tumor wasfound in 37, two were found in 19, and three or more tumors were found in 15 cases.Two or more tumors were seen at two years in 28/99 (28%) of subjects without afamily history of colorectal cancer and in 6/14 (43%) with a positive family history;16/76 (21%) of subjects had five or fewer tumors before the time of entry; 18/37(49%) had six or more; 13/66 (20%) of subjects had tumor diameters no greater than9 mm; and 21/48 (44%) had tumors larger than 10 mm (TABLE 1). New tumors wereseen more frequently at two years in subjects with a large number of lesions initially,or those who had the largest tumor diameters.

REFERENCES

1. THE RESEARCH GROUP FOR POPULATION-BASED CANCER REGISTRATION IN JAPAN. 1998.Cancer Incidence in Japan in 1991: Estimates based on data from population-basedcancer registries. Jpn. J. Clin. Oncol. 28: 574–577.

2. ISHIKAWA, H., I. AKEDO, T. SUZUKI, T. OTANI & T. SOBUE. 1995. Interventional trialfor colorectal cancer prevention in Osaka: An introduction to the protocol. Jpn. J.Cancer Res. 86: 707–710.

TABLE 1. Characteristics at entry and two years after treatment

New Tumor at 2 Years Relative Risk

Characteristics 0 – 1 1< (95% confidence interval)Number of tumors2–5 60 (79%) 16 (21%) 2.315< 19 (51%) 18 (49%) (1.18–4.53)

Diameter of largest tumor (mm)1–9 53 (80%) 13 (20%) 2.2710< 27 (56%) 21 (44%) (1.14–4.53)

Family history of colorectal cancerAbsence 71 (32%) 28 (28%) 1.51Presence 8 (57%) 6 (43%) (0.63–3.66)

Body mass indexa

<24 45 (70%) 19 (30%) 1.0324 or 24< 34 (69%) 15 (31%) (0.52–2.03)

Smoking statusNonsmokers 39 (78%) 11 (22%) 1.68Current smokers 29 (63%) 17 (37%) (0.79–3.59)

aThe body mass index is weight in kilograms divided by the square of the height in meters.