Jordan Axelrad

Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment.

In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.

Effects of cancer treatment on inflammatory bowel disease remission and reactivation.

BACKGROUND & AIMS Little is known about the effects of cancer therapy for extraintestinal malignancy in patients with inflammatory bowel diseases (IBDs). METHODS We analyzed data from the Massachusetts General Hospital and the Brigham and Womens Hospital on 84 patients diagnosed with Crohns disease, ulcerative colitis, or indeterminate colitis found to have a solid malignant extraintestinal neoplasm between January 15, 1993, and December 15, 2011. We investigated the incidence of remission with cancer treatment (cytotoxic chemotherapy, hormone therapy, or both) among patients with active IBD (n = 15) and time to disease activation after cancer treatment of those with inactive disease (n = 69). Cox proportional hazards models and survival curves were constructed to identify independent predictors of these outcomes. RESULTS Among patients with active IBD at cancer diagnosis, 66.7% (n = 10/15) achieved remission during cancer treatment; the median duration of remission was 27 months. Ninety percent of these patients had received cytotoxic chemotherapy. For patients with IBD in remission at cancer diagnosis, 17.4% (n = 12/69) developed active IBD; the type of treatment was the strongest predictor of IBD reactivation. The risk of IBD reactivation was greatest among patients who received a combination of cytotoxic chemotherapy and adjuvant hormone therapy (hazard ratio, 12.25; 95% confidence interval, 1.51-99.06) or only hormone therapy (hazard ratio, 11.56; 95% confidence interval, 1.39-96.43). Ninety percent of patients who received cytotoxic chemotherapy remained in remission at 5 years compared with 64% of those who received only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy (log rank, P = .02). CONCLUSIONS IBD is more likely to remit among patients who receive cytotoxic chemotherapy for solid malignancies than those who receive only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy. Among patients with inactive IBD at the time of cancer diagnosis, hormonal therapy, alone or in combination with cytotoxic chemotherapy, increases the risk of IBD reactivation.

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn’s disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Previous Cancer/Lymphoma and Refractory Inflammatory Bowel Disease.

Immunomodulators and biologic agents are effective in treating inflammatory bowel diseases (IBDs), and recent evidence supports their introduction earlier in the disease course. An important concern to both patients and physicians considering immunosuppression (IS) for the treatment of IBD is the potential associated cancer risk. Several important clinical questions deserve attention with respect to IBD therapy and cancer. First, does medical therapy for IBD predispose to developing cancer? Second, in an IBD patient with a history of cancer, does IBD therapy impact cancer recurrence? Third, once cancer develops in an IBD patient, is the cancer outcome different? Finally, in an IBD patient with current cancer, does the cancer therapy affect IBD outcomes? In a recent multicentric study, patients were identified based on a diagnosis of IBD and cancer with subsequent exposure to anti-tumor necrosis factor α (anti-TNFα arm), thiopurines or methotrexate (antimetabolite arm) or without subsequent IS exposure (control arm). Two hundred and fifty-five patients met the inclusion criteria. Prior cancers included 121 solid, 62 gastrointestinal, 55 dermatologic and 17 hematologic malignancies. During the follow-up period, 75 (29.4%) patients developed incident cancer: 36 (14.1%) a new cancer, 33 (12.9%) a recurrent cancer and 6 (2.4%) a new and recurrent cancer. Incident cancer rate per 100 person-years for patients exposed to anti-TNFα, anti-metabolites and controls was 2.6 with 795 person-years of follow-up, 14.8 with 122 person-years of follow-up and 8.52 with 422 person-years of follow-up, respectively. In this series of IBD patients with a history of cancer, exposure to IS following a cancer diagnosis was not associated with an increased risk of incident cancer compared to patients who did not receive these agents. Prospective data are needed to confirm these findings.

Sa1138 Patients With Inflammatory Bowel Disease and a History of Cancer: The Risk of Cancer Following Exposure to Immunosuppression

Back ground: The calcineurin inhibitor (CNI) tacrolimus (TAC) has been reported to be effective for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). However, CNI has nephrotoxic potential leading to acute and chronic renal damage in some cases. To date, little is known about the influence of long term administration of oral TAC on renal function in patients with UC. Aim: The aim of our study was to evaluate the incidence and the severity of renal function impairment in UC patient who received TAC treatment. Methods: In this retrospective study, the medical charts of 71 adult patients with steroid-refractory UC treated with TAC between 2012 and 2014 in a single Japanese center were analyzed. In principle, TAC was orally administrated as a 2 week-induction (target trough levels 10-15ng/ml) followed by a maintenance therapy (target trough levels 5-10ng/ml). Estimated glomerular filtration rate (eGFR) was evaluated during the treatment. Acute kidney injury (AKI) was defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of function, Loss of function and End-stage kidney disease) consensus criteria using the maximal change in serum creatinine (Scr) and eGFR during the TAC treatment compared with baseline value before treatment. Results: The mean duration of TAC administration was 210 days. At 12weeks, TAC produced a clinical response in 54 patients (76.1%) and remission was achieved in 29 of those 54 (40.8%). The AKI rate during TAC treatment was 46.5% (33 of 71 patients). RIFLE class R (Scr increase > 1.5 times or eGFR decrease > 25%) accounted for 27 patients (38.0%), and RIFLE class I (Scr increase > 2 times or eGFR decrease > 50%) for six (8.5%). The AKI rate was 76.8% (10/13) in patients who had been administrated TAC for more than 1 year and 37.5% (18/48) in patients with TAC treatment within 6 months (p=0.006). After withdrawal of TAC, renal function impairment (eGFR decrease > 25%) was still observed in 10 patients (14.1%). Conclusions: Oral TAC therapy appears to be effective for patients with refractory UC. However, renal function impairment was frequently observed during this treatment. Thus, careful monitoring of renal function must be required to avoid irreversible chronic renal damage during long-term administration of TAC.