Résumé. Des polypes gastroduodénaux se développentdans près de 90% des sujets atteints de polypose adé-nomateuse familiale et les cancers péri-ampullaires con-stituent dans ce syndrome l’affection maligne extra-coli-que la plus fréquente. Les adénomes péri-ampullaires sesont révélés être des précurseurs des carcinomes péri-am-pullaires. Des travaux ont montré que le sulindac, un anti-inflammatoire non stéroïdien, permet la régression des po-lypes rectaux en cas de polypose adénomateuse familiale.Toutefois le rôle de ce médicament dans la régression despolypes péri-ampullaires n’est pas précisé. Depuis mai1993, une étude prospective a débuté afin d’évaluer le rôle du sulindac dans la prévention des récidives de poly-pes après résection de grands polypes duodénaux (plusd’un cm) chez des patients atteints de FAP. Huit patientsdont l’âge moyen est de 50 ans (35 à 65) porteurs de lar-ges polypes péri-ampullaires bien documentés, ont été sou-mis à un traitement de sulindac à raison de 150 mg deuxfois par jour. Avant d’étre inclus dans l’étude, tous les pa-tients out subi l’excision de larges polypes de la régionpéri-ampullaire par résection endoscopique ou par chirur-gie. Tous les patients étaient porteurs de multiples petitspolypes duodénaux résiduels. Le follow-up a été réalisépar un endoscopiste expérimenté avec un vidéo-endoscopeà vue latérale. L’endoscopie a été réalisée tous les six mois.Le suivi moyen est de 17,5 mois (10 à 24 mois). Chez troispatients, l’administration de sudinlac a dû être interrom-pue en raison des effets secondaires deux fois, crampes ab-dominales (n = 2), et saignements de la partie supérieuredu tube digestif (n = 1). Aucun de ces patients n’a présentéde régression des petits polypes péri-ampullaires. Chez unpatient, on a assisté au développement d’un cancer péri-ampullaire invasif alors même qui’il était sous sulindac ettrois patients ont développé de larges récidives de polypesnécessitant un traitement complémentaire. En conclusion,dans notre expérience, le sulindac n’a aucun effet bénéfi-que significatif dans le contrôle péri-ampullaire chez despatients porteurs de FAP. Un traitement médical effectifde ces polypes fait toujours défaut.

Abstract. Background: Gastro-duodenal polyps developin up to 90% of familial adenomatous polyposis (FAP) pa-tients and periampullary carcinoma is one of the most com-mon extra-colonic malignancies in this syndrome. Periam-pullary adenomas have been shown to be precursor lesionsto periampullary carcinoma. Sulindac, a non-steroidalanti-inflammatory drug, has been reported to cause regres-sion of rectal polyps in FAP patients, however its role inperiampullary polyp regression is unclear. Methods: InMay 1993, a prospective study was begun to evaluate therole of sulindac in prevention of polyp recurrence after re-section of large (>1 cm) duodenal polyps in FAP patients.Eight patients, mean age 50 years (range 35 to 65), withdocumented large periampullary polyps were placed onsulindac 150 mg twice daily. Prior to enrolment, all pa-tients had their large polyps removed from the periampul-lary region by interventional endoscopy or by surgery. Allpatients had multiple small residual duodenal polyps. Fol-low-up was performed by one experienced endoscopistwith a side-viewing video endoscope. Endoscopy was per-formed 6 monthly. Median follow-up time was 17.5 months(range 10 to 24 months). Results: In 3 patients, sulindacwas discontinued due to side effects: abdominal cramps(n = 2) and upper G-I bleeding (n = 1). None of the patientshad regression of small periampullary polyps. In addition,one patient developed an invasive periampullary carci-noma while on sulindac and 3 patients developed large re-current periampullary polyps requiring further treatment.Summary : In our experience, sulindac is of no significantbenefit for the control of periampullary polyps in FAP. Effective medical treatment of these polyps is still lack-ing.

Int J Colorect Dis (1997) 12: 14–18

Sulindac for periampullary polyps in FAP patients*C. S. Richard1, T. Berk1,2, B. V. Bapat1,2, G. Haber3, Z. Cohen1,2, S. Gallinger1,2

1 The Steve Atanas Stavro Familial GI Cancer Registry, University of Toronto, Ontario, Canada2 The Departments of Surgery and Pathology, Mount Sinai Hospital, University of Toronto, Ontario, Canada3 The Department of Medicine, Wellesley Hospital, University of Toronto, Ontario, Canada

Accepted: 17 December 1996

Springer-Verlag 1996© Springer-Verlag 1997

* Supported in part by the Crohn’s & Colitis Foundation of Canada

Correspondence to: S. Gallinger, Mount Sinai Hospital, 1225-600University Avenue, Toronto, Ontario Canada, M5G 1X5Tel.: 416-586-8550Fax: 416-586-8392E-Mail: Steve@inforamp.net

Several reports have confirmed the very high prevalenceof upper gastro-intestinal polyps in association with famil-ial adenomatous polyposis (FAP) [1–4]. Because of thesefindings, most centres managing patients with FAP havenow implemented screening programs for the detection ofthese polyps. In our registry, duodenal polyps have beenfound in 57% of screened FAP patients. Most FAP patientswith duodenal polyps have small lesions (<1 cm), how-ever, large polyps (>1 cm) develop in up to 10% of pa-tients [5].

Sulindac, a non-steroidal anti-inflammatory drug, hasbeen reported to cause tumour cell growth inhibition bothin laboratory and clinical settings [6, 7]. This drug may in-hibit tumour growth by interfering with prostaglandin sup-pression of the immune system. It may act also by block-ing the induction of ornithine decarboxylase, thereby lim-iting cell proliferation. More recent data suggests an ef-fect of sulindac on apoptosis [8]. Sulindac has been re-ported to cause regression of rectal polyps in post-colec-tomy patients with FAP as well as reduction of total co-lonic adenomas in nonoperated patients [9–13].

The following study was undertaken to investigate therole of sulindac in the prevention of recurrence of endo-scopically or surgically excised large duodenal adenomas(>1 cm) in FAP patients.

Patients and methods

This prospective trial was designed for FAP patients with prior co-lectomy who had documented grade IV duodenal polyps (Table 1)and in whom complete removal of large (>1 cm) duodenal adeno-mas had been performed. Polyp removal had been performed by ei-ther endoscopic or local surgical excision.

Patients were eligible if they fulfilled the following inclusion cri-teria: 15 years of age or over, life expectancy of at least 5 years, abil-ity and willingness to understand informed consent and to cooper-ate with study procedures. Patients were excluded if they had usednon-steroidal anti-inflammatory drugs (NSAIDs) within 6 months,if a prior side effect or hypersensitivity to NSAIDs was document-ed, if pregnancy was present or planned, and if there was documen-tation of renal, cardiac, or hepatic impairment, upper gastro-intesti-nal haemorrhage, intestinal malabsorption, or a bleeding disorder.

The study protocol was approved by the University of TorontoHuman Ethics Committee. Patients began sulindac therapy within 7 days of removal of all large polyps (grade IV). Sulindac 150 mgtwice daily was taken orally and patients were evaluated with side-viewing upper endoscopy every 6 months. All endoscopies were vid-eo-taped and performed by one experienced endoscopist (GH). Su-lindac was mailed to patients every 3 months with a receipt form toensure safe arrival of the drug. One tablet was removed from each

package for quality-control. Compliance and toxicity were verifiedby a telephone call to patients every two weeks by the study co-or-dinator. The main objective of this study was to determine the effectof sulindac on polyp recurrence at the site of prior removal of largepolyps. Secondary outcomes were the effects of sulindac on the re-sidual small duodenal polyps.

The study began in May 1993 and enrolment ceased in March1995. During the enrolment period, 8 patients, mean age 50 (range35–65), were eligible for the study and all participated.

Results

Table 2 shows the characteristics of each patient. Meanage of patients at the time of diagnosis of FAP was 32.2 years and patients had a mean age of 46 years (range30–62) when the first diagnosis of duodenal polyps wasdocumented. Therefore, there was a mean time of 14 years(range 3–37) between diagnosis of FAP and documenta-tion of duodenal polyps. A median of 31 months (range15–90 months) elapsed between diagnosis of duodenalpolyps to progression of polyps to grade IV stage. Sevenpatients had large polyps removed by endoscopy. A meanof 3 sessions (range 2–5) was required for complete endo-scopic removal of the large polyps. There were no com-plications associated with endoscopic treatments. One pa-tient had an operative transduodenal excision of the polypsbecause the large size of the polyps precluded endoscopicexcision. In all patients, pathological analysis confirmeda diagnosis of villous adenoma. Two patients had asso-ciated high grade dysplasia within the polyps removed.

Patients were on sulindac for a mean of 8.75 months (range 0.25–24) and the median follow-up was 17.5 months(range 10–24). Two patients discontinued sulindac ther-apy prematurely because of abdominal cramps; patient 4 after 7 days of treatment and patient 6 after 25 days oftherapy. Neither patient was assessed at the time of cessa-tion of medication because of the short period they re-ceived the drug. Sulindac was discontinued in a third pa-tient (#5) after 6 months of therapy because of documen-tation of antral gastritis, a superficial ulcer in the duodenalbulb, and progression of polyps in the duodenum with vil-lous changes of the ampulla of Vater.

Of the remaining 5 patients, patient 1 experienced a mi-nor episode of gastro-intestinal bleeding after 9 months oftherapy. Upper endoscopy revealed an ulcerated villousadenoma proximal to the papilla and biopsy revealed in-vasive adenocarcinoma. Because of the patient’s poormedical condition, local resection of the duodenal polypwas performed. Sulindac was discontinued at the time ofdiagnosis of the carcinoma. After a period of 13 monthsand 6 months, patients 2 and 8 had documentation on en-doscopic assessments of progression of residual polyps.The latter patient was treated by endoscopic excision andthe former patient required surgery because of the numberand large size of polyps. Histologic examination demon-strated villous changes with severe dysplasia with no evidence of invasive carcinoma. Both patients discon-tinued sulindac at the time of documentation of progres-sion of disease.

Patient 7 was maintained on sulindac for a total of 15 months. The first 2 endoscopic procedures showed

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Table 1. FAP duodenal Polyp Classification at the Mount Sinai Familial GI Cancer Registry

Grade Polyps Action

I None Endoscopy in 5 yearsII 1–2 mm (small) Endoscopy in 3 yearsIII 2.1–10 mm (medium) Endoscopy in 6 monthsIV >10 mm (large) Endoscopic or surgical

resectionV Periampullary Pancreatico-duodenectomy

adenocarcinoma

stable duodenal disease, however, the third endoscopicprocedure showed progression of residual polyps and re-currence of polyps at the site of the original treated gradeIV polyps. The recurrence of the polyps was in a flat ses-sile pattern and biopsies demonstrated multiple sites of se-vere dysplasia. Because of the pathologic findings and theflat characteristics of the lesions, there was concern thatinvasive carcinoma would be difficult to detect or exclude.This patient was thus advised to undergo a pancreatico-duodenectomy (Whipple procedure). Final pathology ofthe resected duodenum did not reveal invasive carcinoma.

Patient 3 remained on sulindac for a period of 24 months. While on sulindac, his small duodenal polypsremained stable. Prior to the onset of sulindac therapy, thispatient had had progressive duodenal disease requiringmultiple repeated sessions of ablative endoscopic treat-ments. Sulindac was stopped after 24 months because thepatient required chemotherapy for progression of largesymptomatic abdominal desmoid tumours.

Discussion

With the widespread acceptance of prophylactic colec-tomy, the other extra-colonic manifestations of FAP havebecome a source of considerable morbidity and mortality.Upper gastro-intestinal polyps are among the most com-mon extra-colonic manifestation of the disease. Gastricpolyps develop in up to 50% of patients and duodenalpolyps have been reported in 64% to 90% of screened FAPpatients [1–4]. Duodenal polyps tend to cluster around theampulla of Vater where they are often multiple, small, andsessile. Whereas gastric polyps are usually non-neoplas-tic fundic gland polyps (hamartomas), duodenal polyps arepredominantly adenomatous, with either tubular, villousor mixed morphology [2, 5]. In a proportion of FAP pa-tients, duodenal polyps become larger with associated se-vere dysplasia. Among 461 FAP patients enrolled in ourRegistry, 2 to 5 patients per year are diagnosed withgrade IV polyps.

Most FAP patients who develop invasive carcinoma ofthe duodenum have had prior adenomatous polyps at thesite of the cancer. Similar to colo-rectal adenomas, a def-inite adenoma-to-carcinoma sequence exists in the duo-

denum of FAP patients although the natural history of thisprogression is less well understood in the upper gastro-in-testinal tract [14]. Since periampullary carcinoma has nowbecome a frequent extra-colonic cause of mortality in FAPpatients [15–19], strategies to detect and effectively treatpatients with high risk duodenal polyps has become a pri-ority in the management of these patients.

Management of periampullary polyps is more proble-matic than that of colorectal adenomas. Endoscopic exci-sion is not always feasible because of the risk of damageto the ampulla of Vater. Local surgical excision is not al-ways suitable for sessile lesions. Moreover, of great con-cern is the fact that recurrence rates are high following en-doscopic treatment and local surgical excision of highgrade polyps [2, 20]. Although pancreatico-duodenectomy(Whipple operation) would presumably be an effectivepreventive treatment, it is a major procedure with signifi-cant potential morbidity. Furthermore, following a Whip-ple procedure, bile would likely continue to have a dele-terious effect on the jejunum at the choledojejunal anas-tomosis since bile may be a promoting factor for the de-velopment of adenomatous duodenal polyps [21–24].

This study was designed to assess the effects of sulin-dac on recurrence of duodenal polyps after treatment ofgrade IV polyps. Positive data from previous trials of su-lindac for treatment of rectal polyps in FAP patientsprompted us to test the effect of this drug for upper gas-tro-intestinal polyps. Our hypothesis was that sulindacmay prevent recurrence of polyps and may also act on thesmall remaining duodenal polyps by slowing their progres-sion or even potentially causing regression as reported incases of rectal polyps following colectomy and ileo-rectalanastomosis [9–13].

To date, there is one reported randomised trial compar-ing sulindac to placebo for FAP patients with duodenalpolyps [25]. In this study, twenty-four patients were ran-domised to either placebo or sulindac. All patients had un-treated high grade polyps. Patients who received sulindachad a significant reduction in the rate of mucosal prolife-ration compared to the control group. However, there wasno significant difference between groups with respect topolyp regression or growth. Since only a small number ofpatients were enrolled, the study lacks adequate power toaccept with certainty the null hypothesis i.e. that sulindac

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Table 2. Characteristics of patients enrolled in the Sulindac trial

Patient Age at Interval between Histopathology of Prior treatment of diagnosis diagnosis of FAP grade IV polyps removed grade IV polypsof FAP and diagnosis of

duodenal polyps(years)

1 22 37 Villous adenoma with severe dysplasia Endoscopy (5 sessions)2 20 10 Villous adenoma with severe dysplasia Endoscopy (2 sessions)3 38 3 Villous adenoma with moderate dysplasia Endoscopy (3 sessions)4 35 20 Villous adenoma with moderate dysplasia Endoscopy (2 sessions)5 44 2 Villous adenoma with moderate dysplasia Endoscopy (2 sessions)6 37 7 Villous adenoma with mild dysplasia Surgery (local excision)7 19 14 Villous adenoma with moderate dysplasia Endoscopy (2 sessions)8 43 19 Villous adenoma with mild dysplasia Endoscopy (5 sessions)

did not have a significant impact on polyps by endoscopicevaluations. In a subsequent report by Debinski et al., thevideotaped endoscopies from this prior study were re-viewed [26]. The purpose of this review was to documentthe effect of sulindac therapy according to different sizeof polyps. In this post-hoc analysis, a statistically signifi-cant decrease in the size of small polyps (<2 mm) was dem-onstrated in the sulindac treated group. Nine of 11 patientsin the sulindac group had regression of small polyps com-pared to 4 of 12 patients in the control group. It was con-cluded that sulindac was effective for treatment of smallduodenal polyps in FAP patients suggesting that sulindacmay present progression from small to large duodenalpolyps.

Parker et al. [27] reported the effects of sulindac on asingle FAP patient who had large recurrent periampullarypolyps requiring repeated endosopic treatments. Aftertreatment with sulindac, the patient was reported to havea decrease in the number of recurrent polyps. Moreoverafter endoscopic treatment of the final periampullarypolyp, the patient was reported to have a duodenum freeof polyps for 6 months. However, since this is an anecdo-tal report, one can only hypothesize that sulindac may havebeen involved in polyp control.

Our trial, although prospective, does not provide a de-finitive answer regarding the role of sulindac for treatmentof duodenal polyps. Only a small number of patients (n = 5)received the drug for more than 6 months and there wasno control group. However, despite these limitations, thisstudy further contributes to an understanding of the roleof sulindac in FAP patients. In our study, of the 5 patientsmaintained on sulindac for 6 months or more, only one pa-tient was found to have stable duodenal disease after 24 months on therapy. No patient had regression of remain-ing smaller duodenal polyps and 4 of the 5 patients whotolerated the treatment longer than 6 months had progres-sion of their duodenal disease after a mean follow-up of13 months. Two patients (25%) did not tolerate the treat-ment because of abdominal cramps and one patient (15%)required cessation of medication because of antral gas-tritis. Thus, in our patient population, sulindac seems tobe associated with significant side effects. Moreover, su-lindac was of little benefit for control of polyp recurrencein our patients treated for grade IV duodenal polyps.

There may be pharmacological properties during themetabolism of sulindac that prevents it from being effec-tive in the duodenum compared to its positive effect onrectal polyps. The antiproliferative effect of sulindac islikely caused by a sulfide metabolite derived after sulfor-eduction [28–29]. After intake of sulindac, the sulfide me-tabolite is present in high concentrations in the colon com-pared to low concentrations in the duodenum [28]. Stud-ies performed to assess the role of bile on polyp formationin FAP patients indicate that bile of FAP patients may bemore carcinogenic than bile from controls [22, 23]. Thiseffect of FAP bile may partially explain differences in theeffects of sulindac on rectal and duodenal polyps; the highconcentration of bile in the duodenum may attenuate anypotential anti-neoplastic effects associated with sulindac.

In our study, although patients received sulindac afterremoval of grade IV polyps, patients may have had duod-

enal disease that was already too advanced and aggressiveto benefit from any form of medical therapy. The poten-tial of a prophylactic agent to prevent development of largepolyps in FAP patients would perhaps be of more benefitat earlier stages of duodenal disease [25]. However, be-cause there are many FAP patients with early stage duod-enal polyps and only a minority of these patients will de-velop stage IV disease, we do not feel that it is appropri-ate to treat all patients with lower stages of disease. Giventhe documented high rate of side effects from sulindac ther-apy in our study population, this drug is of questionablevalue as a prophylactic treatment in FAP patients with du-odenal polyps.

Conclusion

Since duodenal polyps are frequently detected in FAP pa-tients, it is important to develop measures to control pro-gression of the disease in order to prevent the developmentof periampullary carcinoma. Pharmacologic therapywould seem most appropriate due to anatomic difficultiesin excising adenomas from the duodenum. Based on avail-able data, the effectiveness of sulindac on duodenal polypsremains questionable. Further knowledge of sulindac’spharmacological properties and mechanisms of antineo-plastic effects are needed.

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