Tumor necrosis factor inhibitors (TNFi) are usually considered contraindicated in patients with a recent history of malignancy. General conservative recommendations have included often waiting 5 years after a cancer diagnosis before initiating TNFi therapy [1,2]. However, these recommendations were based more on expert opinion than supportive data in patients with inflammatory disease.

Initial concerns of increased cancer risk associated with TNFi use arose from data in transplant patients with a history of a previous malignancy [3]. Subsequently, an Food and Drug Administration (FDA) postmarketing report observed 2 out of 26 cases of lymphoma regressing once TNFi therapies were halted in rheumatoid arthritis (RA) and IBD patients [4]. In addition, a 2006 meta-analysis reported a 3-fold increased risk for all malignancies (pooled OR of 3.3) in patients treated with TNFi therapies [5]. These data led to an FDA black box warning for TNFi in 2009 in regards to malignancy [4]. However, when these drugs are stopped in the setting of malignancy, clinicians are often left to deal with patients feeling poorly from active inflammatory disease.

Faced with this difficult clinical situation, various studies have attempted to address this concern by focusing on risk of cancer recurrence in patients exposed to TNFi. A retrospective study using Medicare databases found no increased risk of recurrence of breast cancer in patients on immunosuppressants including methotrexate and TNFi [6]. However, the study excluded cases where TNFi was used during the first year following cancer diagnosis, which leaves the question of continuing TNFi in these patients unanswered. Similarly, a meta-analysis of observational studies also found no increase in cancer recurrence rates but the majority of these studies also excluded cases with TNFi use in the immediate period following cancer diagnosis [7]. In contrast, survival in cancer patients with concurrent TNFi use has been less well studied. Therefore, our primary aim was to assess the survival outcomes of patients with TNFi exposure leading up to or during concomitant cancer diagnosis and treatment. Our secondary objective was to assess recurrence rates for patients with malignancy exposed to TNFi use.

In our matched cohorts of veterans with inflammatory disease and malignancies, we found that the use of TNFi did not affect overall survival or cancer recurrence. Similarly, when our veteran cohort treated with TNFi was compared with age, sex and cancer type matched control patients from the SEER database, there was no difference in overall survival. These findings are in line with recent studies in both RA and IBD populations. A Swedish cohort study specifically evaluating RA patients with breast cancer who were treated with TNFi found no differences in recurrence rates with similar patients who did not receive treatment with TNFi [8]. However, the median time to starting TNFi after breast cancer diagnosis in this study was over 9 years later and thus not generalizable to patients with a recent diagnosis of cancer who need TNFi. Similarly, a study using a British registry of RA patients starting biologics reported no difference in incident malignancies of all types in patients using TNFi as compared to those treated with traditional disease-modifying antirheumatic drugs, but the average time between starting a TNFi and prior cancer diagnosis was 11.5 years [9]. A strength of our study was that we excluded patients starting TNFi 5 years or more after malignancy diagnosis, improving generalizable to patients needing TNFi at the time of their cancer diagnosis or soon thereafter.

A French study identified a cohort of 79 patients with IBD who received TNFi on average 17 months after diagnosis with malignancy. They found that 1-year survival was 96% and 5-year survival was 66% with a total of 19% developing incident cancers [10]. Unfortunately this study had no control group with which to compare outcomes. A retrospective study from New York including 106 patients with IBD who were treated with TNFi after a malignancy reported that there was no difference in incident cancer rates for those treated with TNFi alone, combination TNFi and immunomodulator or controls [11]. However, there were significant baseline differences between the TNFi treated patients in this study and the controls including differences in cancer staging and cancer types which may bias survival heavily. Another strength of our study is that we included a control group without TNFi use who also had a history of malignancy and were matched 2:1 to the cases by type of cancer. Our cases and controls were similar in regard to inflammatory disease type, CCI, smoking status, concomitant medications at the time of cancer diagnosis, cancer type, staging and cancer treatments. Our groups only differed in the TNFi group having fewer African Americans than the control group as well as the TNFi treated group having a slightly longer disease duration (on average 3 years longer) and being diagnosed slightly younger with their inflammatory disease (on average 6 years younger). In addition to our control cohort of veterans, we additionally included an age, sex, and cancer-matched control survival rates from the SEER database, further supporting our conclusions.

Our data included detailed chart review that allowed us to calculate not only survival rates after cancer diagnosis, but to also assess recurrence rates of the original cancer that was diagnosed. In our Kaplan-Meier analysis, while there was a numerically higher recurrence rate in the patients treated with TNFi, there was no statistical significant difference between those treated or not treated with TNFi. Interestingly, when we analyzed the data in subgroups, comparing recurrence rates between those who were exposed to TNFi and stopped it at cancer diagnosis with those who continued it or restarted it soon after cancer diagnosis, there was again no significant difference in recurrence rates (P=0.45). Our study is the first to compare these 2 strategies of TNFi use in the time around a malignancy diagnosis; stopping TNFi without restarting versus continuing or restarting soon after cancer diagnosis.

Despite its many strengths, several limitations should be taken into consideration for this study. These include the relatively small sample size and a heterogeneous population of inflammatory diseases. This limits the analysis of individual cancer types and individual inflammatory diseases. Additionally, our subgroup analysis of the discontinuation of TNFi as compared to continuing or restarting soon after cancer diagnosis is likely underpowered given the small sample size. Further, our veteran population is predominately male making it less generalizable to women. Lastly, despite the well-matched cohorts, given the retrospective nature of the study, there is always the potential for selection bias of unmeasured characteristics that may have influenced providers to discontinue versus restart TNFi after cancer diagnosis.

In conclusion, the findings of this study suggest TNFi appear safe to use in selected inflammatory patients with concomitant cancer. However, clinical decisions to start TNFi in these patients should still be made on a case-by-case basis in conjunction with oncologists by taking the apparent safety of the TNFi into consideration for patients suffering from active inflammatory diseases despite having a concomitant malignancy. Future studies should include multiple institutions to provide larger cohorts of patients to allow disease specific and cancer specific analysis of outcomes. Moreover, if feasible, a randomized study of stopping therapy versus continuing through cancer treatment would bring even stronger data to guide our clinical practice.