Carcinoid Tumor

A total of 154,900 men and women 55 to 74 years of age were enrolled from 1993 through 2001; they provided written informed consent and completed baseline questionnaires. The primary exclusion criteria were a history of prostate, lung, colorectal, or ovarian cancer; ongoing treatment for any type of cancer except basal-cell or squamous-cell skin cancer; and, beginning in 1995, assessment by means of a lower endoscopic procedure (flexible sigmoidoscopy, colonoscopy, or barium enema examination) in the previous 3 years. Further details, including data on recruitment through mass mailing, have been reported previously.^{15 (link),16 (link)} Randomization was performed in blocks stratified according to screening center, age, and sex. The study was sponsored by the National Cancer Institute. All the authors vouch for the accuracy of the data and the fidelity of the study to the protocol. The protocol and statistical analysis plan are available with the full text of this article at NEJM.org.
Participants in the intervention group were offered flexible sigmoidoscopy at baseline and at 3 years (for those who underwent randomization before April 1995) or at 5 years. Repeat screening in persons who received a diagnosis of colorectal cancer or adenoma after the initial screening was discouraged but did occur^{14 (link)} (see Fig. S1 in the Supplementary Appendix, available at NEJM.org). Physicians and nurse examiners followed standardized procedures for flexible sigmoidoscopic examinations. An examination was considered to be positive if a polyp or mass was detected. Biopsies were not routinely performed. Participants were referred to their primary care physicians for decisions regarding diagnostic follow-up. Medical records related to follow-up, a diagnosis of cancer, and cancer complications were collected.
Death from colorectal cancer was the primary end point. Secondary end points included colorectal-cancer incidence, cancer stage, survival, harms of screening, and all-cause mortality. All cancers and deaths were ascertained primarily by means of a mailed Annual Study Update questionnaire. Participants who did not return questionnaires were contacted by repeat mailing or telephone. Cancer incidence, stage, and location were verified from medical records.¹⁷ Information on vital status was supplemented by periodic linkage to the National Death Index. Deaths that were potentially related to prostate, lung, colorectal, or ovarian cancer were reviewed in a blinded fashion, in an end-point adjudication process.^{18 (link)} Colorectal-cancer deaths included deaths due to colorectal cancer and those due to its treatment. Carcinoid tumors were included as colorectal-cancer cases. Cancers located in the rectum through the splenic flexure were defined as distal, and those in the transverse colon through the cecum were defined as proximal. A screening-detected cancer was defined as a colorectal cancer diagnosed within 1 year after a positive flexible sigmoidoscopic examination.

The relationship between PCP visits and previous CRC screening was evaluated using multivariable logistic regression. Likewise, we used multivariable logistic regression models to examine the relationship between PCP visits and early-stage diagnosis, excluding persons with unknown stage (n=8049). Odds ratios of early-stage (0 or I) compared with late-stage (II, III, or IV) diagnosis and corresponding 95% CIs were calculated for each category of PCP visits compared with the reference group (0 or 1 visit). To determine whether PCP visits were associated with early-stage diagnosis beyond receipt of previous CRC screening, we fitted logistic models with and without previous CRC screening and examined changes in the estimated odds ratio for PCP visits.
We considered the following potential confounders in multivariable models: number of non-PCP visits, age at diagnosis, sex, race/ethnicity, marital status at diagnosis, census-derived measures of median household income (approximate quin-tiles within each registry), educational levels (approximate quintiles within each registry), metropolitan statistical area, SEER geographic registry (with indicator variables for each registry), Charlson comorbidity index^{29 (link)} (determined from both inpatient and outpatient physician claims), anatomic site (proximal vs distal lesions), and histologic cancer type (adenocarcinomas, including all subtypes, carcinoid tumors, and other). Medicare reimbursement of CRC screening occurred incre mentally, with no coverage from 1994 to 1997, limited coverage between 1998 and 2000 (FOBT yearly, flexible sigmoidos-copy every 4 years, and colonoscopy only for high-risk persons), and full coverage thereafter (colonoscopy every 10 years for all persons). We therefore created indicator variables corresponding to these 3 periods and included them in the models. To account for healthy behaviors in patients seeking more primary care,^{30 (link)} we added receipt of an influenza vacciation in the preceding 3 to 27 months as a proxy for healthy behavior.
We examined CRC-specific mortality and all-cause mortality among persons having invasive CRC (excluding 7732 in situ cancers).^{8 (link),28 (link)} The association between PCP visits and CRC mortality was analyzed using Cox proportional regression models, adjusting for potential confounding factors described in the preceding paragraph in addition to tumor characteristics to control for residual confounding within each stage. To determine whether associations between PCP visits and CRC mortality were primarily the result of previous CRC screening and an earlier stage at diagnosis, models were first performed without previous CRC screening, stage at diagnosis, and tumor characteristics and then repeated including previous CRC screening, stage at diagnosis, and tumor characteristics. Similar analyses were performed to examine the relationship between PCP visits and all-cause mortality. All analyses were performed using commercial software (SAS version 9.2; SAS Institute, Inc, Cary, North Carolina). Data are given as mean (SD) unless otherwise indicated.