Treatment of Colonic and Rectal Adenomas with Sulindac in Familial Adenomatous Polyposis
Francis M. Giardiello, Stanley R. Hamilton, Anne J. Krush, Steven Piantadosi, Linda M. Hylind, Paul Celano, Susan V. Booker, C. Rahj Robinson, and G. Johan A. Offerhaus
Background Familial adenomatous polyposis is an autosomal dominantdisorder characterized by the formation of hundreds of colorectaladenomas and eventual colorectal cancer. Administration of thenonsteroidal antiinflammatory drug sulindac has been followedby regression of polyps in patients with this disorder, butno controlled trial of this drug in patients who have not hadsurgery has been reported.
Methods We conducted a randomized, double-blind, placebo-controlledstudy of 22 patients with familial adenomatous polyposis, including18 who had not undergone colectomy. The patients received sulindacat a dose of 150 mg orally twice a day for nine months or identical-appearingplacebo tablets. The number and size of the polyps were evaluatedevery three months for one year.
Results A statistically significant decrease in the mean numberof polyps and their mean diameter occurred in patients treatedwith sulindac, as compared with those given placebo. When treatmentwas stopped at nine months, the number of polyps had decreasedto 44 percent of base-line values and the diameter of the polypsto 35 percent of base-line values (P = 0.014 and P<0.001,respectively, for the comparison with the changes in the groupgiven placebo). No patient had complete resolution of polyps.Three months after treatment with sulindac was stopped, boththe number and the size of the polyps increased in sulindac-treatedpatients but remained significantly lower than the values atbase line. No side effects from sulindac were noted.
Conclusions Sulindac reduces the number and size of colorectaladenomas in patients with familial adenomatous polyposis, butits effect is incomplete, and it is unlikely to replace colectomyas primary therapy.
Familial adenomatous polyposis is an autosomal dominant disordercharacterized by the formation of hundreds of colorectal adenomasin young adults1,2. This condition is due to a germline alterationof the adenomatous polyposis coli gene on the long arm of chromosome53,4,5,6. Virtually all patients with familial adenomatous polyposiswill have colorectal cancer by the fifth decade of life if prophylacticcolectomy is not performed1.
The regression of rectal adenomatous polyps in patients withfamilial adenomatous polyposis who were treated with sulindac(Clinoril), a nonsteroidal antiinflammatory drug (NSAID) thatinhibits the synthesis of prostaglandin, was reported in 19837and again in 19898. Subsequently, a decrease in the number ofadenomatous polyps after treatment with sulindac was found inone crossover controlled study of five patients with familialadenomatous polyposis and previous ileorectal anastomosis9 andin one uncontrolled study of five such patients who had nothad surgery10. No controlled trial of this drug in patientswho have not had surgery has been reported.
Methods
Study Population
The subjects were recruited from the Johns Hopkins PolyposisRegistry. Patients with familial adenomatous polyposis who eitherhad not undergone colectomy or had undergone subtotal colectomywith ileorectal anastomosis were eligible for the study, aswere patients who had five or more adenomatous polyps at thetime of enrollment in the study. The following were reasonsfor exclusion from the study: use of NSAIDs for more than oneweek during the three months before the study began; absenceof effective birth control (in women of childbearing age); pregnancy;a white-cell count of less than 4000 per cubic millimeter, plateletcount of less than 100,000 per cubic millimeter, blood ureanitrogen level of more than 25 mg per deciliter (8.9 mmol perliter), or serum creatinine concentration of more than 1.5 mgper deciliter (132.6 µmol per liter); unwillingness todiscontinue taking NSAIDs; history of peptic ulcer disease orgastrointestinal hemorrhage; history of cancer; active bacterialinfection; use of dimethyl sulfoxide; or a history of allergyto aspirin.
Informed consent was obtained from all patients, and the protocolwas approved by the Johns Hopkins University Joint Committeeon Clinical Investigation (the institutional review board).
Study Design
The patients were stratified into two groups (those who hadnot undergone colectomy and those who had undergone subtotalcolectomy), and each group was randomized separately. Each patientreceived sulindac at a dose of 150 mg orally twice a day fornine months or identical-appearing placebo tablets. The degreeof patient compliance was assessed by pill counts and weeklytelephone contact.
Rectosigmoid colonic polyps and rectal polyps were assessedby flexible sigmoidoscopy with an Olympus flexible video sigmoidoscope.One observer, who had no knowledge of previous examination results,performed all the assessments. The assessments were performedbefore treatment with sulindac or placebo was begun (0 months)and 3, 6, 9, and 12 months after treatment was begun. At baseline the colorectal mucosa was tattooed with sterile India inkabout 20 cm from the anal verge, in an area in which the sizeof the polyps was representative of the size of those in therest of the colorectum visualized by sigmoidoscopy. The endoscopistcounted the total number of polyps in the circumference of thecolorectum from the tattoo mark to the anal verge, and the examinationwas recorded on videotape11. The diameter of the first fivepolyps just distal to the tattoo was measured in millimeterswith a graduated scale passed through the sigmoidoscopy biopsychannel.
Evaluation of Safety
Adverse effects were monitored by weekly telephone calls andat visits. Complete blood count and levels of glucose, bloodurea nitrogen, serum creatinine, serum electrolytes, and bilirubinwere monitored.
Statistical Analysis
It was calculated that the trial would require 40 patients toprovide an 80 percent power to detect a difference of 1 SD inthe percent change in the number of polyps. One interim analysiswas planned after approximately half the patients had been recruited,including a review by a monitoring committee. Statistical guidelinesfor early termination of a trial12 were followed to maintainthe overall type I error rate at 5 percent with a significancelevel of 0.05.
The primary statistical outcome variable was the percent changein the number of polyps and was analyzed by a t-test. We studiedthree additional variables: the percent change in the diameterof polyps, analyzed by a t-test; endoscopic assessment of therapeuticeffect at nine months (improvement vs. no improvement), analyzedby the chi-square test; and side effects. The primary analysiswas based on the intention to treat, regardless of whether patientssubsequently withdrew from the study. To determine whether chancedifferences in prognostic features between treatment groupsexplained the outcomes, a linear regression model (analysisof covariance) was used to adjust for differences between treatmentgroups in age, sex, and surgical status.
Results
Demographic Characteristics
Twenty-two patients had been randomly assigned to treatmentgroups when the study was stopped because statistical guidelinesfor an early halt to the study were met. Eleven patients hadreceived sulindac, and 11 placebo. There were no significantdifferences in demographic characteristics between the treatmentgroups (Table 1). All the patients enrolled were white. Althoughthe average number of polyps at entry was larger in the groupgiven placebo because two patients had more than 100 polyps,analysis of the data in terms of the change relative to base-linevalues largely prevented the outlying data from distorting theresults. Two patients were withdrawn from the study (Table 1),but their data were analyzed in accordance with the intention-to-treatstrategy.
Table 1. Demographic Characteristics of the Study Patients, According to Treatment Group.
Clinical Efficacy
The number of polyps, measured as the percent change from base-linevalues, was significantly decreased in the group given sulindacat 3, 6, 9, and 12 months (Figure 1A). Similar decreases occurredin the size of the polyps (Figure 1B), although at 12 monthsthe difference between groups was marginally significant (P= 0.05). At nine months, the number of the polyps decreasedto 44 percent of base-line values (P = 0.014) and the size ofthe polyps decreased to 35 percent of base-line values (P<0.001)in the group given sulindac. A videotaped evaluation at ninemonths also revealed a significant decrease in the number andsize of polyps (P<0.001) in the group given sulindac. Nopatient had complete resolution of polyps. Furthermore, at 12months, 3 months after the discontinuation of sulindac, thenumber and size of the polyps had increased slightly in thegroup given sulindac (P>0.05).
Figure 1. Mean (±SE) Percent Change from Base Line in the Number (Panel A) and Size (Panel B) of Polyps.
The maximal effect of sulindac occurred at six months. The number and size of the polyps increased after treatment with sulindac was stopped at nine months. The asterisks (P<0.001), dagger (P<0.05), and double daggers (P<0.01) indicate significant differences between groups.
When only the subgroup of 18 patients who had not had colectomywas analyzed, the differences in the number and size of thepolyps between the sulindac and placebo groups were still statisticallysignificant at three, six, and nine months; in the sulindacgroup the number of polyps had fallen to 47 percent of the base-linevalue at nine months (P = 0.015 for the comparison with theplacebo group), and the size of the polyps had decreased to37 percent of the size at base line (P<0.001). At 12 months,the number of polyps but not the size of the polyps was significantlydecreased in the group given sulindac as compared with the groupgiven placebo.
Four patients had undergone subtotal colectomy and ileorectalanastomosis, three of whom received sulindac. After nine monthsof treatment, the number of polyps in these three patients haddecreased to 23 percent of the base-line value, and the sizeof the polyps had decreased to 20 percent of base line. Theone patient with an ileorectal anastomosis who received placebohad an increase in the number of polyps to 190 percent of thebase-line value and in the size of the polyps to 137 percentof base line.
Differences in the results of treatment remained significantat all times when the two patients withdrawn from the sulindacgroup were eliminated from the analysis and when the two patientsin the placebo group who had large numbers of polyps were excluded.The differences also remained statistically significant afteran adjustment for age, sex, and surgical status, except forthe percent change in the size of the polyps at 12 months, whichwas only marginally significant (P = 0.05).
Adverse Events and Compliance
No adverse effects could be attributed to sulindac. The overallrate of compliance with scheduled drug doses was 85 percent.
Discussion
In this study we showed that sulindac is effective in reducingthe size and number of colonic and rectal polyps in patientswith familial adenomatous polyposis without previous colectomyas well as in those who have had subtotal colectomy and ileorectalanastomosis. In this young cohort of patients, sulindac producedvirtually no side effects or perturbations in laboratory values.The effect was evident after only three months of therapy. Thegreatest reduction in the number and size of polyps occurredbefore the sixth rather than the ninth month of treatment. Thisfinding may reflect decreasing compliance with the drug regimen,the development of resistance, or the development of additionalpolyps despite the beneficial effects of sulindac. Althoughthe effect of sulindac persisted for three months after thedrug was discontinued, the number and size of polyps did increase(Figure 1A). The drug was efficacious in patients with a widerange in the number of polyps (from 10 to 300), but the polypsdid not resolve completely in any patient. These findings areconsistent with the work of other investigators9,10 and withobservations on the effect of other NSAIDs in experimental coloniccarcinogenesis13,14,15,16,17,18,19.
The mechanism by which sulindac causes regression of adenomasis unknown. NSAIDs inhibit cyclooxygenase and thereby blockthe production of prostaglandins,20 but the precise relationbetween prostaglandins and carcinogenesis is unclear. Severalinvestigators have noted that NSAIDs inhibit the progressionfrom the G1 to the S phase of the cell cycle in vitro21,22,23,24and suppress ornithine decarboxylase activity25.
Long-term clinical studies of sulindac therapy are needed inpatients with familial adenomatous polyposis who have had subtotalcolectomy and ileorectal anastomosis to evaluate its efficacyin reducing the occurrence of rectal cancer. The side effectsof sulindac,20 including gastrointestinal bleeding, could bemore frequent in older patients.
Long-term clinical trials of sulindac as primary treatment inyoung patients who have polyposis but who have not yet undergoneprophylactic colectomy raise difficult issues. Unlike Waddellet al.8 and Rigau et al.,10 who described one patient each withcomplete regression, we did not observe complete regressionof polyps in any of our patients with intact colons. Therefore,treatment with sulindac would not eliminate the attendant riskof cancer and would require repeated study of the entire colon.Consequently, sulindac is unlikely to replace colectomy as themainstay of therapy.
The role of sulindac in the treatment of other patients at riskfor colorectal cancer remains to be investigated. Patients witha mutated adenomatous polyposis coli gene who do not yet havecolorectal polyposis, those with hereditary nonpolyposis colorectalcancer, and those with sporadic colorectal adenomas are potentialcandidates for chemoprevention trials with this drug.
Supported by the Clayton Fund, the McAshan Fund, and a grant(CA 53802) from the National Institutes of Health.
We are indebted to Drs. Benjamin M. Baker and John H. Yardleyfor advice and guidance, to Drs. Steven N. Goodman and CurtisL. Meinert for their expertise, to Dr. Albert H. Owens, Jr.,for his support, to Ms. Linda Welch for assistance in the preparationof the manuscript, to Dr. Mary C. Corretti for her encouragement,and to Merck Sharp and Dohme for providing sulindac and placebo.
Source Information
From the Departments of Medicine (F.M.G., A.J.K, L.M.H.) and Pathology (S.R.H., C.R.R.) and the Oncology Center (F.M.G., S.R.H., S.P., P.C., S.V.B.), Johns Hopkins University School of Medicine and Hospital, Baltimore; and the Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands (G.J.A.O.).
Address reprint requests to Dr. Giardiello at the Gastroenterology Division, Blalock 935, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287.
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