Combination therapy increases malignancy risk

Feb 3, 2015 - E-Mentoring in IBD | Volume 08 • 2015

Issue 02

Clinical Question

Is there an increased risk of malignancy for Crohn’s disease (CD) patients taking adalimumab (ADA) combination therapy?

Editor’s Bottom Line

The malignancy rate with ADA monotherapy is not increased over the general population. ADA combination therapy increases the relative risk of malignancy.

Editorial Note

This study confirms previously demonstrated data for anti-TNF therapy where the malignancy risk increases with combination therapy. However, the absolute increased risk is small, increasing from 4/10,000 to 6/10,000. Overall, the risk (malignancy rate) of combination therapy is markedly out-weighed by the benefit (clinical efficacy).


Osterman MT, Sandborn WJ, Colombel JF, et al. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn’s disease. Gastroenterology. 2014 Apr;146(4):941–9.


This meta-analysis pooled data from 6 studies of which 5 were RCTs and an open-label long-term extension study (ADHERE). Data from patients who had at least 1 dose of ADA were included for analysis. ADA combination therapy was defined as: (i) ADA with either thiopurine or methotrexate, or; (ii) ADA with thiopurine. Sub-categorization of ADA combination therapy was needed as patients could switch between immunomodulators during the ADHERE study. The study endpoint was malignancy diagnosis during therapy or within 70 days after the last ADA dose. Malignancy rates of the general population were determined using the SEER database.

Of the 1,594 patients (3,050 patient years), 44% were receiving combination therapy (thiopurines, n=563; methotrexate, n=131). There were no significant differences between the patient groups at baseline although corticosteroid and prior biologic use was more prevalent among patients assigned to the combination group. There were 34 patients (2.1%) who developed 44 malignancies: ADA monotherapy=10 patients with 12 malignancies, versus ADA combination=24 patients with 32 malignancies. Combination ADA therapy increased the relative risk of nonmelanoma skin cancer (NMSC) in CD patients by 3.46 and other non-NMSC malignancies by 2.82.

Compared to the general population, the ADA monotherapy had the same risk of malignancy development. Conversely, patients receiving ADA combination therapy had greater than expected risks of developing NMSC or other non-NMSC malignancies (standard incident ratio (SIR) of 4.59 and 3.04, respectively).


Study Design: Meta-analysis of 6 studies: CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE
Funding: AbbVie, Inc.
Allocation: n/a
Setting: n/a
Level of Evidence: 1a (Oxford Levels of Evidence)

The summary and conclusion in this issue of E-mentoring in IBD pertains to the manuscript(s) being reviewed, and should be considered in the context of what is already known surrounding the topic and incorporated into practice as deemed appropriate by the individual learner.