447 subjects enrolled, 67
073 screened at least once, and 39
443 screened twice, repeating the FSG increased the yield of cancers and advanced adenomas detected in the PLCO trial by 32%. A high percentage (22.9%) of enrollees had at least one abnormal FSG, leading to diagnostic intervention. About one in five (3338 [18.8%; 1.4% + 17.4%] of 17
772; ) subjects who received diagnostic intervention because of a positive FSG received a diagnosis of advanced neoplasia. Among subjects with a diagnosis of advanced neoplasia, 75.9% were diagnosed as a result of the initial FSG and 24.1% were diagnosed as a result of the repeat FSG. There were 223 subjects diagnosed with colorectal carcinoma within 1 year of a positive FSG: 64.6% at stage I and 82.1% at stage I or II.
Repeated testing or relaxation of the threshold for referral to colonoscopy will affect the frequency of the colonoscopic evaluation of the proximal colon and the associated detection of premalignant adenomas and early colorectal cancers. The rate of colonoscopy under the PLCO FSG screening program approached 22% (). By using two FSG cycles, the investigators of the PLCO trial increased the percentage of all enrollees who received a diagnostic intervention from 15.3% after the first screen to 22.9% after both screens (). The European single-FSG trials reported colonoscopy rates of 5.0% [United Kingdom (18
)], 7.8% [Italy (19
)], and up to 21% [Norway (16
)], and the 5% colonoscopy rate in the United Kingdom had no measurable effect on proximal cancer incidence (15
). Assuming benefit from colonoscopy, higher rates of colonoscopy such as those in the PLCO trial, which used two rounds of screening FSGs, could produce greater reductions in proximal colorectal cancer incidence or mortality. Subsequent analyses that compare the PLCO intervention group and control group (usual care) will determine whether screening works to reduce incidence or mortality, from colorectal cancer overall and from cancer in the rectum, distal colon, and proximal colon specifically.
There are also reasons why repeating an FSG screening might not be beneficial. Although repeated FSG increases screening yields, it also increases the costs of screening, the need for diagnostic intervention, and the risks of complication. In addition, participants may become fatigued or disenchanted by requests for more frequent screenings or by unnecessary diagnostic interventions generated by false-positive screens. Both the frequency of repeat screening and the number of primary sites screened increase the cumulative incidence of unnecessary diagnostic intervention (24
). Also, analysis of PLCO trial data regarding complications identified three instances when the bowel was perforated during one of 107
236 FSG screening examinations (2.8 perforations per 100
000 FSGs). In persons without detected colorectal cancer, there were 19 instances when the bowel was perforated during one of 17
672 diagnostic colonoscopy examinations completed for evaluation of a positive FSG screening (1.1 perforations per 1000 diagnostic colonoscopies). Benefits produced by the PLCO FSG program must be weighted against costs and harms, including bowel perforation, which occurred at rates similar to those described in the literature (25
), typically one perforation for every 10
000 FSGs and one perforation for every 1000 colonoscopies. The current analysis shows equivalent, if not higher, rates of diagnostic intervention after a positive repeat FSG compared with a positive first FSG (78.7% vs 74.9%, ). These results suggest that PLCO screening and intervention procedures, instead of producing participant fatigue, sustained participants’ willingness to undergo screening and diagnostic intervention for FSG-detected abnormalities.
We observed some sex-specific differences in the results from PLCO FSG screening. Inadequate FSGs occurred more frequently in women than men, a difference consistent with our 2005 report (20
) and the reports of others (30
). FSGs are sometimes said to be more difficult in women than in men because of anatomical differences, including those caused by hysterectomy (32
), which may make the procedure more uncomfortable (33
). Also, consistent with other studies (34
), adenoma was more frequent in men than women. Consistent with the higher colorectal cancer risk generally observed in men relative to women, the diagnosis of colorectal cancer or adenoma after FSG was two times more common in men than women, whether evaluated after first or after repeat FSG ().
We also observed some age-specific differences in the results from PLCO FSG screening. As reported in our 2005 analysis of data from the entry FSG (20
), cancer or advanced adenoma yields from the PLCO FSG program increased with age, at least through age 65–69 years (Supplementary Table 2
, available online). Cancer or advanced adenoma yields per 1000 persons screened were 30% higher for subjects who enrolled at 60–64 years of age than for subjects who enrolled at 55–59 years of age. Yields were 14% higher in subjects who enrolled at age 65–69 years than in subjects who enrolled at age 60–64 years. Perhaps affected by a small decline in repeat FSG among subjects in the oldest age group (data not shown), yields were not statistically greater in subjects who enrolled at age 70–74 years compared with subjects who enrolled at age 65–69 years. The value of screening the elderly for colorectal cancer is uncertain. These observations serve to remind us that screen detectable adenoma, though common in the elderly, may stop increasing in prevalence after a certain age. Any age-related increase in yield from screening must be balanced against age-related risks from diagnostic or therapeutic intervention (37
). The elderly (ie, persons aged ≥80 years) can plausibly expect to gain less life expectancy from screening colonoscopy than younger persons (39
). Though guidelines suggest exceptions for persons not previously screened, the US Preventive Services Task Force now discourages routine colorectal cancer screening in persons aged 76–85 years (40
There are limitations to this study. The efficacy endpoints for PLCO FSG are colorectal cancer mortality and incidence, for which data are not yet available. Because the PLCO FSG program included two rounds of screening, any differences in colorectal cancer mortality and incidence attributed to the PLCO FSG program will include contributions from both rounds. Despite our ability to measure the yields from first and repeat FSG, it may not be possible to distinguish specific mortality benefits derived from first as opposed to repeat FSG.
There are also several factors to consider with regard to the generalizability of our study. PLCO used 10 geographically representative centers to enroll a large study group, completed screening FSG using dedicated examiners, and relied on community resources for diagnostic intervention. These factors make our results especially relevant to any discussion of results one should expect from efforts to apply FSG to the US population. However, conclusions about outcomes from the PLCO FSG program must take the following four factors into account. First, the yields observed from programmatic screening partially reflected the repeat FSG completion rates achieved in PLCO. Although 86.6% of participants overall completed at least one FSG, only 58.8% of those screened at least once also completed the repeat FSG. Unlike our detailed 2002 analysis of factors associated with repeat FSG adherence (41
), these estimates of FSG completion should not be accepted as measures of participant adherence to PLCO FSG protocols. Most notably, our calculations of FSG completion do not take into account those persons ineligible or unavailable for repeat FSG by virtue of death, interval colorectal cancer, or adenoma detection at first FSG. Second, yields from repeat FSG may not be able to be generalized to repeat colonoscopy because adenoma recurrence risks are higher in persons who are found to harbor proximal as opposed to distal adenoma (42
). Third, practitioners of sigmoidoscopy (44
) and colonoscopy (46
) vary considerably with respect to detecting adenoma and, to a lesser extent, advanced adenoma (46
). The accumulated experience of individual PLCO FSG examiners or temporal changes in the panel of PLCO FSG examiners could have contributed to the different outcomes observed at repeat FSG, relative to first FSG. Finally, outcomes specifically related to repeat FSG reflect not only aging subjects or different examiners but also the characteristics of subjects who returned for repeat FSG.
Midway through the trial, PLCO extended the interval between first and repeat FSG from 3 to 5 years. Ostensibly, this change permits examination of the effect of time interval on incident colorectal neoplasia risk. Results from such a comparison in PLCO could add to the evidence base that supports the currently recommended 5-year interval between FSG screenings (48
). However, in addition to temporal change in examiner and subject composition, other factors distinguish the 3- and 5-year repeat FSG study populations. Most importantly, diagnostic intervention for screen-positive repeat FSG occurred more often in the 5-year than the 3-year group (data not shown). For these reasons, comparison of clinical outcomes at 3-year as opposed to 5-year repeat FSG demands careful analysis best reserved for a separate report.
In conclusion, repeat FSG in the PLCO Cancer Screening Trial increased colorectal cancer or advanced adenoma detection in women by one-fourth and in men by one-third. Final study results will examine the effects of the PLCO FSG program on colorectal cancer incidence and mortality.