for the PLCO Project Team
Affiliations of authors: University of Pittsburgh Cancer Institute, Pittsburgh, PA (JLW, RES); Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (PFP, PCP, JKG); Henry Ford Hospital, Detroit, MI (RSB); University of Minnesota, Minneapolis, MN (TC); Westat, Rockville, MD (SY); Information Management Services, Inc., Rockville, MD (JHA)
Correspondence to: Joel L. Weissfeld, MD, MPH, UPMC Cancer Pavilion (POB II), 3rd Floor Centre Medical Building, 5150 Centre Avenue, Pittsburgh, PA 15232 (e-mail: jwepid{at}pitt.edu).
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ABSTRACT |
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INTRODUCTION |
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The PLCO is evaluating the effect of screening 60-cm flexible sigmoidoscopy on colorectal cancer mortality when performed once and then repeated 35 years later. The PLCO trial implemented flexible sigmoidoscopy screening in a manner different from that of the European trials. Biopsies are not part of the PLCO screening protocol; instead, subjects with screen-detected abnormalities are referred to personal physicians for diagnostic follow-up.
Clinical findings for screening flexible sigmoidoscopy have already been reported for the European trials (79). Given the size and unique characteristics (e.g., geographically diverse study population, numerous flexible sigmoidoscopy examiners recruited from various clinical backgrounds, and diagnostic follow-up managed by community-based practitioners working in non-research clinical settings) of the PLCO trial, it is capable of approximating the results that could be expected from a screening flexible sigmoidoscopy intervention targeting the general U.S. population. In this study, we report clinical results from the initial PLCO screening flexible sigmoidoscopy examination.
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SUBJECTS AND METHODS |
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Trial Subjects
Beginning in November 1993 and ending in July 2001, the PLCO trial enrolled men and women 5574 years of age who had no prior history of prostate, lung, colorectal, or ovarian cancer. Criteria for exclusion included current treatment for cancer (other than basal cell and squamous cell skin cancer); prior total colectomy, pneumonectomy, prostatectomy, or bilateral oophorectomy (with bilateral oophorectomy dropped as an exclusion criterion beginning in 1996); participation in another cancer screening or primary prevention study; and recent use of finasteride (Proscar) or tamoxifen (Nolvadex). Beginning in April 1995, the PLCO trial excluded men who reported more than one serum PSA test and men and women who reported any lower gastrointestinal procedure (proctoscopy, sigmoidoscopy, barium enema, or colonoscopy) within 3 years before study enrollment.
The primary method for recruiting study subjects involved mailing informational brochures and letters of invitation to age-eligible individuals identified on public, commercial, or screening center-specific mailing lists. Three screening centers initially used a dual consent procedure that was designed to limit, in the control group, knowledge about the screening tests being offered to the intervention group. Under the dual consent procedure, screening centers recruited subjects who agreed only to a baseline questionnaire and periodic contacts to determine morbidity and mortality endpoints. Random assignment of the subjects to either the control or intervention group then occurred without any other additional consent. After randomization, subjects assigned to the intervention group were asked to sign a second consent form that mentioned the screening procedures under investigation. Although three screening centers evaluated the dual consent procedure, all centers eventually abandoned this approach in favor of a single consent procedure, in which prior consent for both randomization into trial arms and cancer screening was obtained. Only one screening center recruited a meaningful number of subjects under the dual consent procedure. The study coordinating center managed the randomization scheme, which was blocked according to screening center, sex, and age.
Screening centers obtained written informed consent from each subject. The institutional review boards at each of the screening centers listed above reviewed the PLCO protocol and approved the use of human subjects.
Baseline Characteristics
A baseline questionnaire was given to each participant on entry into the study. The questionnaire recorded personal socio-demographic characteristics (e.g., age, race, sex, marital status, and education), cancer family history, personal medical history (including history of colorectal polyp), cigarette-smoking history, and cancer screening history within 3 years.
Flexible Sigmoidoscopy Procedure
Physician and non-physician examiners, who were all centrally registered, followed standardized procedures to perform and record results from the 60-cm flexible sigmoidoscopy examination. Examiners used depth of insertion, adequacy of bowel preparation, and primary visual findings to place each sigmoidoscopy examination into one of three mutually exclusive result categories. The positive result category signified a finding of a polyp or mass. The inadequate result category signified a <50-cm depth of insertion or visual inspection limited to <90% of the mucosal surface due to inadequate bowel preparation, with no detection of a polyp or mass. The negative result category signified a technically adequate examination with no detection of a polyp or mass.
Subjects experiencing a technically inadequate sigmoidoscopy could return at a later date for a second examination. By protocol, a repeat sigmoidoscopy was to be offered to individuals experiencing an inadequate examination due to incomplete bowel preparation. A repeat procedure was not routinely offered to individuals with limited bowel examination due to pain or discomfort. In 7522 cases of technical inadequacy on an initial examination, 632 (8.4%) subjects returned for a second flexible sigmoidoscopy examination; after that examination, a total of 7099 cases of technical inadequacy remained. All subjects were classified according to the result of their last sigmoidoscopy examination.
Using visual size estimates at sigmoidoscopy, PLCO examiners recorded the maximum dimensions for the four largest polyps or masses detected at the baseline (T0) screening flexible sigmoidoscopy examination. The PLCO protocol did not prohibit or preclude colonic biopsy or polypectomy at screening flexible sigmoidoscopy. However, the PLCO screening centers and examiners chose, with rare exception, not to biopsy or remove polyps or masses during the PLCO screening flexible sigmoidoscopy examination. Instead, the PLCO staff referred subjects with screen-detected abnormalities to their personal physicians for diagnostic follow-up. PLCO staff debriefed subjects at the end of each screening examination and communicated the sigmoidoscopy test results. Letters and reports that were mailed later to each participant and a personal physician of record communicated all PLCO test results, including detailed sigmoidoscopy findings and reinforced recommendations for physician follow-up when appropriate.
The PLCO trial protocol did not include study-wide standards or guidelines for the diagnostic evaluation of screen-detected abnormalities. However, study subjects and personal physicians were given access to screening center consultants, who could respond to questions and deliver advice regarding diagnostic approaches. The PLCO tracked subjects for at least 12 months after screening and identified, requested, and abstracted medical records pertaining to subsequent diagnostic work-ups. Information abstracted from medical records included the occurrence and date of follow-up flexible sigmoidoscopy and/or colonoscopy examinations, the anatomic location, and the size (as recorded on clinical endoscopy reports) and histology of removed polyps and masses. Dates of diagnosis, TNM clinical stages (10), and TNM pathologic stages were collected for subjects with invasive colorectal cancer.
By definition, the advanced adenoma classification included cases of villous or tubulovillous adenoma, large (1.0 cm) adenoma, or severe or high-grade dysplasia. Analyses treated designations of carcinoma in situ and severe dysplasia as synonymous terms. The PLCO colorectal cancer endpoint excluded cancers involving the anus or anal canal but included carcinoid tumors involving the appendix, colon, or rectum. To estimate diagnostic consequences and yields, analyses tabulated lower endoscopic procedures and colorectal cancer and adenoma diagnoses occurring within 365 days of a positive PLCO screening flexible sigmoidoscopy examination.
Statistical Analysis
We used CochranMantelHaenszel statistics and logistic regression (SAS System for Windows Release 8.01, Cary, NC) to evaluate the statistical significance of differences in proportions according to sex (in both unadjusted and age-adjusted analyses), sex-specific differences according to age, and sex-specific trends according to age. Subsequent text and tables present results according to 5-year age groupings (5559, 6064, 6569, and 7074 years of age at study enrollment). In large studies, such as the PLCO screening trial, small absolute differences can be statistically significant. Unless otherwise indicated, every mention of an association involving sex or age had a P of <.001. All statistical tests were two-sided.
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RESULTS |
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According to the PLCO definitions, the sigmoidoscopy examination was inadequate in 7099 subjects (11.0% of 64 658; Table 2). An inadequate sigmoidoscopy examination occurred more frequently in women than in men (15.2% versus 7.0%) and increased with each age grouping in both women (13.9%, 14.4%, 16.3%, and 18.8%) and men (6.2%, 6.5%, 7.7%, and 8.7%; P = .95 age * sex interaction).
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Over all age groups, the finding of at least one large (1.0 cm) polyp or mass occurred less frequently among women than in men (2.1% versus 4.2%; Table 2), as did the finding of at least one 0.5-cm or larger polyp or mass (7.5% versus 12.8%). Among women and men considered separately, the prevalence of polyps of 0.50.9 cm and of
1.0 cm increased with age (Table 2).
Table 3 summarizes the baseline screening flexible sigmoidoscopy results by age-sex subgroup. We analyzed the proportions of enrolled individuals who accepted screening; proportions of screened individuals with a positive screen; proportions of positive screens with diagnostic follow-up (i.e., cancer diagnosis, sigmoidoscopy, colonoscopy, or lower endoscopy not otherwise specified) within 365 days of screening; positive predictive values for cancer, advanced adenoma, and non-advanced adenoma in individuals with diagnostic follow-up subsequent to the screen detection of a polyp or mass; and cancer and adenoma yields, expressed both as proportions of all intervention subjects and as proportions of screened intervention subjects.
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Depending on sex and age, cancer yields ranged between 0.9 and 4.7 per 1000 subjects, cancer or advanced adenoma yields ranged between 15.8 and 46.7 per 1000 intervention subjects, and cancer or adenoma (advanced or non-advanced) detection yields ranged between 41.7 and 111.2 per 1000 intervention subjects (Table 3). Cancer and adenoma yields were lower in women than in men, whether they were calculated in terms of enrolled women and men (cancer yield: 1.5 cases in women per 1000 screened versus 3.3 cases in men; cancer or adenoma yield: 51.5 cases in women per 1000 screened versus 100.5 cases in men; Table 3) or calculated in terms of screened women and men (cancer yield: 1.8 cases in women per 1000 screened versus 3.8 cases in men; cancer or adenoma yield: 63.8 cases in women per 1000 screened versus 116.6 cases in men; Table 3). When women and men were analyzed together (data not shown), cancer and adenoma yields increased with age, whether calculated in terms of enrolled subjects (cancer yield among those aged 5559, 6064, 6569, and 7074 years: 1.4, 2.7, 2.9, and 3.2 cases per 1000, respectively; cancer or adenoma yield: 63.7, 78.9, 86.7, and 80.4 cases per 1000, respectively) or calculated in terms of screened subjects (cancer yield: 1.7, 3.2, 3.5, and 4.0 cases per 1000, respectively; cancer or adenoma yield: 75.7, 93.6, 104.2, and 99.8 cases per 1000, respectively).
The frequency and relative odds of cancer or adenoma among screened subjects according to sex and age are shown in Table 4. Overall, the age-adjusted odds of cancer or adenoma among screened men relative to that among screened women was 1.92 (95% CI = 1.82 to 2.04). Male sex moderated the effects of age on screen detection of cancer or adenoma (P = .002 age * sex interaction). Relative to 55- to 59-year-old women, the odds of cancer or adenoma among screened women aged 6064 years, 6569 years, and 7074 years were 1.26 (95% CI = 1.12 to 1.42), 1.56 (95% CI = 1.38 to 1.77), and 1.62 (95% CI = 1.41 to 1.87), respectively. By comparison, relative to 55- to 59-year-old men, the odds ratios of cancer or adenoma among screened men aged 6064 years, 6569 years, and 7074 years were 1.22 (95% CI = 1.12 to 1.33), 1.30 (95% CI = 1.19 to 1.42), and 1.19 (95% CI = 1.06 to 1.33), respectively (data not shown).
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DISCUSSION |
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Discussion of the broader implications of the baseline colorectal cancer screening results from the PLCO trial must take into account certain aspects of the PLCO screening intervention, including the conscious decision not to include colonic biopsy or polyp excision as an integrated part of the screening flexible sigmoidoscopy examination. Persuasive concerns underlying this decision included challenges related to both financial costs and examiner training. The PLCO encouraged strategies to improve efficiencies and to reduce costs directly associated with the screening examination procedures. Relevant strategies included simultaneous screening for prostate, lung, colorectal, and ovarian cancer; use of non-physician examiners; economies of scale (i.e., efficiencies created by having a few screening centers perform many examinations as opposed to having many screening centers perform a few screening examinations); and other organizational steps designed to reduce personnel and overhead costs. Colonic biopsy and polypectomy were precluded as integrated parts of the screening experience because they were seen as threats to efficiency and because of concerns regarding the clinical credentials of non-physician examiners. These same issues, pertaining to cost, feasibility, and organization, clearly pertain to mass screening programs in general.
Arguments favoring biopsy or polypectomy at screening are based, at least in part, on the belief that hyperplastic polyps do not require follow-up colonoscopy. Imperiale et al. (11) have evaluated trade-offs, in terms of detecting advanced proximal neoplasia relative to colonoscopy resource use, associated with three alternative strategiescolonoscopy for those with any distal polyp on screening sigmoidoscopy, colonoscopy for only those with biopsy-verified adenoma on screening sigmoidoscopy, and colonoscopy for everyone without preliminary screening sigmoidoscopy. With respect to flexible sigmoidoscopy screening, the first strategy may be most commonly used in primary care settings, whereas the second strategy may be more commonly favored by professional organizations (11). In any case, relative to colonoscopy for any distal polyp, restricting colonoscopy to those with biopsy-verified adenoma may reduce the colonoscopy need by approximately 50% and the detection of proximal advanced neoplasia by 25% (11).
A high proportion of subjects (83.5%) accepted the initial PLCO screening flexible sigmoidoscopy examination, reflecting the extent to which screening can be implemented in a motivated population (1215). In the PLCO trial, sigmoidoscopy was adequate (depth of insertion beyond 50 cm and visualization of 90% of the intestinal mucosa) in 89.0% of subjects, a measure of adequacy similar to that seen in European trials (79). These results also compare favorably with the 40- to 50-cm average insertion depths reported in the past (16). However, a relatively high proportion of women, especially 70- to 74-year-old women (23.6%), did not accept screening sigmoidoscopy. In addition, sigmoidoscopy was often inadequate in women, especially older women. Perceptions by women regarding the tolerability of flexible sigmoidoscopy may contribute to their lower acceptance of screening. Women report pain or discomfort from flexible sigmoidoscopy more often than do men (17) and are more likely to have an inadequate exam. Inadequate exams, in turn, are more likely to be associated with advanced lesions detected at a later time (18). Consequently, colonoscopy may be preferred to flexible sigmoidoscopy to achieve adequate screening in older women.
Screening flexible sigmoidoscopy detected one or more polyps, particularly small polyps, in 23.4% of screened subjects. The results from diagnostic follow-up sigmoidoscopy or colonoscopy depended on the size of the index polyp detected at screening. For example, diagnostic follow-up documented cancer or adenoma in 83.0% of individuals in whom a large polyp or mass (1.0 cm) was detected by flexible sigmoidoscopy screening (data not shown). In addition, the prevalences of large (
1.0 cm), intermediate (0.50.9 cm), or any size polyp or mass were consistently and substantially greater in men than in women and generally increased with age, especially in women. As a corollary of higher polyp prevalence in men, cancer and advanced adenoma diagnoses were twice as frequent in men, consistent with results from other, smaller case series (1922).
Data on endoscopic colorectal follow-up were lacking for approximately 25% of subjects with a screen-detected polyp or mass. Diagnostic follow-up may not occur for many reasons, both participant- and physician-related, including personal choice, lack of health insurance, physician recommendation, and failure to retrieve the data. Diagnostic follow-up was much less frequent among subjects with small (<0.5 cm) colorectal polyps than in those with larger (1.0 cm) polyps. The rate of follow-up for subjects with larger polyps in our study was similar to that in a large group-model health maintenance organization, in which 83.5% of patients with a finding of multiple distal adenomas or a distal advanced adenoma at screening sigmoidoscopy had colonoscopy follow-up within 6 months (23). Because the PLCO follow-up procedures occurred as part of regular medical care, our observations constitute a realistic picture of the results expected from a large-scale U.S. flexible sigmoidoscopy screening program.
Our diagnostic yields for flexible sigmoidoscopy compare favorably with historical sigmoidoscopy standards (19,24,25). Table 6 examines yields observed in the PLCO trial relative to the yields observed in concurrent European studies (79). The subjects in the European studies were younger, on average, than those in the PLCO study; in addition, unlike the PLCO study, the European studies integrated biopsy into the flexible sigmoidoscopy screening procedure and conducted colonoscopy according to prespecified criteria and as a study-directed follow-up activity. For example, the United Kingdom study (7) required colonoscopy referral for individuals with high-risk findings on screening sigmoidoscopy, with high risk being defined as a polyp of 1.0 cm or larger, three or more adenomas, adenoma with tubulovillous or villous histology, severe dysplasia or malignancy, or 20 or more hyperplastic polyps above the distal rectum (7). By comparison, the PLCO trial referred subjects with any visible polyp or mass to personal physicians for evaluation and management. Therefore, colonoscopy use in the PLCO study reflected local medical practice standards, physician practice patterns, access to medical care, and subject compliance with recommendations to seek medical care.
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Subjects with procedures following an abnormal screening, without cancer or adenoma detected, include both subjects with other polypoid abnormalities (e.g., hyperplastic polyp) and subjects without any abnormality detected at all. The latter result, in which a follow-up diagnostic colonoscopy fails to confirm the presence of polypoid abnormalities observed at screening, reflects both the variability of decision thresholds used by different examiners to report mucosal findings and the possibility of missing lesions during diagnostic follow-up. Sigmoidoscopy positivity rates are known to vary according to examiner (19,2628). For example, in 18.5% of 249 subjects who received back-to-back flexible sigmoidoscopy in one study (29), a second examiner detected one or more polyps missed by the initial examiner. Similarly, in tandem colonoscopy studies, individual examiners missed polyps smaller than 0.5 cm up to 27% of the time (30). Detection of polypoid abnormalities on follow-up sigmoidoscopy or colonoscopy was associated with the size of the largest index abnormality on initial screening. Hence, smaller polyps are easily missed and are particularly subject to variable interpretation.
In the PLCO trial, 80% of colorectal cancers associated with positive sigmoidoscopy were discovered in the distal colon, as one might expect from a procedure that examines the distal colon primarily. However, the induction of colonoscopy by screening, enables evaluation and treatment of the proximal colon. In accordance with the frequency of follow-up colonoscopy, proximal adenoma yields from initial sigmoidoscopy and associated follow-up were greater in the PLCO study than in the UK and Italian studies (Table 6).
Diagnostic stage is an important intermediate outcome for cancer screening studies. In the PLCO study, early-stage cancer (i.e., stage I or II) occurred in nearly 77% of cases associated with positive sigmoidoscopy. However, diagnostic stage distribution cannot be used to infer mortality benefit, and judgments regarding the colorectal cancer-specific mortality benefit from screening flexible sigmoidoscopy require long-term follow-up.
Finally, volunteers to clinical trials are not necessarily representative of the general population. Relative to the general population, the PLCO trial included better-educated individuals and fewer individuals from ethnic and racial minority groups. However, given the size and diversity of the PLCO study population, the number and geographic distribution of the PLCO cancer screening centers, and the reliance on community physician referral for completion of diagnostic evaluations, the screening sigmoidoscopy findings and subsequent diagnostic results reported here can be viewed as an approximation of the potential of screening flexible sigmoidoscopy in a real-world setting. By providing age- and gender-specific findings, we offer general benchmarks for what could be expected from large-scale implementation of screening sigmoidoscopy in the United States.
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NOTES |
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This work was supported by individual contracts from the National Cancer Institute to each of the 10 screening centers and to the coordinating center.
The PLCO trial team includes more than 1000 dedicated staff members who are actively involved in the PLCO Trial. Key personnel from the 10 Screening Centers, NCI, and support staff are noted below. A more complete list as of December 2000 can be found elsewhere (6). Primary authors on this manuscript are noted with an asterisk. (PI = Principal Investigator or co-PI, C = Screening Center Coordinator, PO = Project Officer)
SCREENING CENTERS: Birmingham, ALMona FouadPI, MD, MPH; Albert Oberman, MD, MPH; Edward Partridge, MD; Donald A. Urban, MD; Darlene HigginsC; Denver, COE. David CrawfordPI, MD; Sheryl L. OgdenC, RN, BSN; Detroit, MIPaul KvalePI, MD; Christine C. JohnsonPI, PhD, MPH; Robert S. Bresalier*, MD; Karen BroskiC; Lois Lamerato, PhD, MS; Honolulu, HILance YokochiPI, MD, MPH; Victoria JenkinsC, BSN, Med; Marshfield, WIDouglas RedingPI, MD, MPH; William HockingPI, MD; Karen LappeC, BSN; Minneapolis, MNTimothy R. ChurchPI*, PhD, MS; Martin M. OkenPI, MD; Deborah EngelhardC, MA; Jill CordesC, BSN, RN; Pittsburgh, PAJoel L. WeissfeldPI*, MD, MPH; Robert E. SchoenPI*, MD, MPH; Betsy GahaganC, RN, BSN; Salt Lake City, UTSaundra S. BuysPI, MD; Thomas M. BeckPI, MD; Lisa H. GrenC, MSPH; Jeffery C. Childs; Bonita WohlersC, RN, MSN; St. Louis, MOGerald L. AndriolePI, MD; Heidi LoweryC, RN, MS; Washington, DCEdward P. GelmannPI, MD; Colleen McGuireC, RN, MSN.
NATIONAL CANCER INSTITUTE: Division of Cancer PreventionChristine D. BergPO, MD; Philip C. ProrokPO*, PhD; John K. Gohagan*, PhD; Barnett S. Kramer, MD, MPH; David L. Levin, MD, MS; Ping Hu, ScD; Paul F. Pinsky*, PhD; Jian-Lun Xu, PhD; Anthony B. Miller, MB (consultant); Division of Cancer Epidemiology and GeneticsRichard B. Hayes, PhD.
COORDINATING CENTER (Westat Inc)Barbara O'BrienPI, MT, MPH; Lawrence R. Ragard, MD; Susan Yurgalevitch*, MS, MPH; Keith Umbel; Beth Bridgeman.
STATISTICAL CENTER (IMS)Thomas RileyPI; Jonathan D. Clapp; Joseph H. Austin*; Jerome Mabie; Craig Williams; Steve Winslow.
SPECIMEN LABORATORYDavid ChiaPI, PhD; Jean Reiss, MT.
Although Barnett S. Kramer, the editor-in-chief of JNCI, is a member of the PLCO trial team, he was not involved in the writing of this manuscript or the interpretation of the data.
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Manuscript received January 3, 2005; revised April 29, 2005; accepted May 12, 2005.
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