Abstract
Background:
Antibiotics may increase colorectal neoplasia risk by modifying the gut microbiome. It is unknown whether use is associated with the risk of new colorectal adenomas among individuals with prior adenomas.
Methods:
We performed a secondary analysis of 4 randomized clinical trials for the chemoprevention of colorectal adenomas. Participants self-reported all currently used prescription drugs shortly after an initial colorectal adenoma diagnosis and 2 or 3 times a year thereafter over 3 to 5 years of follow-up. We estimated adjusted risk ratios (RR) with 95% confidence intervals (CI) for incident adenomas analyzing the 4 trials together.
Results:
Cumulatively, the 4 trials enrolled 5,174 participants (3,491 men and 1,683 women), of whom 4,769 (92%) completed ≥1 follow-up colonoscopy. A total of 763 (15%) participants reported using oral antibiotics on ≥2 occasions. Overall, 39% of those using oral antibiotics at least twice developed new colorectal adenomas compared with 40% of those with no use or a single report of use (RR, 0.99; 95% CI, 0.90-1.10). No statistically significant associations were found in study-specific analyses, and results were similar for high- and low-risk adenoma findings, antibiotic class, anatomic location of adenomas, and analyses excluding those with interim colorectal exams.
Conclusions:
Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps.
Impact:
Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas.
Keywords: antibiotics, colorectal adenomas, colorectal cancer, colonoscopy
Introduction
Antibiotic use may affect colorectal neoplasia risk by modifying the gut microbiome (1). A meta-analysis of 10 observational studies concluded oral antibiotic use was associated with 17% higher risk of colorectal cancer (2). This association may be stronger for broad-spectrum (2) and anti-aerobic (3) antibiotics, and for neoplasia of the proximal colon (3,4). One study found early-life oral antibiotic use, but not recent use, was associated with higher risk of colorectal adenomas, the most common precursor lesions for colorectal cancer (4). It is unknown whether oral antibiotic use among those with an initial colorectal adenoma diagnosis is associated with subsequent risk of these polyps.
Materials and Methods
We aggregated individual-level data from the 4 Polyp Prevention Study trials (5-8). Conducted by a single consortium using similar protocols, each was a multicenter placebo-controlled randomized clinical trial among those recently diagnosed with colorectal adenomas. The Antioxidant trial investigated β-carotene and the combination of ascorbic acid and α-tocopherol among 864 participants enrolled between 1984-1988 (5). The Calcium trial investigated calcium among 930 participants enrolled between 1988-1992 (6). The Aspirin/Folate trial investigated aspirin at 2 doses and folic acid among 1,121 participants enrolled between 1994-1998 (7). The Vitamin D/Calcium trial investigated cholecalciferol and calcium among 2,259 participants enrolled between 2004-2008 (8). These studies were approved by institutional review boards and all participants provided written informed consent.
In each trial the primary endpoint was the occurrence of colorectal adenomas during the treatment period, planned to end at the time of a follow-up colonoscopy 3 to 5 years after randomization. A review of colorectal biopsies by a single study pathologist distinguished conventional adenomas from non-adenomatous polyps and adenocarcinomas. High-risk adenoma findings were defined as ≥1 advanced adenoma (tubulovillous/villous adenomas, ≥1 cm in diameter, with high-grade dysplasia, or adenocarcinoma) or ≥3 synchronous adenomas. Low-risk adenoma findings were defined as 1 or 2 non-advanced adenomas.
At baseline, the Antioxidant, Calcium, and Aspirin/Folate trials asked about current use of prescription drugs including antibiotics, whereas the Vitamin D/Calcium trial asked about use in the past year. Follow-up questionnaires administered every 6 months (4 months in the Aspirin/Folate trial) asked about use since the last questionnaire. Oral antibiotic types were classified by Anatomical Therapeutic Chemical (ATC) code and grouped by class, narrow- or broad-spectrum, and anti-aerobic or anti-anaerobic.
Risk ratios (RR) with 95% confidence intervals (CI) adjusted for age, sex, clinical center, study, and treatment assignment (placebo vs. active) were estimated using log-linear Poisson regression for adenoma occurrence as a binary outcome with robust variance among those with ≥1 follow-up colonoscopy during the treatment period. Subgroup analyses were performed according to study, antibiotic class, and adenoma location. Adenomas diagnosed during interim colorectal exams before the scheduled end of the surveillance interval were included, unless <1 year after randomization. In sensitivity analyses, we excluded participants with interim exams. We defined antibiotic use as ≥2 separate reports of use at baseline or follow-up and evaluated total count of reports of antibiotic use as a continuous variable in a secondary analysis. Two-sided P<0.05 was considered statistically significant.
Results
Of 5,174 participants across the 4 trials, 763 (15%) participants used oral antibiotics at least twice (Table 1; Supplemental Table 1). Overall, 4,769 (92%) participants completed ≥1 follow-up colonoscopy. Oral antibiotic use was not associated with colorectal adenoma risk in any trial or the 4 trials combined (RR, 0.99; 95% CI, 0.90-1.10; Table 2; Supplemental Table 2). Results were similar by high- and low-risk status (Table 2), drug class (Supplemental Tables 3 and 4), anatomic location (Supplemental Table 5), and after excluding those with interim exams (Supplemental Table 6).
Table 1.
Baseline characteristics of 5,174 participants of the 4 Polyp Prevention Study trials.
| Oral antibiotic usea | |||
|---|---|---|---|
| Baseline characteristics | Total | No | Yes |
| All 4 trials, nb | 5,174 | 4,411 | 763 |
| Age, years, mean (SD) | 59 (8) | 59 (8) | 58 (9) |
| Men, n (%) | 3,491 (67%) | 3,061 (69%) | 430 (56%) |
| Antioxidant trial, nb | 864 | 796 | 68 |
| Age, years, mean (SD) | 61 (8) | 61 (8) | 61 (10) |
| Men, n (%) | 684 (79%) | 631 (79%) | 53 (78%) |
| Calcium trial, nb | 930 | 878 | 52 |
| Age, years, mean (SD) | 61 (9) | 61 (9) | 62 (9) |
| Men, n (%) | 672 (72%) | 640 (73%) | 32 (62%) |
| Aspirin/Folate trial, nb | 1,121 | 773 | 348 |
| Age, years, mean (SD) | 57 (10) | 58 (10) | 57 (10) |
| Men, n (%) | 712 (64%) | 517 (67%) | 195 (56%) |
| Vitamin D/Calcium trial, nb | 2,259 | 1,964 | 295 |
| Age, years, mean (SD) | 58 (7) | 58 (7) | 58 (7) |
| Men, n (%) | 1,423 (63%) | 1,273 (65%) | 150 (51%) |
Abbreviation: SD, standard deviation.
Oral antibiotic use defined as ≥2 reports of use at baseline or during the study treatment period.
Number who underwent randomization.
Table 2.
Association between oral antibiotic use and colorectal adenoma risk in the 4 Polyp Prevention Study trials.
| No. with endpoint (%) | |||||
|---|---|---|---|---|---|
| Oral antibiotic usec | |||||
| Endpointa | Totalb | No | Yes | RRd (95% CI) | P |
| All 4 trials | 4,769 | 4,034 | 735 | ||
| Any adenoma | 1,853 (40%) | 1,578 (40%) | 275 (39%) | 0.99 (0.90, 1.10) | 0.91 |
| Low-risk adenoma findings | 1,152 (29%) | 977 (29%) | 175 (29%) | 0.99 (0.86, 1.14) | 0.87 |
| High-risk adenoma findings | 628 (18%) | 536 (19%) | 92 (17%) | 1.02 (0.83, 1.25) | 0.85 |
| Antioxidant trial | 751 | 689 | 62 | ||
| Any adenoma | 275 (37%) | 255 (38%) | 20 (33%) | 0.87 (0.60, 1.28) | 0.49 |
| Low-risk adenoma findings | 167 (26%) | 156 (27%) | 11 (21%) | 0.78 (0.45, 1.35) | 0.38 |
| High-risk adenoma findings | 94 (17%) | 86 (17%) | 8 (16%) | 0.90 (0.46, 1.76) | 0.77 |
| Calcium trial | 832 | 785 | 47 | ||
| Any adenoma | 281 (35%) | 270 (35%) | 11 (26%) | 0.80 (0.47, 1.36) | 0.41 |
| Low-risk adenoma findings | 161 (24%) | 156 (24%) | 5 (14%) | 0.61 (0.26, 1.40) | 0.24 |
| High-risk adenoma findings | 100 (16%) | 97 (16%) | 3 (9%) | 0.58 (0.19, 1.72) | 0.33 |
| Aspirin/Folate trial | 1,084 | 740 | 344 | ||
| Any adenoma | 417 (40%) | 295 (41%) | 122 (37%) | 0.94 (0.80, 1.11) | 0.46 |
| Low-risk adenoma findings | 265 (30%) | 185 (31%) | 80 (28%) | 0.95 (0.76, 1.18) | 0.62 |
| High-risk adenoma findings | 137 (18%) | 98 (19%) | 39 (16%) | 0.91 (0.65, 1.28) | 0.60 |
| Vitamin D/Calcium trial | 2,102 | 1,820 | 282 | ||
| Any adenoma | 880 (43%) | 758 (42%) | 122 (44%) | 1.10 (0.96, 1.27) | 0.18 |
| Low-risk adenoma findings | 559 (32%) | 480 (32%) | 79 (34%) | 1.13 (0.93, 1.36) | 0.22 |
| High-risk adenoma findings | 297 (20%) | 255 (20%) | 42 (22%) | 1.21 (0.91, 1.62) | 0.19 |
Abbreviations: CI, confidence interval; RR, risk ratio.
High-risk adenoma findings were defined as ≥1 advanced adenoma (tubulovillous/villous adenomas, ≥1 cm in diameter, with high-grade dysplasia, or adenocarcinoma) or ≥3 synchronous adenomas of any size. Low-risk adenoma findings were defined as 1 or 2 non-advanced adenomas. In total, 123 participants were missing any adenoma endpoint and 73 participants were missing high- and low-risk adenoma findings status.
Count of participants who completed a follow-up colonoscopy during the study treatment period.
Oral antibiotic use defined as ≥2 reports of use at baseline or during the study treatment period.
RR adjusted for age, sex, clinical center, study, and treatment assignment (placebo, active). Study-specific RRs are not adjusted for study. For each RR, those without the endpoint were participants with no incident colorectal adenomas.
Discussion
Oral antibiotic use during colonoscopic surveillance was not associated with colorectal adenoma risk in a secondary analysis of the 4 Polyp Prevention Study trials. Our results are inconsistent with a meta-analysis of 10 observational studies of invasive colorectal cancer (2), but consistent with an assessment of recent oral antibiotic use in a case-control study nested within the Nurses’ Health Study of colorectal adenomas regardless of prior adenoma history (4).
Our study has limitations. The trials did not collect antibiotic dose or duration. History of antibiotic use before study enrollment was not ascertained, preventing us from assessing early-life use, previously found to be a risk factor for colorectal adenomas (4). Distinct reports of antibiotic use were separated by several months, and we could not distinguish continuous from discontinuous use. It was not possible to determine whether antibiotic use at baseline was related to symptoms leading to the initial adenoma diagnosis that qualified participants for these studies. Likewise, some participants may have been more likely to use antibiotics shortly before or after unscheduled follow-up exams that identified adenomas, but results were not meaningfully different when considering only those who completed the planned surveillance interval without any interim colorectal evaluations. In conclusion, these data suggest no association between oral antibiotic use, not otherwise specified, during surveillance and the risk of new colorectal adenomas.
Supplementary Material
Acknowledgments
On behalf of the Polyp Prevention Study Group, the authors express their appreciation to the study participants, investigators, and staff. The Polyp Prevention Study trials were funded by the National Cancer Institute at the National Institutes of Health (U01CA37287 and P30CA23108 to E. R. Greenberg; U01CA046927, R01CA059005, and R01CA098286 to J. A. Baron), and this analysis was funded in part by the National Institute of General Medical Sciences at the National Institutes of Health (P20GM104416 to M. N. Passarelli).
Footnotes
Disclosure of Potential Conflicts of Interest
Together with the Trustees of Dartmouth College, J. A. Baron holds use patents, not licensed, for the chemopreventive use of aspirin and calcium for colorectal cancer. No potential conflicts of interest were disclosed by the other authors.
ClinicalTrials.gov Identifiers: NCT00272324 and NCT00153816
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