Case Case PresentaionPresentaion::Duodenal Duodenal Adenomatosis Adenomatosis and and PolypharmacyPolypharmacy

John WeaverJohn WeaverDepartment of General SurgeryDepartment of General SurgeryUniversity of ColoradoUniversity of ColoradoOctober 27, 2008October 27, 2008

SHSH

67 67 y/o y/o female with FAPfemale with FAP Total Total colectomy colectomy in 1950in 1950’’ss

33--6 month 6 month sigmoidoscopies/biopsiessigmoidoscopies/biopsies

Duodenal polyps on EGD since 1990Duodenal polyps on EGD since 1990 Surveillance BiopsiesSurveillance Biopsies

high grade dysplasiahigh grade dysplasia EUS EUS –– mucosal thickening/stricture of pancreatic ductmucosal thickening/stricture of pancreatic duct

Referral forReferral for a a pancreaticoduodenectomypancreaticoduodenectomy

SHSH PMHxPMHx

FAP FAP s/p s/p total total colectomy colectomy with IRA in 1950with IRA in 1950 Rectal polypsRectal polyps C1C1--C2 fusionC2 fusion D/C 1972; tubal ligation 1979D/C 1972; tubal ligation 1979 Rheumatoid ArthritisRheumatoid Arthritis Multiple GI bleeds Multiple GI bleeds –– ulcerations in rectumulcerations in rectum BipolarBipolar GerdGerd

PSHxPSHx Bilat Bilat total hips; left femur ORIF;total hips; left femur ORIF; C1C1--2 fusion2 fusion

Family HistoryFamily History FAPFAP

SocialSocial No ETOH or tobaccoNo ETOH or tobacco

SHSH

MedicationsMedications –– (active medications at pre(active medications at pre--op)op)

Prednisone 15mg/dayPrednisone 15mg/day Prevacid Prevacid 30mg BID30mg BID Valtrex Valtrex 500mg BID500mg BID Lamictal Lamictal 300mg300mg Zyprexa Zyprexa 7.5mg7.5mg Ibuprofen QID PRNIbuprofen QID PRN Atenolol Atenolol 20mg Daily20mg Daily Detrol Detrol 2mg Daily2mg Daily Methotrexate Methotrexate 50mg/wk50mg/wk Leucovorin Leucovorin 5mg/wk5mg/wk

SHSH

(Medications Continued)(Medications Continued)

MVI; MVI; Vit Vit E; Magnesium supp; vitamin DE; Magnesium supp; vitamin D Imodium PRNImodium PRN Glucosamine 1000mgGlucosamine 1000mg Actonel Actonel 300mg300mg Prilosec Prilosec 30 mg BID30 mg BID Simethicone Simethicone BIDBID Testosterone powderTestosterone powder BonivaBoniva Iron supplementsIron supplements Fish oilFish oil

SHSH

(Medications cont)(Medications cont)

Detrol Detrol LA 1 tab dailyLA 1 tab daily Nasacort 2 puffs QIDNasacort 2 puffs QID Vicodin Vicodin 11--2 tab q6hrs PRN2 tab q6hrs PRN Florinef ophth gttFlorinef ophth gtt Calcium 500mg TIDCalcium 500mg TID Restasis ophth gttRestasis ophth gtt Selenium 100mcgSelenium 100mcg

(30 active medications)(30 active medications)

SHSH Surgical procedureSurgical procedure

PDPD Histology Histology –– high grade dysplasiahigh grade dysplasia No evidence of invasive cancerNo evidence of invasive cancer

ComplicationComplication Staple line bleed at Staple line bleed at gastrojejunostomygastrojejunostomy

ResultResult Discharged to nursing homeDischarged to nursing home

Familial Familial Adenomatous Adenomatous PolyposisPolyposis Autosomal Autosomal dominant inheritance dominant inheritance -- 5q215q21 APC gene APC gene –– germline germline mutationmutation

Tumor suppressor gene Tumor suppressor gene –– Wnt/wingless Wnt/wingless pathwaypathway Affects cell cycle Affects cell cycle –– inhibition or enhancementinhibition or enhancement

Cameron J, et al. Current Surgical Therapy 9th ed. 2008.

Extracolonic Extracolonic manifestationsmanifestations UGI tumorsUGI tumors OsteomasOsteomas Desmoid Desmoid tumortumor Malignant fibrous Malignant fibrous histiocytomahistiocytoma Thyroid nodule/papillary Thyroid nodule/papillary thryoid thryoid cancercancer PinealoblastomaPinealoblastoma Skin Skin fibromatafibromata Brain cystBrain cyst Retinal Retinal hyperpigmentationhyperpigmentation Pouch Pouch adenoma/anorectal adenoma/anorectal adenomaadenoma

Duodenal Duodenal AdenomatosisAdenomatosis

Patients will develop duodenal adenomasPatients will develop duodenal adenomas 100% by age 75100% by age 75

200 fold higher risk of duodenal cancer200 fold higher risk of duodenal cancer 5% with duodenal polyps develop cancer5% with duodenal polyps develop cancer 50% develop stage 4 disease by 7050% develop stage 4 disease by 70

40% cumulative cancer risk40% cumulative cancer risk

Pandolfi M, et al. JOP. 2008;9:1-8.

SpigelmanSpigelman’’s s ClassificationClassification

Sarin G, et al. J Clin Onc 2004; 22:493-499.

Duodenal cancer in patients with familial Duodenal cancer in patients with familial adenomatous polyposisadenomatous polyposis: : results from a 10 year prospective studyresults from a 10 year prospective study

Prospective Study 1988Prospective Study 1988--19981998

Endoscopic analysis with multiple biopsiesEndoscopic analysis with multiple biopsies 11stst, 2, 2ndnd, 3, 3rdrd portions of duodenumportions of duodenum

114 patients114 patients 99 patients with full endoscopic follow over 10 years99 patients with full endoscopic follow over 10 years

Germline Germline mutationsmutations 73% precise 73% precise germline germline analysis analysis –– no conclusions based on no conclusions based on

stagestage

Groves C, et al. Gut. 2002;50:636-641

Duodenal cancer in patients with familial Duodenal cancer in patients with familial adenomatous polyposisadenomatous polyposis: : results from a 10 results from a 10 year prospective studyyear prospective study

OutcomeOutcome 6/114 patients developed cancer (median 6 years)6/114 patients developed cancer (median 6 years)

–– Median age 68 at diagnosisMedian age 68 at diagnosis

Stage 1Stage 1 (0/15)(0/15)

–– Stage progression 20%Stage progression 20%

Stage 2Stage 2 (1/43) (1/43) –– 2.3% risk of CA2.3% risk of CA

–– Stage progression 15.9%Stage progression 15.9%

Stage 3Stage 3 (1/41) (1/41) –– 2.4% risk of CA2.4% risk of CA

–– Stage progression 12.2%Stage progression 12.2%

Stage 4Stage 4 (4/11) (4/11) –– 36.4% risk of CA36.4% risk of CA

–– Dx Dx between 5between 5--10 years of initial screen10 years of initial screen–– Stage progression 36.4%Stage progression 36.4% Groves C, et al. Gut. 2002;50:636-641

Duodenal Duodenal adenomatosis adenomatosis in in familial familial adenomatous polyposisadenomatous polyposis

Prospective 5 nation study Prospective 5 nation study -- largest studylargest study

368 patients FAP368 patients FAP

Endoscopies 2, 4, 6, 8 yearsEndoscopies 2, 4, 6, 8 years

6 random biopsies6 random biopsies

Bulow S, et al. Gut 2004;53:381-386.

Duodenal Duodenal adenomatosis adenomatosis in familial in familial adenomatous polyposisadenomatous polyposis

-50% progression from stage 0 in 6yr

68% progression in 8yr

-15% progression to stage 4 in 8

years

-52% stage 4 by age 70

Bulow S, et al. Gut 2004;53:381-386.

Duodenal Duodenal adenomatosis adenomatosis in in familial familial adenomatous polyposisadenomatous polyposis

Time from entryTime from entry Increase in size (p <0.0001)Increase in size (p <0.0001) Increase in numbers (p <0.0001)Increase in numbers (p <0.0001) Minimal change in dysplasia (p = 0.07)Minimal change in dysplasia (p = 0.07)

2/26 (7.7%) stage 4 developed cancer2/26 (7.7%) stage 4 developed cancer Median age 52Median age 52 0.7% stage 3 developed cancer0.7% stage 3 developed cancer

1.6% developed duodenal cancer (4 pts)1.6% developed duodenal cancer (4 pts) Lifetime risk of duodenal cancer 3Lifetime risk of duodenal cancer 3--5%5%

Bulow S, et al. Gut 2004;53:381-386.

Endoscopic Surveillance Endoscopic Surveillance RecommendationsRecommendations Initial surveillance Initial surveillance –– 2525--30 years old30 years old

Stage 0Stage 0--11 5 year endoscopic follow up5 year endoscopic follow up No progression beyond stage 2 in 10 yearsNo progression beyond stage 2 in 10 years

Stage 2Stage 2--33 22--3 year endoscopic follow up3 year endoscopic follow up 2% developed CA in 10 years2% developed CA in 10 years 1212--15% progressed in stage in 10 years15% progressed in stage in 10 years Endoscopic treatment of polyps/ChemopreventionEndoscopic treatment of polyps/Chemoprevention

Stage 4 Stage 4 (or severe dysplasia)(or severe dysplasia)

Offer surgery Offer surgery –– PD vs. PSDPD vs. PSD

Groves C, et al. Gut. 2002;50:636-641

Treatment Options for Treatment Options for Duodenal PolypsDuodenal Polyps

Endoscopic RemovalEndoscopic Removal Transduodenal polypectomyTransduodenal polypectomy PancreasPancreas--sparing sparing duodenectomyduodenectomy PancreaticoduodenectomyPancreaticoduodenectomy

Endoscopic ResultsEndoscopic Results

Ampullary Ampullary adenomas adenomas –– LGD/HGDLGD/HGD ComplicationsComplications

Morbidity 23%; Mortality 0.4%Morbidity 23%; Mortality 0.4% Pancreatitis 8Pancreatitis 8--15%15% Perforation 0Perforation 0--4%4% Bleeding 2Bleeding 2--13%13% Cholangitis Cholangitis 2%2% Papillary Papillary stenosis stenosis 00--8%8%

Outcomes Outcomes -- Endoscopic resection for stage 2/3 or LGDEndoscopic resection for stage 2/3 or LGD FollowFollow--up 19up 19--66 months 66 months –– no progression to cancerno progression to cancer NonNon--surgical candidatessurgical candidates

Pandolfi M, et al. JOP. 2008.

Treatment Options for Duodenal Treatment Options for Duodenal PolypsPolyps Endoscopic RemovalEndoscopic Removal Transduodenal polypectomyTransduodenal polypectomy

High recurrence rates in FAPHigh recurrence rates in FAP Extensive Extensive polyposispolyposis

PancreasPancreas--sparing sparing duodenectomyduodenectomy Easier followEasier follow--up up survelliancesurvelliance Similar complication rateSimilar complication rate

PancreaticoduodenectomyPancreaticoduodenectomy HGD in FAP Suspicion/evidence of invasion on EUS

Alternative Alternative treatementstreatements

Celocoxib Celocoxib TrialTrial 800mg daily800mg daily Reduction in duodenal Reduction in duodenal adenomatosisadenomatosis ? Cancer? Cancer benefitbenefit

Sulindac Sulindac Trial Trial -- little to no effectlittle to no effect AspirinAspirin RanitidineRanitidine Photodynamic therapy Photodynamic therapy -- no long term datano long term data NdNd:YAG laser :YAG laser -- high risk of perforationhigh risk of perforation

PolypharmacyPolypharmacy 30 medications daily30 medications daily 36 tabs daily36 tabs daily 252 tabs/ week252 tabs/ week 1008 tabs/month1008 tabs/month 12,096 tabs/year12,096 tabs/year

Polypharmacy Polypharmacy and the and the Geriatric PatientGeriatric Patient By 2040, By 2040, ¼¼ of the worldof the world’’s population is s population is

estimated to be over 65 years oldestimated to be over 65 years old

44% of men and 57% of women over 65 44% of men and 57% of women over 65 use 5+ drugs/weekuse 5+ drugs/week

12% use 10 or more meds12% use 10 or more meds

44% of patients over 65 with home health 44% of patients over 65 with home health receive 9+ medsreceive 9+ meds

Drug use in elderlyDrug use in elderly

elderly aged 65+population

65+ years<65 years

30% of all prescription drug use among those aged 65+

12% of population aged 65+

aged 65+<65 years

50% of all OTC drug use among those 65+

Adverse Drug ReactionsAdverse Drug Reactions

82%82% risk of ADR at 6 medicationsrisk of ADR at 6 medications

$177 billion spent in 2000$177 billion spent in 2000

Every $1 spent on drugs, $1 spent on Every $1 spent on drugs, $1 spent on ADRADR’’ss

95% considered predictable95% considered predictable

7 fold increase in elderly7 fold increase in elderly

1/7 require hospital admission1/7 require hospital admission

Exponential Relation between Exponential Relation between ADR and ADR and PolypharmacyPolypharmacy

0102030405060708090

100

drug moredrugs

even moredrugs

lots-o-drugs

65+

Nolan L, et al. JAGS. 1998;36:142-149.

Ris

k of

AD

R

PharmacodynamicsPharmacodynamics Affinity for the site of action is inherentAffinity for the site of action is inherent

ResponseResponse of patient to drug at receptor of patient to drug at receptor changeschanges

Exaggerated response to analgesic effects Exaggerated response to analgesic effects but less sensitive to but less sensitive to betabeta--agonists/antagagonists/antag

50% decreased in 50% decreased in benzodiazapine benzodiazapine dose dose needed for sedationneeded for sedation

may be explained by changes at may be explained by changes at GABAGABA--benzo benzo receptor receptor complexcomplex

PharmacokineticsPharmacokinetics

AbsorptionAbsorption Increased lean body mass Increased lean body mass Slow GI motilitySlow GI motility Decreased gastric emptyingDecreased gastric emptying

DistributionDistribution Increased fat mass, decrease muscle massIncreased fat mass, decrease muscle mass Decreased total body waterDecreased total body water Decreased albuminDecreased albumin

EliminationElimination Altered renal function Altered renal function –– low GFR, loss of tubular functionlow GFR, loss of tubular function Decreased renal blood flowDecreased renal blood flow Clinically very important Clinically very important -- changes dosingchanges dosing

MetabolismMetabolism Decreased hepatic mass and blood flowDecreased hepatic mass and blood flow Cp450 Cp450 –– affecting metabolism of other medicationsaffecting metabolism of other medications

Updating the Beers Criteria for potentially Updating the Beers Criteria for potentially inappropriate medication use in older adults inappropriate medication use in older adults ––est. 1997est. 1997

30% of hospital admissions in the elderly 30% of hospital admissions in the elderly are related to drug problems or toxic drug are related to drug problems or toxic drug effectseffects

ADEs ADEs –– related to depression, falls, related to depression, falls, constipation, immobility, confusion and hip constipation, immobility, confusion and hip fracturesfractures

Of Of ADEs ADEs –– 1/7 require hospital admission1/7 require hospital admission Cause 106,000 deaths annuallyCause 106,000 deaths annually

Fick, D et al. Arch Intern Med 2003;163:2716-2723

Updating the Beers Criteria for potentially Updating the Beers Criteria for potentially inappropriate medication use in older adultsinappropriate medication use in older adults

23% decrease in PIM (potentially 23% decrease in PIM (potentially inappropriate medication use) with use of inappropriate medication use) with use of Beers list in review of Beers list in review of medicare/medicaid medicare/medicaid populationpopulation

Fick, D et al. Arch Intern Med 2003;163:2716-2723

Beers Beers Medication Medication ListList

Polypharmacy Polypharmacy ManagementManagement GoalsGoals

Limit new drug prescribingLimit new drug prescribing–– Once daily dosingOnce daily dosing–– Increased meds = decreased complianceIncreased meds = decreased compliance

Review BeerReview Beer’’s Lists List–– Know most common DDIKnow most common DDI

Follow up planning with geriatricianFollow up planning with geriatrician–– Inpatient geriatrics consultInpatient geriatrics consult

ReferencesReferences Bulow S, Bulow S, Bjork Bjork J, Christensen J, J, Christensen J, Fausa Fausa O, O, Jarvinen Jarvinen J, J, Moesgaard Moesgaard F, F, Vasen Vasen H. Duodenal H. Duodenal

adenomatosis adenomatosis in familial in familial adenomatous polyposisadenomatous polyposis. Gut 2004; 53:381. Gut 2004; 53:381--386.386. Cameron J. Current Surgical Therapy 9Cameron J. Current Surgical Therapy 9thth Ed. 2004.Ed. 2004. Fick Fick D, Cooper J, Wade W, Waller J, Maclean R, Beers M. Updating the D, Cooper J, Wade W, Waller J, Maclean R, Beers M. Updating the Beers Criteria for Beers Criteria for

Potentially Inappropriate Medication Use in Older Adults. Arch IPotentially Inappropriate Medication Use in Older Adults. Arch Intern Med 2003;163:2716ntern Med 2003;163:2716--2723.2723.

Groves C, Saunders B, Groves C, Saunders B, Spigelman Spigelman A, Philips R. Duodenal cancer in patients with familial A, Philips R. Duodenal cancer in patients with familial adenomatous polyposisadenomatous polyposis: results from a 10 year prospective study. Gut 2002;50:636: results from a 10 year prospective study. Gut 2002;50:636--641.641.

Hayes B, Klein W, Hayes B, Klein W, Barrueto Barrueto F. F. Polypharmacy Polypharmacy and the geriatric patient. and the geriatric patient. Clin Geriatr Clin Geriatr Med Med 2007; 23:3712007; 23:371--390.390.

Gozansky Gozansky W. W. PolypharmacyPolypharmacy. CRIT 2008.. CRIT 2008. Pandolfi Pandolfi M, Martino M, M, Martino M, Gabbrielli Gabbrielli A. Endoscopic treatment of A. Endoscopic treatment of ampullary ampullary adenomas. JOP adenomas. JOP

2008;9:12008;9:1--8.8. Sarmiento J, Thompson G, Sarmiento J, Thompson G, Nogorney Nogorney D, Donohue J, D, Donohue J, Farnell Farnell M. Pancreas sparing M. Pancreas sparing

duodenectomy duodenectomy for duodenal for duodenal polyposispolyposis. Arch . Arch Surg Surg 2002;137:5572002;137:557--563.563.