Prior Adenoma Research Articles

Physician Decision-Making About Surveillance in Older Adults With Prior Adenomas: Results From a National Survey.

There is no clear guidance on when surveillance colonoscopies should stop in older adults with prior adenomas. We aimed to examine physicians' decision-making regarding surveillance colonoscopies in older adults. In a national mailed survey of 1,800 primary care physicians (PCP) and 600 gastroenterologists, we asked whether physicians would recommend surveillance colonoscopy in vignettes where we varied patient age (75 and 85 years), health (good, medium, and poor), and prior adenoma risk (low and high). We examined the association between surveillance recommendations and patient and physician characteristics using logistic regression. We also assessed decisional uncertainty, need for decision support, and decision-making roles. Of 1,040 respondents (response rate 54.8%), 874 were eligible and included. Recommendation for surveillance colonoscopies was lower if patient was older (adjusted proportions 20.6% vs 49.8% if younger), in poor health (adjusted proportions 7.1% vs 28.8% moderate health, 67.7% good health), and prior adenoma was of low risk (adjusted proportions 29.7% vs 41.6% if high risk). Family medicine physicians were most likely and gastroenterologists were least likely to recommend surveillance (adjusted proportions 40.0% vs 30.9%). Approximately 52.3% of PCP and 35.4% of gastroenterologists reported uncertainty regarding the benefit/harm balance of surveillance in older adults. Most (85.9% PCP and 77.0% gastroenterologists) would find a decision support tool helpful. Approximately 32.8% of PCP vs 71.5% of gastroenterologists perceived it as the gastroenterologist's role to decide about surveillance colonoscopies. Studies to better evaluate the benefits/harms of surveillance colonoscopy in older adults and decisional support tools that help physicians and patients incorporate such data are needed.

Systematic review and meta-analysis: Associations between metabolic syndrome and colorectal neoplasia outcomes.

Metabolic syndrome (MetS) is a cluster of factors including obesity, hypertension, diabetes, hypercholesterolemia and hyperlipidaemia. It has been associated with an increased risk of colorectal neoplasia. This systematic review and meta-analysis assessed the association between MetS and (i) recurrence of adenomas or occurrence of CRC in patients with prior adenomas, and (ii) survival in patients with CRC. MEDLINE, Embase, Scopus and Web of Science were searched up to 22 November 2019. Two authors independently conducted title and abstract screening; full text of eligible studies was evaluated. Where ≥3studies reported effect measures for a specific outcome, meta-analysis using random effects model was conducted. I2 was used to assess between-study heterogeneity. Quality appraisal was undertaken with the Newcastle-Ottawa Score. The search identified 1,764 articles, 55 underwent full text screening, resulting in a total of 15 eligible studies. Five studies reported on metachronous neoplasia, with differing outcomes precluded a meta-analysis. No consistent relationship between MetS and metachronous neoplasia was found. Ten studies reported on survival outcomes. MetS was associated with poorer CRC-specific survival (HR=1.8, 95% CI: 1.04-3.12, I2 =92.7%, n=3). Progression-free survival was also worse but this did not reach statistical significance (HR=1.12, 95% CI: 0.89-1.42, I2 =85.6%, n=3). There was no association with overall survival (HR=1.04, 95% CI: 0.94-1.15, I2 =43.7%, n=7). Significant heterogeneity was present but subgroup analysis did not account for this. MetS is associated with poorer CRC-specific survival, but evidence is inconsistent on metachronous neoplasia. Further research is warranted to better understand the impact of MetS on the adenoma-carcinoma pathway.

Yield and Predictors of Surveillance Colonoscopies in Older Adults With Long-standing Ulcerative Colitis

Although colonoscopies for dysplasia surveillance are standard of care in patients with long-standing ulcerative colitis (UC), there is a paucity of data on the yield of surveillance colonoscopies in those older than 75 years of age. We conducted a multicenter retrospective cohort study including patients with UC who underwent ≥1 colonoscopy at age ≥75 years. The primary outcome was diagnosis of dysplasia (visible or random) and colorectal cancer. Multivariable regression adjusted for relevant confounders examined the predictors of polypoid or non-polypoid dysplasia or colorectal cancer. The primary cohort included 211 patients with UC who underwent 635 colonoscopies after age ≥75 years. A total of 83 patients (39.3%) patients had dysplasia or cancer detected. Among colonoscopies, 123 (19.4%) identified visible dysplasia, 23 (3.6%) had random dysplasia (1 high-grade dysplasia found in each group, respectively), and 5 (0.8%) had colon cancer. In multivariable analysis, prior adenoma or colon cancer below age 75 tears (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07-3.96), flat dysplasia before 75 years (OR, 2.78; 95% CI, 1.05-7.44), and older age (80-84 years (OR, 2.29; 95% CI, 1.20-4.38), ≥85 years (OR, 3.54; 95% CI, 1.27-9.82) were associated with detection of dysplasia or cancer. Only 1 patient was noted to have a procedure-related complication. Patients with long-standing UC without prior dysplasia may have a low yield on continued endoscopic surveillance at age ≥75 years. A targeted approach to surveillance may be appropriate in older individuals with UC.

Oral Antibiotics and Risk of New Colorectal Adenomas During Surveillance Follow-up.

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. We performed a secondary analysis of four 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 two or three 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 four trials together. Cumulatively, the four 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. Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps. Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas.

Primary Care Clinician Decision-Making Around Surveillance Colonoscopies in Older Adults with Prior Adenomas

While guidelines recommend against routine colorectal cancer screening in adults >75 years and/or those with limited life expectancies, there is no clear guidance on when surveillance colonoscopies following prior adenoma detection should stop. How primary care clinicians weigh the potential risks and benefits of surveillance colonoscopies in older adults with prior adenomas is unknown. We conducted semistructured in-person interviews with 30 primary care clinicians from 21 clinics in Maryland. We asked how clinicians decided whether to continue or stop surveillance colonoscopies in older adults (65+ years) with prior adenomas. Interview transcripts were independently coded by 2 investigators using qualitative content analysis. Participants described a range of decision-making approaches. Some deferred to specialists because they did not feel confident making decisions about stopping surveillance in light of the higher cancer risk involved. Some took a more active role and discussed the decision with patients and/or specialists. Other clinicians felt comfortable stopping surveillance colonoscopies and made these decisions based on patient age, comorbidities, or life expectancy. We found a range of decision-making approaches among primary care clinicians on whether to continue surveillance colonoscopies in older adults with prior adenomas. Separate bodies of evidence currently exist on how prior adenoma characteristics influence colorectal cancer risk and on how older age and declining health influence the benefit/harm balance of screening. Information is lacking on the benefits and harms of surveillance in older adults with prior adenomas. Developing the evidence to address this knowledge gap is critically needed to inform clinical decision making.

Su1735 TRADITIONAL RISK FACTORS FOR COLORECTAL CARCINOGENESIS AND THEIR RELATION TO DEVELOPMENT OF INTERVAL AND NON-INTERVAL CANCERS AFTER COLONOSCOPIC SCREENING OR SURVEILLANCE

Post-colonoscopy colorectal cancers (PCCRC) are defined as those detected ≤10 years after index colonoscopy negative for cancer. Although traditional factors implicated in carcinogenic risk (e.g., family history, history of prior adenomas, high risk adenomas) might be predicted to influence PCCRC emergence, this has not been evaluated in PCCRC subsets of non-interval and interval colorectal cancer. The aim of this study was to test this concept.

P058 INCREASES IN HEMOGLOBIN ARE ASSOCIATED WITH A DECREASED RISK FOR COLORECTAL CANCER IN VETERAN’S AFFAIRS INFLAMMATORY BOWEL DISEASE PATIENTS

Colorectal cancer (CRC) has long been associated with inflammatory bowel disease (IBD), thought to be due to chronic mucosal inflammation. With newer IBD treatments, the incidence of CRC is decreasing, possibly due to improved therapies or improved treatment endpoints. Our primary aim was to assess for risk factors for CRC in IBD patients compared to IBD patients with adenomas to identify those at higher risk for CRC to target preventive measures. We performed a retrospective case-control study at a Veteran’s Affairs (VA) medical center. Data collection included IBD history, presence of active inflammation, history of prior adenomas, family history of CRC, labs, endoscopy and pathology results at the time of CRC or adenoma diagnosis (Table 1). The cases of CRC were then compared to a cohort of IBD patients with adenomas matched for age, IBD diagnosis, and gender. A matched-pair (1 case: 2 controls) conditional logistic regression model used backward, forward, and stepwise procedures for variable selection. Only 17 IBD patients with CRC (8 UC, 9 CD) met criteria and were disease- and age-matched with 34 IBD patients with adenomas (16 UC, 18 CD) (Table 2). In the IBD cases, a higher hemoglobin was found to have an estimated odds ratio of 0.343 (95% CI 0.137 – 0885). This indicates that with one unit increase in hemoglobin, the odds of developing colon cancer is decreased by 65%. No other variables were significant. In this single-center, case-control, retrospective analysis, higher hemoglobin levels were associated with a lower risk of having CRC. This finding is likely due to mucosal healing or due to occult blood loss in those with CRC. Though larger studies are still needed, our results suggest no difference between IBD patients with CRC versus adenomas and stress the importance of regular CRC surveillance in IBD patients, particularly those with anemia.

Abstract A18: Gut microbiota changes in response to treatment with ursodeoxycholic acid (UDCA)

Abstract Compelling evidence suggests that gut flora influences colorectal cancer risk through direct effects on colonic bile acid composition. Bile acids are widely implicated in the etiology of colorectal cancer with the strongest evidence involving a detrimental role for the secondary BA, deoxycholic acid (DCA) and a protective effect of ursodeoxycholic acid (UDCA). In a study of patients with prior colorectal adenomas who were randomized to UDCA (n=188 males, 64 females), a bile acid based intervention aimed at modulating bile acid composition, or placebo (n=162 males, 89 females), we determined effects of the intervention on the gut microbiome through 16S rRNA sequencing and bile acid composition at baseline using mass spectrometry. We observe a consistent shift in microbial composition for males (t=5.83, p=3.6e-8) and females (t=3.14, p=0.003) treated with UDCA. No effect was observed in the placebo group for either males (t=-0.08, p=0.93) or females (t=-0.09, p=0.92). There were significant correlations between the gut microbiome and BA composition (r=0.31, p<0.001). This suggests that UDCA treatment had an effect on the gut microbial communities relative to the placebo group. Interestingly, the magnitude of the change in the microbiome over time is similar in the two groups, but UDCA treatment seems to drive specific microbiome changes. These results are consistent with our previously reported observation that UDCA appears to have a greater effect in men for the prevention of colorectal adenomatous polyps, while increasing risk for women. Citation Format: Talima Pearson, J Gregory Caporaso, Monica Yellowhair, Jessica A. Martinez, Betsy Wertheim, Denise Roe, Patricia Thompson-Canino, Peter Lance. Gut microbiota changes in response to treatment with ursodeoxycholic acid (UDCA). [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A18.

Abstract IA09: Realizing the promise of prevention (at the personal and population levels)

Abstract IA09: Realizing the promise of prevention (at the personal and population levels)

Development of a Novel Marker of Endoscopist Performance: LT5R

Introduction: Endoscopist performance is reflected by a metric known as the adenoma detection rate (ADR), or the ratio of colonoscopies with an adenomatous polyp removed compared to the total number of screening colonoscopies performed. An ADR of 25% is now endorsed as the benchmark to reduce the rate of interval colorectal cancer. Despite this, ADR has been shown to have weaknesses, such as the inability to distinguish any adenomas detected after the first in an examination, or that it does not account for proximal colon lesions which are known to account for a majority of interval colorectal cancers. The aim of this study is to analyze existing metrics and to create a novel metric which may account for some of the aforementioned weaknesses of ADR. Methods: We conducted a retrospective review of average-risk screening colonoscopies performed by 7 endoscopists over an 18-month period (June 1, 2013 to November 1st 2015). Patients with prior adenomas, colorectal surgery, IBD, suboptimal bowel preparation, or a family history of colorectal cancer were excluded. Our novel metric, LT5R, accounts for the number of small adenomas ( < 5mm) in the right colon as well as data for known metrics such as ADR, advanced-ADR (A-ADR), total adenomas detected, right-sided ADR (R-ADR), Sessile-Serrated ADR (SS-ADR), and right-sided Sessile-Serrated ADR (RSS-ADR). Chi-square and appropriate rank tests were used to compare the groups among the studied metrics. Results: Of the 4000 screening colonoscopies queried, 807 qualified for analysis. Endoscopists ADR ranged from 41-54%, but differences were not significant. Amongst known metrics, only R-ADR and SS-ADR were able to distinguish significant differences between endoscopists with p=0.022 and 0.018, respectively. Our novel metric, LT5R, was also able to distinguish differences between endoscopists, p=0.03. Conclusion: ADR alone may be insufficient to determine differences amongst endoscopists. Not only is ADR unable to account for adenomas detected after the first detected adenoma, it is also unable to account for adenomas in the right colon, where most interval cancers occur. However, our new metric, LT5R, incorporates the size, number, and location of adenomas in one metric. In this study, LT5R was able to find significant differences in endoscopist performance even amongst our high performing endoscopists. The key to our metric or any other performance metric is the ability to translate into improved outcomes in terms of interval cancer prevention.

Abstract LB-298: Gut microbiota changes in response to treatment with ursodeoxycholic acid

Abstract Compelling evidence suggests that the gut flora influences colorectal cancer risk through direct effects on colonic bile acid composition. Bile acids are widely implicated in the etiology of colorectal cancer and the strongest evidence is for the secondary bile acid deoxycholic acid. In a study of patients with prior colorectal adenomas who were randomized to ursodeoxycholic acid (n = 188 males, 64 females), a bile acid based intervention aimed at modulating bile acid composition, or placebo (n = 162 males, 89 females), we determined effects of the intervention on the gut microbiome through 16S rRNA sequencing and bile acid composition using mass spectrometry. We observe a consistent shift in microbial community phylogenetic composition for males (t = 5.83, p = 3.6e-8) and females (t = 3.14, p = 0.003) treated with UDCA. No effect was observed in the placebo group for either males (t = -0.08, p = 0.93) or females (t = -0.09, p = 0.92). This suggests that UDCA treatment, but not placebo treatment, is having an effect on the gut microbial communities of study participants. Interestingly, the microbiomes of the UDCA group do not change more than those of the placebo group: rather the magnitude of change is similar in the two groups, but UDCA treatment seems to drive specific microbiome changes. We also observe significant correlations between the gut microbiome composition and bile acid composition (r = 0.31, p&amp;lt;0.001). Specifically we find that (prior to treatment) bile acids including CA, CDCA, and UDCA are negatively correlated with diversity (richness) and to a lesser extent the abundance of Bacteroidetes (phylum) in the gut. These results are consistent with our previously reported observation that UDCA appears to have a greater effect in men for the prevention of colorectal adenomatous polyps, with risk-increasing effects for women. To our knowledge, this is the first study to correlate fecal bile acid levels with fecal microbial composition in humans or to assess the effect of the therapeutic bile acid UDCA on gut microbial composition. This study supports our observation that the efficacy of UDCA for the prevention of colorectal adenoma may be sex-dependent and suggests that the sex-specific effect may reflect differential effects of UDCA on the gut microbial community and the relationship between sex, the gut microbiome, and risk of colorectal adenomatous polyps. Citation Format: J Gregory Caporaso, Talima Pearson, Monia Yellowhair, Jessica Martinez, Peter Lance. Gut microbiota changes in response to treatment with ursodeoxycholic acid. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-298.

A Case of Incidental Intestinal Spirochetosis

Introduction: Adenoma development is the result of a sequence of mutational events that modifies growth regulation. Epidemiologic studies suggest that environmental factors such as the colonic microbiome may influence pathogenesis in susceptible individuals. We report a case of a patient with intestinal spirochetosis incidentally diagnosed post-biopsy at the site of a prior adenoma. Case Report: A 64-year-old asymptomatic male underwent a screening colonoscopy. The patient had no significant symptoms, including diarrhea, change in bowel habits, or abdominal pain. The colonoscopy revealed 2 diminutive polyps in the sigmoid and descending colon that were successfully removed. The patient was noted to have a small, linear clean-based rectal ulcer, which was biopsied. Histopathology revealed the sigmoid and descending colon polyps to be tubular adenomas, and oddly identified adenoma histology in the area of the linear ulcer, although no adenoma was found in the rectum. Given the unexpected finding of tubular adenoma histology from the rectal linear ulcer, the patient underwent a subsequent flexible sigmoidoscopy 1 month later to re-evaluate the region and assure there was no residual tissue. He was noted to have a linear, well-healed scar at the site of previous biopsy. Repeat biopsy showed warthin-starry stain positive for intestinal spirochetes. Of note, spirochetes were not found on initial histopathology of the rectal ulcer. Conclusion: We report a rare case of intestinal spirochetosis in an asymptomatic immunocompetent adult with no risk factors. Furthermore, it is interesting to note that the spirochetosis might have been the cause of linear ulceration seen endoscopically. It is unusual to have tubular adenoma histology from a small, endoscopically benign-appearing ulcer. This atypical finding prompted our team to do a repeat flexible sigmoidoscopy to assure removal, which led to an incidental post-biopsy diagnosis of spirochetosis. The diagnosis of intestinal spirochetosis from a site of prior adenoma raises a question of correlation of spirochetosis to prior adenoma. Recent studies show an association of spirochetosis with sessile serrated adenoma. Additionally, there are no guidelines to treat intestinal spirochetosis. Our patient was seen by an infectious disease specialist and treated with a 10-day course of Flagyl.

Prior Adenomas, Villous Adenomas, and Family History Associated with Interval Cancer

Interval cancer is cancer occurring after a colonoscopy that did not diagnose cancer and before the next scheduled colonoscopy. Factors previously shown to be associated with the development of interval cancer include proximal cancer location, microsatellite instability, hypermethylation, performance by a colonoscopist with a low adenoma detection rate (ADR), low polypectomy rate, or low cecal intubation rate, performance by a non-gastroenterologist, and performance of colonoscopy for the indication of positive fecal occult blood test. In the current study, researchers examined predictors of interval cancers …

Prevention of Colorectal Cancer by Aspirin and/or Calcium: Efficacy, Mechanisms, and Cost Effectiveness

Chemoprevention of colorectal cancer (CRC) by aspirin use or calcium supplementation has been studied for almost two decades. Recently, the use of aspirin has been reported to be efficacious for the chemoprevention of CRC at the lowest dose ever, one that corresponds to that recommended for the primary prevention of cardiovascular disease. There is also new evidence that aspirin at higher doses may be helpful in controlling familial adenomatous polyposis (FAP). Several cost effectiveness studies have emerged to demonstrate that use of aspirin in combination with colonoscopy is cost-effective compared with colonoscopy alone in prevention of CRC. Likewise, calcium supplementation in a chemoprevention strategy also has been shown to be cost-effective when used alone or in combination with colonoscopy in CRC prevention, compared to natural history. The chemopreventive mechanisms of these agents continue to be studied, and prominent molecular targets for aspirin are cyclooxygenase (COX)-2, and perhaps COX-1, as well as the calcium-sensing receptor (CaSR) as the likely target for calcium supplementation. The evidence is compelling for the widespread use of these non-prescription agents, either alone or in combination, for either primary prevention of CRC in the general population, or as part of a colonoscopy surveillance program in high-risk populations with a prior adenoma.

Aberrant crypt foci as predictors of colorectal neoplasia on repeat colonoscopy

To estimate the risk for colorectal neoplasia detected on repeat colonoscopy in relation to aberrant crypt foci (ACF) frequency reported during the previous baseline examination. From July 2003 until December 2008, patients had a colonoscopy with an ACF study using a magnifying colonoscope. The distal 20 cm section of colon was sprayed with Methylene Blue to ascertain the ACF frequency, the independent variable. Patients were categorized into low and high ACF count using the median as the cut point. Data collected from consenting patients included age, gender, height, weight, ethnicity, smoking history, family history of colorectal cancer (CRC), and personal history of colorectal neoplasia. A follow-up colonoscopy was performed at an interval as dictated by clinical surveillance guidelines. The main outcome was surveillance detected advanced colorectal neoplasia (SDAN) detected on repeat colonoscopy. Logistic Regression was used to calculate risk of SDAN on repeat colonoscopy in relation to baseline ACF count. 74 patients had a baseline ACF exam and a repeat surveillance colonoscopy. The median ACF was six and thus a high ACF count was >6 ACF and a low ACF count was ≤6 ACF. Patients diagnosed with SDAN were more likely to have had a high ACF number at baseline compared to patients without these lesions at follow-up (adjusted odds ratio = 12.27; 95% confidence interval: 2.00-75.25) controlling for age, sex, smoking, history of prior adenoma, family history of colon cancer, obesity, and time interval to surveillance exam. A sub analysis of our results demonstrated that this relationship was observed in 48 patients who were undergoing a surveillance colonoscopy for a previous adenoma and not those receiving surveillance for a family history of neoplasia. Increased number of ACF in the distal colorectum was independently associated with substantial risk for future advanced neoplasia. This relationship was observed in patients undergoing surveillance for previous adenomas. Thus, ACF may serve as potential biomarkers in patients with adenomas to help identify patients who may need additional surveillance.

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy

Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Aspirin Should Not Be Promoted for Colon Cancer Prevention: Counterpoint

There is little question that aspirin can decrease the risk of large bowel cancer. A large number of observational studies in humans, both case-control and cohort, consistently show a strong protective effect of aspirin ([1][1]). Importantly, three randomized controlled trials show that aspirin

Abstract LB-142: Marked efficacy of difluoromethylornithine plus sulindac in reducing recurrent colorectal adenomas in patients with prior adenomas: Results of a randomized, placebo-controlled, double-blind Phase III trial.

Abstract Introduction: Epidemiologic and experimental data suggests that colon cancer should be largely preventable through dietary or chemical intervention. Polyamines are actively involved in proliferation and differentiation of many tissues. Lowering of intracellular levels via inhibition of the initial step (ornithine decarboxylase) in the polyamine synthesis pathway by the specific enzyme-activated inhibitor DFMO results in a decrease of adenomas and cancers in many preclinical organ-site cancer models, most notably in the colon. Methods: From 1989-1997 we conducted a series of pilot and Phase IIa (short term) and Phase IIb (long term) trials in which we determined the lowest dose of DFMO at which polyamine content of the colonic flat mucosa would be lowered, with the goal of finding a non-toxic dose. In 1997 we debated whether to do a definitive trial with DFMO alone or to combine it with another chemoprevention compound. We settled on combining DFMO with the NSAID sulindac at low dose for a variety of mechanistic, experimental, and clinical reasons and began a Phase IIb trial in which the recurrence of adenomas would be correlated with polyamine changes in the flat mucosa. Several years later we expanded the trial to a full Phase III trial in which recurrence of adenomas became the primary endpoint. Results: Based on the recommendation of the Data Safety and Monitoring Board an accelerated second analysis was done after 70% of patients had completed their 3 year or off-study colonoscopy and the study was stopped for efficacy as the study goals had been met. Overall, a highly significant reduction (70%) of all adenomas, advanced adenomas (92% reduction), and multiple adenomas (95% reduction) was seen (all P&amp;lt;0.001), an effect comparable to that seen in animal models. Both adjacent rectal mucosal biopsy putrescine and spermidine levels were also markedly reduced in the active intervention arm after both 12 and 36 months, and there was a significant correlation between reduction in polyamines and adenoma recurrence. PGE2 levels were unaffected, although there was a trend in the correlation of reduction in prostaglandin E2 and adenoma recurrence which most likely is due to an independent action of sulindac. An exploratory analysis of the effect of the active regimen on the different segments of the colon suggested no preference in effectiveness. Toxicity was carefully monitored and all toxicities (adverse events of any nature) as well as hematologic, gastrointestinal, and cardiovascular toxicities were analyzed individually and in a number of ways; clinical toxicities were low and comparable in the two arms. Careful serial audiograms showed subclinical changes that were more frequent in the active intervention arm and were largely reversible after six months off drugs. Conclusions: These results confirm the value of de-escalation studies prior to launching a full Phase III trial in identifying a dose and regimen for the therapeutic prevention of adenomas that is both efficacious and non-toxic; this strategy may be generally applicable in the design of future large chemoprevention trials, particularly those in which combinations would be used. Larger trials will be needed to determine the absolute risk of cardiovascular events and audiologic changes from this regimen, and longer-term studies will be needed to determine whether the absolute endpoint of colorectal cancer incidence can be reduced in either patients with low stage prior colorectal cancers or in very high risk individuals.

804 Marked Efficacy of Difluoromethylornithine (DFMO) Plus Sulindac in Reducing Recurrent Colorectal Adenomas in Patients with Prior Adenomas: Results of a Randomized, Placebo-Controlled Double-Blind Trial

804 Marked Efficacy of Difluoromethylornithine (DFMO) Plus Sulindac in Reducing Recurrent Colorectal Adenomas in Patients with Prior Adenomas: Results of a Randomized, Placebo-Controlled Double-Blind Trial

Aspirin chemoprevention in patients with increased risk for colorectal cancer: a cost‐effectiveness analysis

Aspirin chemoprevention combined with colonoscopy screening is not cost-effective for the general population. However, the cost-effectiveness of aspirin in individuals with prior adenoma resection has not been evaluated. To evaluate the cost-effectiveness of aspirin chemoprevention alone and in combination with colonoscopy surveillance in patients with prior adenoma resection. A model of the natural history of individuals with a history of endoscopic polypectomy was constructed. Four strategies were compared: (i) no intervention, (ii) routine colonoscopy surveillance, (iii) aspirin chemoprevention alone, and (iv) aspirin therapy combined with colonoscopy. Compared with no intervention, all other strategies were more costly but were associated with gains in years of life saved. Aspirin chemoprevention alone was associated with a gain of 0.0092 years, whereas routine colonoscopic surveillance and combination strategy were associated with further gains in years of life saved (0.0124 and 0.0138 years, respectively). Compared with no intervention, the incremental cost-effectiveness ratio of routine colonoscopy surveillance was $78,226 per year of life saved, and the incremental cost-effectiveness ratio of combination aspirin and colonoscopy was $60,942 per year of life saved. Aspirin chemoprevention combined with colonoscopic surveillance in post-polypectomy patients may be considered a cost-effective strategy.