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Review
Colorectal cancer
 Safety and efficacy of chemoprevention for familial adenomatous polyposis: a systematic review and meta-analysis
Francisco Tustumi1,2orcid, Amanda Park3orcid, Eric Toshiyuki Nakamura1orcid, Thaís Cabral de Melo Viana1orcid, Elis Nogara Lisboa2orcid, Rodrigo Moisés de Almeida Leite2orcid, Sergio Eduardo Alonso Araujo2orcid, Pedro Luiz Serrano Usón Jr2orcid, Kaique Flávio Xavier Cardoso Filardi4orcid
Annals of Coloproctology 2026;42(1):34-46.
DOI: https://doi.org/10.3393/ac.2025.01018.0145
Published online: February 25, 2026

1Department of Gastroenterology, Universidade de São Paulo, Sao Paulo, Brazil

2Department of Health Sciences, Hospital Israelita Albert Einstein, Sao Paulo, Brazil

3Department of Evidence-based Medicine, Centro Universitário Lusíada, Santos, Brazil

4Department of Surgery, Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, MA, USA

Correspondence to: Francisco Tustumi, PhD Department of Gastroenterology, Universidade de São Paulo, Rua da Reitoria, 374, Sao Paulo 05508-220, Brazil Email: francisco.tustumi@einstein.br
• Received: August 26, 2025   • Revised: October 20, 2025   • Accepted: November 8, 2025

© 2026 The Korean Society of Coloproctology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Purpose
    Familial adenomatous polyposis is a hereditary condition that predisposes individuals to colorectal cancer. This study aimed to evaluate the efficacy and safety of pharmacological therapies for reducing polyp number, burden, and size in individuals with familial adenomatous polyposis.
  • Methods
    A systematic search was conducted in PubMed, Embase, Web of Science, and Cochrane. Randomized trials assessing the effects of pharmacological interventions on polyp number, polyp burden, and polyp size were included, and adverse events were also analyzed.
  • Results
    Sixteen studies (n=985) met the inclusion criteria. The mean participant age was 38±8.3 years, with a mean follow-up of 14.6±15.8 months. Of these studies, 62.5% focused on colorectal polyps, 18.8% on rectal polyps, 18.8% on duodenal polyps, and 12.5% addressed both colorectal and duodenal polyps. Pharmacological interventions were associated with a modest but statistically significant reduction in the number of polyps (Hedges g, −0.57; 95% confidence interval [CI], −1.08 to −0.05) and in average polyp size (Hedges g, −0.26; 95% CI, −0.49 to −0.04). However, no significant reduction in overall polyp burden was observed (Hedges g, −1.07; 95% CI, −2.21 to 0.06). In subgroup analyses, nonselective cyclooxygenase inhibitors produced a large reduction in polyp burden (Hedges g, −2.72; 95% CI, −3.28 to −2.16), while metformin also demonstrated benefit in a single study (Hedges g, −1.06; 95% CI, −1.86 to −0.27). Adverse events were generally infrequent and comparable to placebo.
  • Conclusion
    Chemopreventive interventions may reduce polyp number, burden, and size, and they appear to have a favorable safety profile.
  • Keywords: Adenomatous polyps; Adenoma; Colorectal neoplasms; Hereditary neoplastic syndromes
Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder caused by germline mutation in the adenomatous polyposis coli gene [1]. It results in the development of hundreds to thousands of colorectal polyps, typically beginning during puberty, and confers an almost certain lifetime risk of colorectal cancer (CRC) if left untreated [1].
Currently, the only established method for preventing CRC in patients with FAP is colectomy [2–4]. Surgical options include prophylactic total colectomy with ileorectal anastomosis or proctocolectomy with ileal pouch-anal anastomosis, followed by postoperative endoscopic surveillance and polypectomy [2]. Although surgery effectively reduces cancer risk, it affects quality of life and does not fully prevent polyposis in the rectal remnant or ileal pouch mucosa [5]. Moreover, approximately 90% of individuals with FAP develop duodenal adenomas, making duodenal disease the second leading cause of mortality among patients who have undergone proctocolectomy [6]. Because pancreaticoduodenectomy carries substantial risk, alternative strategies such as chemopreventive agents warrant investigation.
CRC remains one of the leading causes of cancer-related morbidity and mortality worldwide [7]. While widespread implementation of endoscopic screening has reduced CRC incidence and mortality through early detection and removal of polyps [8], endoscopy has limitations, including the possibility of missed lesions and the substantial burden of frequent surveillance in high-risk populations. These limitations have fostered growing interest in complementary chemopreventive approaches aimed at reducing polyp formation and progression. The strong association between chronic inflammation and colorectal carcinogenesis further reinforces the rationale for chemoprevention. Persistent inflammatory stimuli can promote DNA damage, chromosomal instability, and mutations in key tumor suppressor genes, as well as support angiogenesis and activate oncogenic signaling pathways such as PI3K/Akt and MAPK [9, 10]. These mechanisms provide a biological foundation for evaluating pharmacological agents capable of modulating inflammatory pathways or their downstream molecular effects as a means of reducing adenoma development and growth.
Within this context, pharmacological interventions have emerged as promising strategies for CRC prevention through targeting inflammatory mediators and signaling cascades that contribute to tumor initiation and progression [11]. Several categories of chemoprophylactic agents have been studied, including nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., sulindac, aspirin, celecoxib, and rofecoxib), natural compounds with chemopreventive potential such as curcumin and eicosapentaenoic acid, and biliary acid modulators such as ursodeoxycholic acid [12].
Despite encouraging findings, uncertainties remain regarding the comparative efficacy, safety, and optimal clinical application of these chemopreventive agents. Evaluating their differential impacts and potential risks is therefore crucial for developing more personalized prevention strategies, especially for individuals at elevated risk of CRC.
This study aims to evaluate the effects of multiple pharmacological interventions on colorectal polyp number, burden, and size. By assessing the efficacy and safety profiles of these agents, our findings seek to contribute to the expanding body of evidence supporting pharmacological strategies for CRC prevention and to inform future clinical recommendations.
This systematic review and meta-analysis was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and was prospectively registered in PROSPERO (No. CRD42024575526). The Institutional Review Board of Hospital Israelita Albert Einstein granted an exemption from formal ethics approval, as it involved secondary analysis of deidentified data and posed no potential risk to participants.
Eligibility criteria
We included studies that evaluated the role of chemoprevention in patients with FAP. Randomized clinical trials were eligible only when the sample size was larger than 10 patients. We excluded cross-sectional studies, case reports, animal models, and preclinical studies. Studies available only as abstracts and those for which the full text could not be retrieved were also excluded.
Search strategy
A comprehensive search was performed in PubMed, Embase, Web of Science, and Cochrane (CENTRAL) without restrictions on language or publication date. The search covered all results from database inception through August 1, 2024. The search strategy was constructed using combinations of keywords and MeSH (Medical Subject Headings) terms, including "colonic polyps,” “familial adenomatous polyp*,” “FAP,” "familial polyposis,” “chemoprevention,” “chemoprophylaxis,” "preventive chemotherapy,” “sirolimus,” “aspirin,” “NSAIDs,” “COX-2 inhibitors,” “sulindac,” “celecoxib,” “rofecoxib,” “tiracoxib,” “acetylsalicylic acid,” “coxib,” “cyclooxygenase 2 inhibitors,” “metformin,” “statins,” "long-chain omega-3 polyunsaturated fatty acids,” "vitamin A,” "vitamin C,” "vitamin E,” "beta-carotene,” “selenium,” "folic acid,” “calcium,” "vitamin D,” “DFMO,” “erlotinib,” “curcumin,” “guselkumab,” "hydrogen sulfide,” and "nitric oxide–releasing NSAIDs".
Study selection and data extraction
Two independent reviewers screened all studies for inclusion, and disagreements were resolved by consensus. Extracted data included study design; baseline participant characteristics (age and sex); intervention details (type of chemopreventive agent and dosage); polyp-related outcomes (mean, standard deviation, and absolute counts for number and size); and treatment-related complications (absolute counts).
Study groups
The included studies examined a range of pharmacological interventions for preventing colorectal polyps. Intervention groups consisted of participants receiving cyclooxygenase 2 (COX-2)-specific inhibitors, nonselective COX inhibitors, metformin, combination therapies, or other pharmacological agents as defined by each study. Control groups included participants who received placebo or no intervention. Analyses compared outcomes between intervention and control groups to evaluate both effectiveness and safety. In trials with multiple intervention arms or factorial designs, we followed Cochrane recommendations by selecting only the most clinically relevant comparison to avoid double-counting participants and maintain comparability across studies.
Outcomes
The primary outcomes were the number of polyps after treatment, the polyp burden (defined as the cumulative size of adenomas based on the sum of their diameters detected during colonoscopy) assessed through overall volume reduction, and the average size of polyps following treatment. Additionally, changes in polyp number and size were analyzed as percentage variation from baseline to enhance comparability across studies. Secondary outcomes included the evaluation of adverse events.
Risk-of-bias assessment
The risk of bias for nonrandomized studies was evaluated using ROBINS-I (Risk of Bias in Nonrandomized Studies of Interventions) ver. 2, while the risk of bias for randomized trials was assessed with RoB 2 (Cochrane Risk of Bias tool) [13].
Statistical analysis
Data were synthesized using a random-effects meta-analysis model to account for anticipated clinical heterogeneity. Heterogeneity was assessed using the I2 statistic. Absolute values for all outcome parameters were extracted and analyzed using Stata ver. 18.0 (Stata Corp). Effect estimates were aggregated statistically, with weighted risk differences and 95% confidence intervals (CIs) calculated.
All outcomes were expressed as risk differences or Hedges g standardized mean differences comparing intervention and control groups. Subgroup analyses were conducted according to chemopreventive agent type, including COX-2 inhibitors, nonselective COX inhibitors, metformin, combination therapies, and other pharmacological agents. Additionally, a stratified analysis by anatomical site (duodenum vs. colorectum) was performed exclusively for studies evaluating COX inhibitors, either selective or nonselective, to explore whether anatomical location contributed to heterogeneity.
Baseline characteristics of the included studies
After study selection, a total of 16 studies were included in the analysis (Fig. 1) [14–29]. The average proportion of female participants was 53.3%, with a mean age of 38±8.3 years and a mean follow-up duration of 14.6±15.8 months. Among these studies, 62.5% focused on colorectal polyps, 18.8% on rectal polyps, 18.8% on duodenal polyps, and 12.5% addressed both colorectal and duodenal polyps. The pharmacological interventions evaluated included metformin, ursodeoxycholic acid, nonselective COX inhibitors, and COX-2–specific inhibitors. The baseline characteristics of the included studies are summarized in Table 1 [14–29], and a detailed overview of the outcomes is provided in Supplementary Tables 1 and 2.
Effect of pharmacological interventions on polyp burden
Pharmacological interventions overall were not significantly associated with changes in polyp burden (Hedges g, −1.07; 95% CI, −2.21 to 0.06; I2=94.17%). In subgroup analyses, nonselective COX inhibitors (Hedges g, −2.72; 95% CI, −3.28 to −2.16; I2=0%) and metformin (Hedges g, −1.06; 95% CI, −1.86 to −0.27; I2=0%) demonstrated significant reductions in polyp burden (Fig. 2) [15, 26, 27, 29].
When stratified by anatomical site, COX inhibitors, whether selective or nonselective, showed no significant effect on colorectal polyp burden (Hedges g, −0.22; 95% CI, −0.53 to 0.10; I2=0%). In contrast, their impact on duodenal polyp burden remained significant (Hedges g, −2.72; 95% CI, −3.28 to −2.16; I2=0%).
Effect on polyp number
Pharmacological interventions were associated with a modest but statistically significant reduction in the number of polyps after treatment (Hedges g, –0.57; 95% CI, –1.08 to –0.05; I2=90.19%) (Fig. 3A) [15–22, 24, 26–29]. However, subgroup analyses revealed no specific medication class that significantly reduced the accumulated number of polyps after treatment.
When evaluating the change in polyp number from baseline, the overall effect was not statistically significant (Hedges g, –5.10%; 95% CI, –22.12 to 3.20; I2=99.97%) (Fig. 3B) [15, 16, 18–22, 24–29]. Metformin was associated with a significant reduction in polyp number after treatment (Hedges g, –4.25%; 95% CI, –5.18 to –3.32; I2=0%). None of the other subgroups (COX-2–specific inhibitors, nonselective COX inhibitors, or other agents) demonstrated statistically significant effects in this analysis.
When stratified by anatomical site, COX inhibitors (selective or nonselective) showed no significant effect on colorectal polyp number (Hedges g, −0.56; 95% CI, −1.28 to 0.17; I2=92.14%). However, they significantly reduced duodenal polyp counts (Hedges g, −1.85; 95% CI, −2.33 to −1.36; I2=0%). By contrast, when assessing the percentage change in polyp number from baseline, no significant reductions were found for either colorectal polyps (Hedges g, −13.57%; 95% CI, −36.03 to 8.89; I2=99.97%) or duodenal polyps (Hedges g, −10.88%; 95% CI, −26.41 to 4.65; I2=99.16%).
Effect on polyp size
The average polyp size did not differ significantly between the intervention and control groups (Hedges g, −0.29 mm; 95% CI, −0.58 to 0.00; I2=63.18%) (Fig. 4A) [14, 16–21, 24, 26, 27]. Subgroup analyses showed that none of the individual agents, such as COX-2 specific inhibitors (Hedges g, –0.56 mm; 95% CI, –1.18 to 0.07; I2=64.91%), metformin (Hedges g, 0.21; 95% CI, –0.56 to 0.99; I2=0%), or nonselective COX inhibitors (Hedges g, –0.31 mm; 95% CI, –0.56 to 0.04; I2=60.64%), yielded statistically significant effects.
When evaluating the change in polyp size from baseline, the overall analysis also showed a significant reduction (Hedges g, –11.80%; 95% CI, –23.33 to –0.27; I2=99.92%) (Fig. 4B) [16, 18–21, 24, 26–29]. Among the subgroups, only the category labeled “other” showed a statistically significant decrease (Hedges g, –11.13%; 95% CI, –21.87 to –0.40; I2=96.98%). The other subgroups (COX-2 inhibitors, nonselective COX inhibitors, metformin, and other drugs) did not show significant effects.
In analyses stratified by anatomical site, COX inhibitors (either selective or nonselective) significantly reduced colorectal polyp size (Hedges g, −0.49 mm; 95% CI, −0.78 to −0.20; I2=45.84%). No significant effect was observed for duodenal polyps (Hedges g, 0.21 mm; 95% CI, −0.19 to 0.62; I2=0%). Conversely, when evaluating the percentage change in polyp size from baseline, no significant differences were identified for colorectal polyps (Hedges g, −10.42%; 95% CI, −29.31 to 8.47; I2=99.97%), whereas the duodenal subgroup exhibited a marked reduction (Hedges g, −42.36%; 95% CI, −48.50 to −36.23; I2=99.97%).
Adverse events
Overall, adverse events and severe adverse events were infrequent. Metformin was associated with a significantly increased risk of adverse events (risk difference, 0.17; 95% CI, 0.06 to 0.29; I2=0%), whereas other chemopreventive drugs were not associated with increased risk for overall or severe adverse events (Fig. 5) [14–26, 28, 29]. No significant increases were observed in the risk of headache or bleeding associated with chemoprevention (Fig. 6) [14–17, 19–22, 24–26, 28, 29]. Gastrointestinal symptoms, including nausea or vomiting, diarrhea, and abdominal pain, were also comparable between treatment and control groups (Fig. 7) [14–17, 21, 22, 24–29].
Risk-of-bias assessment
The primary concerns regarding risk of bias were related to allocation concealment, primarily due to insufficient detail on randomization procedures in the included studies, as well as selective reporting, particularly in trials that lacked a predefined, publicly accessible protocol. The full risk-of-bias assessment is presented in Supplementary Fig. 1.
This systematic review and meta-analysis demonstrated that some pharmacological interventions significantly reduce the number and size of polyps in patients with FAP. Additionally, these treatments appear to have a favorable safety profile, with a low incidence of adverse events. These findings support the potential role of chemoprevention as an adjunct to surveillance and surgical management strategies in FAP patients.
The reduction in overall polyp burden observed with nonselective COX inhibitors and metformin highlights the potential of chemopreventive agents to delay or mitigate adenoma progression [30]. Even modest reductions in the volume of large polyps may decrease the number of cells susceptible to subsequent genetic alterations that drive malignant transformation [31]. Adenomatous polyp size is a well-established predictor of malignancy, as larger polyps carry an elevated risk of advancing to CRC [32]. Although reducing size alone cannot eliminate cancer risk, it remains an important component of broader strategies aimed at lowering cumulative neoplastic potential.
In addition to their effect on polyp size, the capacity of pharmacological interventions to reduce the total polyp count is clinically relevant. Patients with FAP typically develop numerous adenomas, contributing to increased cumulative cancer risk and frequent need for endoscopic removal or surgical intervention [3]. The reduction in polyp count observed in this meta-analysis, particularly with metformin, suggests that such agents may help delay disease progression.
Most of the pharmacological agents included in this review act at different points of the inflammatory cascade, underscoring inflammation’s central role in adenoma initiation and progression in FAP. In this hereditary condition, germline APC mutations lead to dysregulated activation of the Wnt/β-catenin pathway, promoting early adenoma formation. Chronic inflammation compounds this predisposition by inducing DNA damage, oxidative stress, and chromosomal instability, thereby facilitating clonal expansion even before dysplasia becomes evident. Through the release of proinflammatory cytokines, activation of nuclear factor–κB (NF-κB), and stimulation of angiogenic mediators, the inflammatory microenvironment accelerates both adenoma initiation and progression to larger and more dysplastic lesions [33, 34].
Among the evaluated agents, nonselective COX inhibitors demonstrated a substantial effect, suggesting that prostaglandin synthesis inhibition plays a central role in modulating polyp growth. NSAIDs have long been recognized for their ability to alleviate pain, reduce inflammation, and control fever. Their primary mechanism involves inhibiting COX enzymes, which regulate the synthesis of prostaglandins, thromboxanes, and prostacyclins—key mediators of inflammation [35]. Beyond these traditional functions, growing evidence indicates that NSAIDs exert antineoplastic effects, particularly in CRC prevention [36]. Epidemiologic and observational studies have consistently identified an association between NSAID use and reduced CRC incidence [37]. Lamont and Dias [38], for instance, reported a significant inverse correlation between NSAID use patterns and CRC incidence using population-based data encompassing 518,590 clinical visits over 15 years. Moreover, in an umbrella review, Wang et al. [39] demonstrated that NSAIDs may reduce the incidence of several other tumor types, including breast, central nervous system, head and neck, liver, esophageal, gastric, lung, and gynecological cancers.
COX inhibitors have shown considerable potential due to their ability to modulate inflammatory pathways implicated in tumorigenesis [40]. Chronic inflammation promotes cancer development through mechanisms such as inducing genetic damage, stimulating angiogenesis, and disrupting normal cell growth, division, and programmed death [41]. COX inhibitors mitigate these processes by suppressing NF-κB–driven transcription, enhancing apoptosis, and limiting angiogenesis, thereby potentially preventing small adenomas from progressing to more advanced neoplastic stages [42].
Although COX inhibition is central to NSAID-mediated anticancer activity, emerging evidence indicates that additional COX-independent mechanisms also contribute [43]. Several studies demonstrate that NSAIDs can inhibit tumor cell proliferation and induce apoptosis regardless of COX-1 or COX-2 expression levels [44]. This is further supported by findings showing that NSAID potency in suppressing COX activity does not necessarily correspond with their antitumor effects. For example, although celecoxib and rofecoxib exhibit similar half-maximal inhibitory concentration values for COX-2 inhibition, celecoxib demonstrates significantly stronger antiproliferative activity in vitro [45]. Additionally, studies using embryonic fibroblasts from COX-knockdown mice revealed that tumor cells remain sensitive to NSAID-induced apoptosis even without COX expression [46]. These observations highlight the complexity of NSAID-mediated anticancer effects and reinforce the need for ongoing investigation into their specific molecular targets, which could inform the development of more selective and effective therapeutic agents.
Despite the considerable anticancer potential of NSAIDs, their clinical applicability is constrained by safety concerns, particularly gastrointestinal and cardiovascular risks associated with long-term use [47]. Selective COX-2 inhibitors were originally developed to reduce the gastrointestinal complications frequently associated with traditional NSAIDs, offering a theoretically safer alternative [48]. However, the findings of this review suggest that concerns regarding adverse effects in FAP patients may be less pronounced than previously thought for both selective and nonselective COX inhibitors, as no statistically significant difference was observed between NSAIDs and placebo for overall or severe adverse events. Nevertheless, among individuals without substantial CRC risk or those with sporadic adenomas, the potential harms of COX inhibition may outweigh any chemopreventive benefits. While NSAIDs may offer meaningful chemoprevention for patients with FAP, their use should not be generalized to lower-risk populations. Future research should therefore aim to establish the optimal dosage and duration of therapy needed to maximize therapeutic benefit while limiting the risk of complications.
Other non-NSAID chemopreventive agents have also been explored for their potential protective effects. Metformin, a widely used antidiabetic medication, has garnered interest due to epidemiologic associations between diabetes and increased cancer risk, largely mediated through insulin and growth factor signaling pathways [49]. Recent studies indicate that metformin substantially reduces reactive oxygen species formation and suppresses several inflammatory signaling cascades [50]. In vitro work has shown that metformin downregulates COX-2 and intercellular adhesion molecule 1 (ICAM-1) expression in breast cancer cells [51]. Additionally, metformin has been reported to inhibit proliferation of human colonic epithelium, decrease the formation of rectal abnormal crypt foci, and modulate gastrointestinal flora [27]. Nevertheless, because well-designed randomized trials remain limited, uncertainty persists regarding which patients may derive the greatest benefit from metformin as a chemopreventive agent. Individuals with insulin resistance may experience more pronounced protective effects, whereas others may benefit less. Further research is needed to clarify metformin’s role and to identify the populations most likely to respond favorably.
Several other medications and naturally occurring compounds have been investigated for their potential roles in reducing carcinogenesis risk. Most exert anti-inflammatory effects, consistent with the well-established contribution of chronic inflammation to cancer development. Curcumin, for example, has antioxidant and anti-inflammatory properties, and a meta-analysis by Jakubczyk et al. [52] reported that curcumin increases total antioxidant capacity (pooled standardized mean difference, 2.7; P=0.045). Similarly, eicosapentaenoic acid, an ω-3 polyunsaturated fatty acid, has demonstrated antineoplastic activity by inhibiting inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor α, and interferon γ [53]. However, studies assessing the use of these agents specifically for FAP remain limited, and additional clinical trials are needed before firm conclusions regarding their chemopreventive efficacy can be established or translated into routine practice.
Despite these encouraging findings, this review has several limitations. The heterogeneity across studies in terms of drug regimens and follow-up duration may affect the generalizability of the pooled results. We conducted a stratified analysis by anatomical site (duodenum vs. colorectum) restricted to studies evaluating COX inhibitors in an effort to identify a possible source of heterogeneity. However, this analysis did not account for the high I2 values observed, suggesting that other clinical or methodological factors likely contributed to the variability between trials. Another important source of heterogeneity concerns the surgical status of participants. Some trials enrolled pre-colectomy individuals, others enrolled post-colectomy patients, and some included both. Because colectomy alters the natural history of FAP and influences both the distribution and progression of polyps, these differences limit comparability across studies. Furthermore, although chemoprevention appears to reduce polyp burden, not all adenomatous polyps inevitably progress to malignancy. Identifying biomarkers or molecular characteristics that help predict which polyps are most likely to undergo malignant transformation remains an important area for future research. Integrating molecular data may support a more individualized approach to chemoprevention by identifying optimal candidates and improving treatment efficacy. Additional concerns arise from the inclusion of patients diagnosed clinically based on phenotype (≥100 polyps) without APC mutation confirmation. Such criteria may have resulted in the inclusion of older pre-colectomy individuals who are not fully representative of the typical FAP trajectory, potentially introducing bias and limiting the applicability of the findings. Given these limitations, professional societies remain cautious in their recommendations. The American Society for Gastrointestinal Endoscopy (ASGE) advises that chemopreventive agents be used only within tertiary hereditary cancer centers or within the context of clinical trials, as evidence supporting their role in hereditary polyposis syndromes continues to evolve [54]. Similarly, the American College of Gastroenterology (ACG) notes that although sulindac and celecoxib have demonstrated adenoma regression in FAP, their impact on cancer prevention remains uncertain, and concerns regarding long-term cardiovascular toxicity have tempered enthusiasm for COX-2 inhibitors [55]. Thus, chemoprevention is not considered a substitute for colectomy but may serve as a useful adjunct aimed at reducing adenoma burden and facilitating surveillance of the rectum or duodenum.
Conclusions
Pharmacological interventions, particularly nonselective COX inhibitors and metformin, may reduce polyp burden, number, and size in patients with FAP while maintaining a favorable safety profile. However, considerable heterogeneity across studies, including variations in drug regimens, follow-up duration, colectomy status, and anatomical site, limits the strength of broad conclusions. These findings should therefore be interpreted cautiously. To clarify the role of chemoprevention in FAP and to identify the patient subgroups most likely to benefit, further well-designed, standardized clinical trials are needed.

Conflict of interest

Francisco Tustumi received financial support through a research scholarship from the Bracell Foundation. No other potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: all authors; Data curation: all authors; Formal analysis: all authors; Funding acquisition: FT; Investigation: all authors; Methodology: all authors; Project administration: FT, SEAA, PLSU; Resources: all authors; Software: RMAL, KFXCF; Supervision: FT, SEAA, PLSU; Validation: FT, SEAA, PLSU; Visualization: all authors; Writing–original draft: all authors; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Supplementary Table 1.

Efficacy outcomes for chemopreventive drugs measured by Hedges g
ac-2025-01018-0145-Supplementary-Table-1.pdf

Supplementary Table 2.

Safety outcomes for chemopreventive drugs measured by risk difference
ac-2025-01018-0145-Supplementary-Table-2.pdf

Supplementary Fig. 1.

Summary of risk-of-bias assessments.
ac-2025-01018-0145-Supplementary-Fig-1.pdf
Supplementary materials are available from https://doi.org/10.3393/ac.2025.01018.0145.
Fig. 1.
PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flowchart of the study selection.
ac-2025-01018-0145f1.jpg
Fig. 2.
Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for polyp burden in familial adenomatous polyposis. Results are shown as the overall pooled estimate and stratified by medication type. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f2.jpg
Fig. 3.
Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for polyp number in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Average number of polyps after treatment. (B) Change in the number of polyps after treatment. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f3.jpg
Fig. 4.
Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for adverse events in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Average polyp size after treatment; (B) change in the size of polyps after treatment. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f4.jpg
Fig. 5.
Forest plot comparing chemoprevention (treatment group) versus placebo or no treatment (control group) for adverse events in familial adenomatous polyposis. Results are presented as overall pooled estimates and stratified by medication type. (A) Any adverse event. (B) Severe adverse event. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f5.jpg
Fig. 6.
Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for headache and bleeding in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Headache. (B) Bleeding. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f6.jpg
Fig. 7.
Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for gastrointestinal adverse events in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Nausea or vomiting. (B) Diarrhea. (C) Abdominal pain. SD, standard deviation; CI, confidence interval.
ac-2025-01018-0145f7.jpg
Table 1.
Baseline characteristics of the included randomized controlled trial studies
Study Type of drug Dosage Location of polyps Surgical status Female sex (%) Mean age (yr) No. of patients Mean follow-up (mo) Control group Efficacy outcome Safety outcome
Burke et al. [15] (2017) Celecoxib 16 mg/kg/day Colorectal Pre-colectomy 52.7 12.6 106 60 Placebo Polyp burden, number of polyps, change in polyp number Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Burn et al. [14] (2011) Aspirin; resistant starch 600 mg/day; 30 g/day Rectal Pre-colectomy 49.6 18 133 17 Placebo Polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Cruz-Correa et al. [16] (2018) Curcumin 7 g/day Colorectal Pre- and post-colectomy 63 41 44 12 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Giardiello et al. [17] (2002) Sulindac 150–300 mg/day Colorectal Pre-colectomy 65.8 14.3 41 48 Placebo Number of polyps, polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Higuchi et al. [18] (2003) Rofecoxib 25 mg/day Rectal Pre- and post-colectomy 47.6 33 21 12 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events
Ishikawa et al. [20] (2013) Aspirin 100 mg/day Colorectal Pre-colectomy 50 38.2 34 NA Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events, bleeding
Ishikawa et al. [19] (2021) Aspirin; mesalazine 100 mg/day; 2 g/day Colorectal Pre-colectomy 48 33.7 102 8 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, bleeding
Iwama et al. [21] (2006) Tiracoxib 150–200 mg/day Colorectal Pre- and post-colectomy 55.7 35.3 61 6 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Lynch et al. [22] (2010) Celecoxib 4–16 mg/kg/day Colorectal Pre-colectomy 55.6 12.3 18 3 Placebo Number of polyps, change in polyp number Severe adverse events, bleeding, nausea, diarrhea
Parc et al. [23] (2012) Ursodesoxycholic acid 10 mg/kg/day Duodenal Post-colectomy 44 40 55 24 Placebo Spigelman classificationa Overall adverse events
Park et al. [24] (2021) Metformin 500–1,500 mg/day Colorectal and duodenal Pre-colectomy 64.7 37 34 7 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Phillips et al. [25] (2002) Celecoxib 200–800 mg/day Duodenal Pre- and post-colectomy 57 34 83 6 Placebo Change in polyp number Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Samadder et al. [26] (2016) Sulindac plus erlotinib 300 mg/day; 75 mg/day Duodenal Pre- and post-colectomy 61 41.5 92 6 Placebo Polyp burden, number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Steinbach et al. [27] (2000) Celecoxib 200–800 mg/day Colorectal Pre- and post-colectomy 42.8 35.9 77 6 Placebo Polyp burden, number of polyps, change in polyp number, polyp size, change in polyp size Diarrhea, abdominal pain
West et al. [28] (2010) Eicosapentaenoic 2 g/day Rectal Post-colectomy 49 41 58 6 Placebo Number of polyps, change in polyp number, change in polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
Zhou et al. [29] (2024) Metformin 1 g/day Colorectal and duodenal Pre- and post-colectomy 33.3 40.5 26 12 Placebo Polyp burden, number of polyps, change in polyp number, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain

NA, not available.

aExcluded from the meta-analysis because outcome definitions were not comparable across studies.

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        Safety and efficacy of chemoprevention for familial adenomatous polyposis: a systematic review and meta-analysis
        Ann Coloproctol. 2026;42(1):34-46.   Published online February 25, 2026
        DOI: https://doi.org/10.3393/ac.2025.01018.0145
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      Safety and efficacy of chemoprevention for familial adenomatous polyposis: a systematic review and meta-analysis
      Image Image Image Image Image Image Image
      Fig. 1. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flowchart of the study selection.
      Fig. 2. Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for polyp burden in familial adenomatous polyposis. Results are shown as the overall pooled estimate and stratified by medication type. SD, standard deviation; CI, confidence interval.
      Fig. 3. Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for polyp number in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Average number of polyps after treatment. (B) Change in the number of polyps after treatment. SD, standard deviation; CI, confidence interval.
      Fig. 4. Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for adverse events in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Average polyp size after treatment; (B) change in the size of polyps after treatment. SD, standard deviation; CI, confidence interval.
      Fig. 5. Forest plot comparing chemoprevention (treatment group) versus placebo or no treatment (control group) for adverse events in familial adenomatous polyposis. Results are presented as overall pooled estimates and stratified by medication type. (A) Any adverse event. (B) Severe adverse event. SD, standard deviation; CI, confidence interval.
      Fig. 6. Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for headache and bleeding in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Headache. (B) Bleeding. SD, standard deviation; CI, confidence interval.
      Fig. 7. Forest plot comparing chemoprevention (treatment group) with placebo or no treatment (control group) for gastrointestinal adverse events in familial adenomatous polyposis. Results are presented as the overall pooled estimate and stratified by medication type. (A) Nausea or vomiting. (B) Diarrhea. (C) Abdominal pain. SD, standard deviation; CI, confidence interval.

      Fig. 1.

      Fig. 2.

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      Fig. 4.

      Fig. 5.

      Fig. 6.

      Fig. 7.

      Safety and efficacy of chemoprevention for familial adenomatous polyposis: a systematic review and meta-analysis
      Study Type of drug Dosage Location of polyps Surgical status Female sex (%) Mean age (yr) No. of patients Mean follow-up (mo) Control group Efficacy outcome Safety outcome
      Burke et al. [15] (2017) Celecoxib 16 mg/kg/day Colorectal Pre-colectomy 52.7 12.6 106 60 Placebo Polyp burden, number of polyps, change in polyp number Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Burn et al. [14] (2011) Aspirin; resistant starch 600 mg/day; 30 g/day Rectal Pre-colectomy 49.6 18 133 17 Placebo Polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Cruz-Correa et al. [16] (2018) Curcumin 7 g/day Colorectal Pre- and post-colectomy 63 41 44 12 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Giardiello et al. [17] (2002) Sulindac 150–300 mg/day Colorectal Pre-colectomy 65.8 14.3 41 48 Placebo Number of polyps, polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Higuchi et al. [18] (2003) Rofecoxib 25 mg/day Rectal Pre- and post-colectomy 47.6 33 21 12 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events
      Ishikawa et al. [20] (2013) Aspirin 100 mg/day Colorectal Pre-colectomy 50 38.2 34 NA Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Severe adverse events, bleeding
      Ishikawa et al. [19] (2021) Aspirin; mesalazine 100 mg/day; 2 g/day Colorectal Pre-colectomy 48 33.7 102 8 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, bleeding
      Iwama et al. [21] (2006) Tiracoxib 150–200 mg/day Colorectal Pre- and post-colectomy 55.7 35.3 61 6 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Lynch et al. [22] (2010) Celecoxib 4–16 mg/kg/day Colorectal Pre-colectomy 55.6 12.3 18 3 Placebo Number of polyps, change in polyp number Severe adverse events, bleeding, nausea, diarrhea
      Parc et al. [23] (2012) Ursodesoxycholic acid 10 mg/kg/day Duodenal Post-colectomy 44 40 55 24 Placebo Spigelman classificationa Overall adverse events
      Park et al. [24] (2021) Metformin 500–1,500 mg/day Colorectal and duodenal Pre-colectomy 64.7 37 34 7 Placebo Number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Phillips et al. [25] (2002) Celecoxib 200–800 mg/day Duodenal Pre- and post-colectomy 57 34 83 6 Placebo Change in polyp number Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Samadder et al. [26] (2016) Sulindac plus erlotinib 300 mg/day; 75 mg/day Duodenal Pre- and post-colectomy 61 41.5 92 6 Placebo Polyp burden, number of polyps, change in polyp number, polyp size, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Steinbach et al. [27] (2000) Celecoxib 200–800 mg/day Colorectal Pre- and post-colectomy 42.8 35.9 77 6 Placebo Polyp burden, number of polyps, change in polyp number, polyp size, change in polyp size Diarrhea, abdominal pain
      West et al. [28] (2010) Eicosapentaenoic 2 g/day Rectal Post-colectomy 49 41 58 6 Placebo Number of polyps, change in polyp number, change in polyp size Severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Zhou et al. [29] (2024) Metformin 1 g/day Colorectal and duodenal Pre- and post-colectomy 33.3 40.5 26 12 Placebo Polyp burden, number of polyps, change in polyp number, change in polyp size Overall adverse events, severe adverse events, headache, bleeding, nausea, diarrhea, abdominal pain
      Table 1. Baseline characteristics of the included randomized controlled trial studies

      NA, not available.

      Excluded from the meta-analysis because outcome definitions were not comparable across studies.

      Table 1.

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