Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies. The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).
The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD). Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE. In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.
- “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
- Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
- Combination therapy was associated with relative risk of NMSC of 3.46
In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”
A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.
- the study captured data from randomized controlled trials.
- median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
- unclear how many adalimumab monotherapy patients had been on a thiopurine previously
- “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
- “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
- This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
- “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.“
- “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.” Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
- “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”
Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5). Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.
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