Nine participants developed colorectal cancer during the PPT follow-up study for a rate of 1.2 cases/1000 PYO, despite undergoing a mean of more than 3 colonoscopy procedures during the PPT trial. This interval cancer rate was 64% of that expected by SEER and when cancers detected in the main PPT trial and the follow-up study were combined, the overall rate was 74% of that expected by SEER. The absolute rates were not statistically significantly different from that expected based on SEER data. Our study included a relatively prolonged >10 year median follow up. Previous studies of interval cancer were limited to a shorter follow-up of three to six years (7
). Our results confirm the need for continued colonoscopy surveillance in at risk subjects due to ongoing risk of colorectal cancer and especially among those with a history of advanced adenoma.
Our data are consistent with studies which demonstrate a continued risk of CRC despite previous colonoscopy. In a review of data from 3 multi-center adenoma prevention trials, 19 cases of colorectal cancer were diagnosed among 2915 patients with an overall incidence of 1.74 per 1000 PYO and an incidence ratio of 0.98 (95% CI, 0.63–1.54) when compared to SEER (7
). A similar incidence was found in the VA cooperative study where among 1171 subjects with neoplasia at baseline colonoscopy, 1.7 cases of CRC per 1000 PYO were diagnosed in follow-up over a 5.5 year period (8
). It should be noted when comparing the CRC incidence ratio in patients under surveillance colonoscopy compared to those in SEER, that surveillance studies include patients with a previous history of adenoma who are at higher risk for subsequent neoplasia. However, they presumably are at lower risk for CRC due to having undergone colonoscopy.
In our study, the majority of subjects who developed CRC had a previous advanced adenoma during the PPT trial. This was the only factor significantly different between patients who developed CRC and those who did not. The association of increased CRC risk in patients with advanced adenomas has been previously observed (17
). In our population, subjects appear to remain at increased risk for CRC even with a negative interval colonoscopy. Four of the nine patients who developed CRC had no polyps found at the final T4 colonoscopy at PPT completion. For example, case #7 was a 44 year old female at enrollment with an advanced adenoma at T0/T1 but no polyps at T4. She was diagnosed with CRC 73 months after T4 colonoscopy or 10 years after her initial advanced adenoma. She did manifest an advanced adenoma at a young age. In contrast, however, cases #6 and #8 had no prior history of advanced adenomas and were polyp-free at T4 but developed CRC. The risk of cancer is certainly not exclusive to subjects with prior advanced adenomas, but ongoing risk is prominent in that subgroup.
Some patients had received multiple colonoscopies over a relatively short time interval, yet they were diagnosed with CRC. Four patients had undergone at least three colonoscopies over approximately eight years. Four of the nine patients had a colonoscopy that did not diagnose their cancer two years previously. Concerns about the quality of colonoscopy have increased amid evidence of a significant miss rate during colonoscopy. In tandem colonoscopy studies, miss rates of 0–6% were observed for adenomas ≥10 mm but the miss rate increased markedly for lesions 5–10 mm, ranging from 12–13%, and in lesions less than 5 mm, miss rates of 16–27% were noted (18
). In studies of CT colonography, the colonoscopy miss rate for adenomas ≥10 mm has been reported at 12–17% (20
). Several factors that adversely affect colonoscopy performance have been identified, including rapid withdrawal time, poor bowel prep, and performance by a non-gastroenterologist (23
). It is difficult to assess the quality of colonoscopy performance due to a lack of standard colonoscopy reporting. To address this issue, the National Colorectal Cancer Roundtable task force recently developed a standardized colonoscopy reporting system to facilitate auditing of procedures and quality improvement (27
Two recent case-control studies of colonoscopy suggest that colonoscopy is not as effective in preventing mortality (28
) or incidence of right sided cancer (29
). One could ask how our results contribute to this concern, given that we do not demonstrate a statistically significant decrease in CRC compared to SEER, despite subjects undergoing frequent colonoscopy. It must be emphasized that this study is not a population based study of colonoscopy effectiveness in that all patients began with adenomatous polyps. Approximately 18% had a history of adenomas in the previous 5 years to enrollment, and over 37% had an advanced adenoma at enrollment (11
). Thus, this cohort is at higher risk for CRC than the general population followed in SEER. Furthermore, although 8 of the 9 cancers in the PPT-CFS were proximal to the splenic flexure, 5 of the 8 were potentially a consequence of suboptimal colonoscopy quality due to one missed lesion, two failed biopsy detections, and two incomplete removals, whereas the others were deemed new or of indeterminate cause
A recent investigation of surveillance colonoscopy found that subjects were more likely to develop recurrent adenomas in the same colonic segment, suggesting that particular attention be paid to where a previous adenoma has been removed (30
). Our data further supports recognition of the site of a previous polyp and close observation of this colonic segment, especially among subjects with an advanced adenoma.
Limitations of our study should be acknowledged. Only a small number of cases of CRC were identified, limiting statistical analysis. It was difficult to determine whether a cancer occurred at the site of a previously identified pre-malignant lesion or whether it merely occurred in the same colonic segment, because of limited descriptive information on adenoma location from colonoscopy reports. Only 68% of subjects originally enrolled in the PPT trial participated in the PPT-CFS and this could have led to a biased sample. When characteristics of the PPT-CFS participants and non-participants were compared, despite some statistical differences, the two populations do not appear to be at a clinically significantly different risk for colorectal cancer (). Finally, the occurrence of colorectal cancer relied on patient self-report. However, additional cases identified via a more comprehensive search would only increase the rate, which was already substantial.
In Pabby et al’s (9
) original algorithm analyzing interval cancers, it was assumed that advanced cancers (≥2 cm in size and stage III or IV) detected > 30 months after the last colonoscopy at a previously polyp-free segment were missed lesions. The longest potential interval between colonoscopy in the PPT trial was 48 months, an interval presumed unlikely to be long enough for a new cancer to develop advanced features. In this study, the longest interval from colonoscopy to CRC diagnosis was 83 months, a time period long enough to develop a new cancer with advanced features. Thus, in this cohort advanced cancers detected years later were categorized as indeterminate.
In conclusion, despite frequent colonoscopy during the PPT trial, there was a persistent ongoing risk for cancer in the years subsequent to the trial. Subjects with a history of advanced adenoma are at increased risk for subsequent cancer and should be followed closely with continued surveillance.