IBD and Cancer: Myths and Facts Thomas A. Ullman, MD Medical Director, Faculty Prac>ce Department of Medicine Icahn School of Medicine at Mount Sinai New York, USA
Risk of Colorectal Cancer in UC Eaden et al. Gut 48:526, 2001
Risk of Colorectal Cancer in Crohn s Crohn s Canavan, APT, 2006
Colorectal Cancer in IBD: Factors that Increase Risk Dura>on >8-10 years Extent of coli>s: Extensive disease Backwash ilei>s Family history of colon cancer Primary sclerosing cholangi>s Early age at onset of coli>s Histologic ac>vity Pseudopolyps Dysplasia at surveillance
Colorectal Cancer in IBD: Factors that Decrease Risk Prophylac>c Colectomy Regular doctor visits (and the unknown) Surveillance colonoscopy Timely surgery/lesion removal Adjunc>ve colonoscopic techniques Chemopreven>on? Mesalamines? UDCA Yes (PSC pts/low dose) Folic Acid? 6MP/Azathioprine?
Cancer Surveillance in Colitis Inflammation Dysplasia Cancer Death Initiate screening and surveillance Intervention to prevent further progression: surgery
So are we decreasing CRC morbidity and mortality in IBD?
Is the Curve Changing with Surveillance? Eaden et al. Gut 48:526, 2001 Ullman, et al. CGH 6:1225, 2008
Has Colitis-Related CRC Declined in Importance? SMR 95% CI Copenhagen, Denmark 1 1.05 0.56-1.79 Olmsted, MN, USA 2 1.1 0.4-2.4 1. Winther, CGH 2004;2:1088 1095 2. Jess, Gastro 2006;130:1039 1046
Do Medicines for IBD Cause Cancer?
What are the main side-effects of 6MP/ Azathioprine? Event Frequency Estimate Stop therapy due to AE 11% Allergic reactions 2% Nausea 2% Hepatitis 2% Pancreatitis 3% Serious infections 5% non-hodgkin s lymphoma 0.04%-0.09% (4-9/10,000) Siegel CA, et al. APT 2005 (weighted average); Siegel CA, et al. CGH 2009; Beaugerie L, et al. Lancet 2009.
Solid tumors and 6MP/Azathioprine in IBD (non-gi and non-skin cancers) Study Types of cancer Number of patients Statistically significant Armstrong 2010 lung, breast 1955 NO Fraser 2002 Connell 1994 breast, bronchial, renal gastric, lung, breast, cervical 6262 NO 755 NO No clear association between thiopurines and solid tumors in IBD
Risk of Skin Cancer Associated with Thiopurines 19,486 IBD patients in CESAME cohort 32 cases of skin cancer (20 basal cell, 12 squamous) Look at denominator (" Incidence rate per 1000 ptyears '" &" %" $" -./012(/3&)$ 403532&6$ -./012(/3&)$ 6/)403532&6$ 7&8&($ 9./012(/3&)$ Wear sunscreen Regular skin checks #"!"!"#$%&'()$ "#*+"$%&'()$,+"$%&'()$ Peyrin-Biroulet L, et al. Gastroenterology 2011
Adverse Events Associated with anti-tnf Treatment Event Stop therapy due to adverse event Siegel CA.. The inflammatory bowel disease yearbook, volume 6. 2009; Infliximab package insert; Vermeire, Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003 Estimated Frequency 10% Infusion or injection site reactions 3%-20% Drug related lupus-like reaction 1% Serious infections 3% Tuberculosis 0.05% (5/10,000) Non-Hodgkin s lymphoma (combo) Multiple sclerosis, heart failure, serious liver injury 0.06% (6/10,000) Case reports only
Risk of NH Lymphoma with anti-tnf + IM treatment for Crohn s Disease: A Meta-Analysis 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin s lymphomas à 6.1 per 10,000 pt-years Mean age 52, 62% male 10/13 exposed to IM* (really a study of combo Rx) NHL rate per 10,000 SIR 95% CI SEER all ages 1.9 - - IM alone 3.6 - - Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9 Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1 Siegel et al, CGH 2009;7:874. *not reported in 2
Risk of Developing non-hodgkin s Lymphoma Patient receiving Immunomodulator +/- anti-tnf Therapy for 1 year Risk without of lymphoma medication with immune suppression Siegel CA, Inflamm Bowel Dis 2010;16:2168.
Solid Tumors and anti-tnf in RA National Data Bank for Rheumatic Diseases (1998-2005) 13,000 patients enrolled, 49% received biologics Type of Cancer Odds Ratio All cancers 1.0 (0.8-1.2) All solid tumors 1.0 (0.8-1.2) Colon 0.8 (0.3-1.7) Lung 1.1 (0.7-1.8) Breast 0.9 (0.5-1.3) Pancreas 0.5 (0.1-2.6) Melanoma 2.3 (0.9-5.4) Non-melanoma skin 1.5 (1.2-1.8) Wolfe, Arthritis and Rheumatism 2007;56:2886.
RA PaDents Treated with AnD- TNF: Similar Stage and Survival as Those without AnD- TNF Cohort of 78,483 RA patients 8,562 started therapy with a biologic agent 98% anti-tnf 314 cancers in patients undergoing or with a history of treatment with biologic 4,650 cancers in biologics-naïve patients Outcomes: Tumor stage at time of diagnosis Post cancer survival Raaschou et al. Arthri's & Rheuma'sm 2011. 63; 1812-22
No overall difference in mortality or stage at diagnosis related to and- TNF exposure Raaschou et al. Arthri's & Rheuma'sm 2011. 63; 1812-22
What if I Have a History of Cancer?
IBD pts with history of cancer: Thiopurine Exposure - No Increased Risk of Subsequent Cancer (CESAME) 19,486 pts with IBD: Enrolled May 2004-June 2005, followed through December 2007 405 with personal history of cancer with at least one follow up visit Compared risk of developing new/recurrent cancer: 93 pts exposed to IT (thiopurine): 6 new cancers 1 recurrence of meningioma 312 not exposed to IT 12 new cancers 4 recurrent cancers (lymphoma, breast, prostate, small bowel) IT Naïve at Entry n=312 IT at Entry n=93 New Cancer (NS) 14.4/1000 PY 23.1/1000 PY Recurrent Cancer (NS) 6.8/1000 PY 3.9/1000 PY P=0.98 P=0.26 L Beaugerie et al. Abstract DDW 2012.
RA PaDents with History of Cancer: AnD- TNF Treatment Did Not Increase Risk of New or Recurrent Cancer (BriDsh Registry) Over 14,000 pts with RA 293 with prior malignancy 177 anti-tnf treated 117 DMARD treated (no anti-tnf) Rates of incident malignancy compared 25.3/1000 PY in anti-tnf 38.3/1000 PY in DMARD Prior Melanoma: 3/17 (18%) in anti-tnf developed incident malignancy 0/10 (0%) in DMARD developed incident malignancy BSR Guidelines at Dme of study read: CauDon should be exercised.in pts with previous malignancy If pts have been free of any recurrence of their malignancy for 10 yrs there is no evidence for a contraindicadon to and- TNF therapy DMARD AnD- TNF Dixon et al., Arthritis Care & Research 2010. 62;755-63.
RA Patients with History of Cancer: Anti-TNF Treatment Did Not Increase Risk of New or Recurrent Cancer (German Registry) Biologic or conventional DMARD therapy between May 2001 and December 2006 Prior malignancy in 122 out of 5,120 pts 58 pts received anti-tnf 55 conventional DMARDs 14 pts exposed to anti-tnf with 15 recurrent cancers Crude recurrence rates: 45.5/1000 PY in anti-tnf exposed 31.4/1000 PY in DMARD exposed Incidence rate ratio 1.4 (P=0.6) Strangfeld et al. Arthri's Research &Therapy 2010. 12:R5.
Summary There is an increased risk of colorectal cancer in IBD With surveillance, time and other factors that risk is about the same as the general population: GET YOUR SURVEILLANCE Some medicines increase the chance of lymphoma, but it is a very small risk 6MP/Azathioprine increase the risk for non-melanoma skin cancer Anti-TNF s may increase the risk for melanoma Those same medicines don t seem to increase the risk of other cancers