We included several variables (age, gender, type of cancer, cancer staging) in the Cox regression analysis to identify the risk factors for the occurrence of incident cancer; the independent variables associated with the development of incident cancers were female gender (odds ratio = 0.47; 95% CI = 0.29–0.76; P < 0.0001) and starting IMT beyond 5 years from the index cancer (odds ratio = 0.30; 95% CI = 0.21–0.73; P = 0.003).
The risk of malignancies in the general population increases with age. The growing prevalence of elderly-onset IBD and elderly patients with long-standing IBD increases the likelihood of developing cancer for patients with IBD and those with a history of cancer. Cancers in patients with IBD may be related to chronic inflammation (i.e., colorectal cancer), to IMT (i.e., lymphoma, nonmelanoma skin cancer, urinary bladder cancer), or unrelated to any of them. The present cohort is somehow particular because we only included patients with a history of cancer who had never been exposed to IMT. Moreover, and unlike all similar cohort studies published to date (11–13), we excluded patients with previous colorectal cancer, because its pathogenesis is mainly driven by the inflammatory process of IBD itself and a protective effect of thiopurines has been already reported (18). Finally, to our knowledge, this is the largest study reported up to now which addresses the risk of incident or recurrent cancers in a population like this.
In agreement with previous studies, we found that thiopurines and anti-TNF agents were not associated with an increased risk of new or recurrent cancers. In the CESAME cohort, a prospective study that included patients with IBD stratified by the use of thiopurines, no excess incidence of recurrent or new cancers was observed among the 93 patients exposed to thiopurines with previous cancer at cohort entry (11). In 2 recent retrospective studies including 79 and 333 patients with IBD and a history of cancer, further exposure to anti-TNF agents or antimetabolites did not increase the risk of incident cancer compared with patients who did not receive immunosuppression (12,13). Comparatively, the overall incident cancer rate in our study was lower than that reported in these studies. These differences might be explained at least partially by the potential impact of exposure to IMT before the index cancer and by the inclusion of patients with colorectal cancer in the abovementioned studies. Moreover, we did not exclude patients who started IMT beyond 5 years after the diagnosis of the index cancer, leading to a longer median follow-up (10 years) compared with previous studies (2–3 years).
We also confirmed that IMTs seem to be safe even when introduced within the first 2 years after the diagnosis of cancer. Our results are in line with those reported by the prospective CESAME cohort in which patients were treated with thiopurines (11) and a retrospective French study of patients treated with anti-TNF (13), in which no increased risk of incident or recurrent cancers was observed either. Furthermore, we found that in patients with a history of cancer and no previous exposure to IMT, starting these drugs beyond 5 years from the diagnosis of the index cancer is associated with a lower risk of cancer recurrence. We think that although this is probably explained by a selection bias (patients who survive 5 years after the diagnosis of cancer are less likely to recur), it could be relevant for clinical practice.
Choosing the appropriate IMT in a patient with a history of cancer is a challenging decision that must be made case by case. Despite the lack of specific guidelines on this issue, the results of the present study suggest that starting IMT in patients with a cancer that is unrelated to immunosuppression (who have never been exposed to these drugs) seems to be safe. In our opinion, previous exposure to IMT should be addressed in depth in future studies and should be taken into account for developing a new recommendation consensus.
Surprisingly, most of the exposed patients in the present study were treated with thiopurine monotherapy or in combination with anti-TNF and only 5 patients were on anti-TNF alone. This reflects the common therapeutic algorithm in IBD in which thiopurine therapy represents the first step in the immunosuppressive approach, followed by combination therapy as the gold standard when anti-TNF agents are started in adult patients with IBD. However, it would be expected that in this clinical setting, physicians should be worried about using combination therapy, prompting the use of anti-TNF alone to avoid excessive immunosuppression. Moreover, the total number of patients treated with combination therapy did not permit the performance of additional analyses to ascertain the impact of combination therapy on cancer recurrence. A recent meta-analysis in rheumatologic patients with a history of cancer observed that although the rates of cancer recurrence were similar among individuals receiving anti-TNF therapy, methotrexate, or no immunosuppressant, recurrent cancers were numerically higher among patients receiving combined immunosuppressive therapy (without reaching statistical significance) (19). However, this is difficult to extrapolate to IBD because there is a different genetic background and methotrexate is used much less frequently than with rheumatologic conditions. Finally, although the retrospective nature of the present study could be seen as a limitation, it is unlikely that controlled or prospective studies will be ever available on this issue. Moreover, although some patients were retrospectively included in the ENEIDA registry, the database is prospectively maintained, a fact that strengthens our results.
There are several limitations of the current study that are inherent to a retrospective study design. First, there was no preestablished criterion for IMT introduction and this relied on the treating physician. Many factors may influence the therapeutic decisions such as the type and stage of cancer, the previous evolution of IBD, comorbidities, and even the patient's age. In fact, patients who were not exposed to IMT were older at the time of diagnosis of the index cancer and had more advanced staging of the tumors compared with those who were further treated with IMT. In addition, our population was treated mostly with thiopurines or combination therapy and only a small proportion was on anti-TNF alone, and we did not evaluate patients treated with neither other biologic therapies nor methotrexate.
In conclusion, the present study confirms that IMT in patients with IBD can be safely used beyond 5 years after cancer diagnosis and that IMTs (including thiopurines alone or in combination with anti-TNF agents) do not seem to increase the risk of new or recurrent cancers in this subset of patients.
CONFLICTS OF INTEREST
Guarantor of the article: Míriam Mañosa, MD, PhD.
Specific author contributions: M.M. and E.D. designed the study, performed the statistical analysis, evaluated the results, and drafted the article. M.C. and J.P.G. generated and managed raw data from the ENEIDA registry and critically reviewed and approved the article. E.C. gave support to the statistical analysis and drafted the article. The remaining authors collected data and critically reviewed and approved the article.
Financial support: AbbVie, Takeda, Pfizer, Kern Pharmaceuticals, and MSD gave financial support to the ENEIDA registry.
Potential competing interests: M.C. has served as a speaker or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma. MTA has served as a speaker for MSD, Abbvie, Takeda, Janssen, Ferring, Shire Pharmaceuticals. I.A. has received fees from Takeda and Shire. M.M. has served as a speaker, a consultant, and an advisory board member for Danone, Allergan, Almirall, MSD, AbbVie, Takeda, and Janssen. M.I. has served as a speaker and consultant from MSD and Takeda. J.P.G. has served as a speaker, a consultant, and an advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma. J.P.G. has served as a speaker, a consultant, and an advisory member for or has received research funding from MSD, Abbvie, Kern Pharma, Takeda, Janssen, Pfizer, Ferring, Shire Pharmaceuticals, Gebro Pharma, and Tillots. P.M. has served as a speaker from Takeda, Janssen, MSD, Abbvie. MDMA has received fees as a speaker, consultant, or travel, or research grants from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Shire Pharmaceuticals, Tillotts Pharma, Faes Pharma. M.V.D. has received lecture fees and travel grants from Abbvie and Kern. E.R. has received lecture fees from Abbvie, MSD, Janssen, Ferring, Takeda, and Shire. M.R. has served as a speaker, a consultant, and an advisory member for MSD, Abbvie, and Janssen. M.E. has served as a speaker or has received research or education funding or advisory fees from MSD, Faes, Takeda, Pfizer, Janssen, Ferring, Tillots. J.L.C. has served as a consultant for or has received research funding from MSD, Otsuka Ph, Pfizer, Takeda, and Janssen. R.L. has served as a speaker or has received research or education funding from MSD, Abbvie, Pfizer, Takeda, Janssen. E.C. has received fees as a speaker from MSD and Ferring. E.D. has served as a speaker or has received research or education funding or advisory fees from MSD, AbbVie, Takeda, Kern Pharma, Pfizer, Janssen, Celgene, Otsuka Pharmaceuticals, Ferring, Shire Pharmaceuticals, Tillots, Thermofisher, Grifols, Gebro.
WHAT IS KNOWN
- ✓ There are scarce data on the use of IMTs in patients with IBD who have a history of cancer.
WHAT IS NEW HERE
- ✓ The use of IMTs in patients with IBD and a history of cancer not related to immunosuppression is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.
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