Surveillance for Second Primary Colorectal Cancer after Adjuvant Chemotherapy: An Analysis of Intergroup 0089

Context Patients who have had colorectal cancer can develop second primary colorectal cancer. The American Cancer Society recommends that surveillance colonoscopy be performed 1 year after surgery, then every 3 to 5 years if results are negative. This surveillance strategy is unproven. Contribution This study documented an incidence rate of 274 cases of second primary colon cancer per 100 000 person-years after surgery with curative intent and 5-fluorouracil-based chemotherapy. The incidence of second cancer was higher than the incidence of first colorectal cancer in the general population, despite surveillance. Cautions This study suggests that surveillance may need to be more vigilant than currently recommended. However, more data are needed to decide how often to do surveillance colonoscopy. The Editors Colorectal cancer is a major public health problem, with more than 130 000 new cases thought to have occurred in the United States in 2001. Patients who have had colon cancer are at risk for second primary colon cancer, but the extent of this risk is unclear. The incidence and rate of development of second primary tumors have implications for appropriate surveillance of the colon after diagnosis of colorectal cancer. After first primary colon cancer is diagnosed, resection with curative intent is possible in approximately 75% of patients because the disease is limited to the bowel or to regional lymph nodes. The standard of care for patients with stage II or stage III disease is surgical resection, followed by adjuvant therapy for stage III disease. After surgery and adjuvant chemotherapy, patients frequently undergo some form of surveillance. Computed tomography of the abdomen, chest radiography, and measurement of carcinoembryonic antigen have been used to detect distant metastatic disease, although no convincing data show that these tests are cost-effective or improve survival (1). Colonoscopy or barium enema combined with flexible sigmoidoscopy has been used to survey for second primary colorectal cancer. Surveillance for second primary colorectal cancer serves two purposes: removal of premalignant polyps and early detection of malignancy. Most colorectal cancer is the product of slow, orderly progression from normal cells to malignancy. Surveillance with endoscopy and polypectomy has been shown to prevent colon cancer (2, 3). The most convincing data for this intervention come from the National Polyp Study, which found that in patients with adenomatous polyps, colonoscopic surveillance significantly decreased the incidence of colorectal carcinoma (3). The National Polyp Study also examined the question of how frequently to perform colonoscopic surveillance by comparing two surveillance strategies in patients who had recently had adenomas removed by colonoscopy (4). The study showed that repeated colonoscopy 3 years after colonoscopy and polypectomy in patients with adenomatous polyps was equivalent to more frequent surveillance. The authors conceded, however, that more frequent follow-up colonoscopy may be needed in patients with a history of colorectal cancer because they may have different biological characteristics and natural history. Current guidelines for surveillance of patients with a history of colon cancer are at least partially based on data from the National Polyp Study. The American Gastroenterological Association and the American Cancer Society recommend complete examination of the colon within 1 year of resection; if findings on this or on complete preoperative examination are normal, examination should be repeated in 3 years and then, if findings are again normal, every 5 years (5). In addition to finding new second primary tumors, surveillance within 1 year of colon cancer surgery may detect previously undetected polyps or synchronous tumors. Recent recommendations from the American Society of Clinical Oncology call for perioperative colonoscopy followed by colonoscopy every 3 to 5 years (1). However, deciding whether to extrapolate surveillance recommendations for patients with polyps to patients with a history of colon cancer requires a better understanding of the absolute and relative risk for second colorectal cancer in such patients. In the general population, the best estimates of the risk ratio for second primary colorectal cancer compared with first primary colorectal cancer have ranged from 1.5 to 3.0 (6, 7). The studies that have addressed this issue have had several deficiencies: incomplete follow-up, incomplete reporting of new cases, reporting of cumulative incidence rates (which do not consider length of follow-up), unknown surveillance practices in the study sample, arbitrary time cutoffs to distinguish new metachronous primary cancer from missed synchronous cancer, and heterogeneous patient samples (6-11). Thus, we do not know enough about the incidence of second primary colorectal cancer in patients with a history of colon cancer to devise optimal surveillance strategies. The purpose of our study was to estimate the incidence of second primary colon cancer in patients with a history of high-risk stage II or stage III colon cancer and to compare this incidence with that of first primary colon cancer in the general population and the National Polyp Study. Methods Patients Our study is a historical cohort analysis of patients who entered a trial of adjuvant therapy after surgery for colon cancer. This trial was designated Intergroup 0089 by the U.S. National Cancer Institute (12) and was approved by the Institutional Review Board of the University of Pennsylvania, Philadelphia, Pennsylvania. Patients with high-risk stage II or stage III cancer were randomly assigned to one of four 5-fluorouracil-based treatments. Patients were enrolled at 683 institutions, 73% of which were community-based medical centers. Surveillance guidelines for patients in the study included mandatory surveillance of the entire colon with colonoscopy or barium enema and flexible sigmoidoscopy at diagnosis, within 6 months of surgery, at 12 months, at 18 months, and then annually. At the discretion of each patient's physician, surveillance could be done less frequently (every 18 to 24 months after the 6-month surveillance). Data Collection Patients were required to visit the treating oncologist at least every 3 months during the first year of the study and then every 6 months for 4 years. After 5 years, follow-up materials were collected annually until death. At each visit, data forms that included information on surveillance and documentation of second primary colorectal cancer were completed. Data on the diagnostic procedures used to diagnose the original colon cancer and on whether the entire colon was visualized at diagnosis were not always available, since these were not primary objectives of the protocol. Original data collection and statistical analysis were done by the Eastern Cooperative Oncology Group. Reference Groups We compared the observed incidence rate of second primary colorectal cancer in Intergroup 0089 with the rates of first primary colorectal cancer expected in two reference groups. The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute monitors the incidence of colorectal cancer in 10 statewide registries (13). These data are routinely used as a surrogate for the average risk for colorectal cancer throughout the United States. We used age-, sex-, and ethnicity-specific rates for calendar years 1989 to 1993 since this period corresponded to the time during which patients were enrolled in Intergroup 0089. The National Polyp Study was a prospective study of 1418 patients who were referred for colonoscopy, during which one or more adenomas of the colon or rectum were removed (3, 4). The patients subsequently underwent periodic colonoscopy (randomly assigned to either years 1 and 3 or year 3 only) during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with rates in three reference groups: two populations of patients with adenomatous polyps who did not have all polyps removed, and the SEER program. Five cases of invasive colorectal cancer were detected in a total of 8401 person-years of follow-up. The National Polyp Study found that colonoscopy with polypectomy decreased the incidence of colon cancer by approximately 90% compared with the other populations of high-risk patients and by 76% compared with the SEER population. Statistical Analysis In Intergroup 0089, the number of person-years at risk was calculated for each patient from the time of study entry until death, diagnosis of second primary colon cancer, or the last known time at which the patient was alive. Median time to second cancer and survival plots were calculated by using the Kaplan-Meier method. Incidence rates were defined as the total number of events divided by the total person-years of follow-up; 95% CIs were calculated by assuming a Poisson distribution. Our study primarily analyzed the diagnosis of second primary colorectal cancer. We established criteria to distinguish second primary cancer from an anastomotic recurrence or metastases. A tumor was classified as a second primary tumor if it was pathologically described as arising from a preexisting polyp or was found at a site distant from the original primary tumor (not at the site of the anastomosis), without evidence of penetration from the serosa of the bowel. Only tumors discovered after the original resection were considered second primary tumors, and only invasive cancer was included. In situ tumors were excluded because they were not included in either of our comparison groups and because, given the lack of potential for metastatic spread, they are of less clinical relevance. In our primary analysis, we did not specify a minimum time interval between treatment of the original primary tumor and detection of a second prim