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Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers

Mañosa, Míriam, MD, PhD1,2; Chaparro, M., MD, PhD2,3; Juan, A., MD1,2; Aràjol, C., MD4; Alfaro, I., MD2,5; Mínguez, M., MD, PhD6; Velayos, B., MD7; Benítez, J.M., MD8; Mesonero, F., MD9; Sicilia, B., MD, PhD10; Zabana, Y., MD, PhD2,11; Villoria, A., MD, PhD2,12; Gisbert, J.P., MD, PhD2,3; Domènech, E., MD, PhD1,2 on behalf of the ENEIDA registry by GETECCU

American Journal of Gastroenterology: May 2019 - Volume 114 - Issue 5 - p 771–776
doi: 10.14309/ajg.0000000000000210
ARTICLE
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OBJECTIVES: Immunosuppressant therapies (IMTs; thiopurines, anti–tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy.

METHODS: Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test.

RESULTS: Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis.

DISCUSSION: In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

1HU Germans Trias i Pujol, Badalona, Spain;

2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Spain;

3Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain;

4H. Universitari de Bellvitge IDIBELL, L'Hospitalet de Llobregat, Spain;

5H Clínic, Barcelona, Spain;

6H Clínico de València. Universitat de València, Valencia, Spain;

7HCU de Valladolid, Valladolid, Spain;

8H Reina Sofía and IMIBIC, Córdoba, Spain;

9H Ramón y Cajal, Madrid, Spain;

10CH Burgos, Burgos, Spain;

11H Mútua de Terrassa, Terrassa, Spain;

12H Parc Taulí, Sabadell, Spain.

Correspondence: Míriam Mañosa, MD, PhD. E-mail: mmanosa.germanstrias@gencat.cat.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A164 and http://links.lww.com/AJG/A165

Received May 30, 2018

Accepted February 21, 2019

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INTRODUCTION

Immunosuppressive therapies (IMTs), including thiopurines and anti–tumor necrosis factor (TNF) agents, have demonstrated their efficacy in maintaining clinical remission in the treatment of inflammatory bowel disease (IBD) and in reverting mucosal lesions (1,2). For these reasons, they are widely used early in the treatment with the aim of achieving complete symptomatic control and of preventing disease-related complications. However, these drugs are hampered by an increase in the risk of infections and certain neoplasms.

Contrarily, patients with IBD have a similar or slightly increased mortality rate compared with the background population, leading to a steady increase in the prevalence of patients with IBD aged above 40 years (3). Aging is associated with a higher risk of malignancies (4). Therefore, there is a growing interest in the safety of IMTs in patients with IBD who have a history of cancer.

As a consequence of their mechanism of action, IMTs may influence the immunologic control of cancer and thereby facilitate the spread and recurrence of cancer (5,6). IMTs may diminish the immunosurveillance of tumor cells and chronic latent viral infections (Epstein-Barr virus, human papilloma virus) and provoke direct DNA alterations of organ cells (7,8). Therefore, reintroduction of IMTs is not advisable in patients who developed a cancer that may be related to immunosuppression (i.e., Epstein-Barr virus-related lymphomas, skin cancers) (4). In addition, it has been reported that the growing number of cancer survivors have an increased risk of developing and dying of a second primary malignancy (9). Hence, a history of cancer is generally considered to be a relative contraindication for IMT, and current guidelines advise against their use within 2–5 years after cancer diagnosis (10). Moreover, a number of other factors are often taken into account for decision making in this clinical setting, such as the natural history of the cancer, the time interval from the completion of cancer treatment, the current severity of IBD, and the known or expected impact of the IMT on the cancer.

There are scarce data on the use of IMTs in patients with IBD and a history of cancer. Recently, 1 prospective study and 2 retrospective studies suggested that neither thiopurines nor anti-TNF agents was associated with an increased risk of recurrent or new cancers in patients with IBD and a recent history of cancer (11–13). However, these studies included small sample sizes, colonic cancer was also included despite its relationship with IBD itself, and they did not take into account the exposure to IMT before cancer diagnosis. Hence, additional larger studies are warranted.

This study describes the risk of incident cancers (recurrent or new) in patients with IBD and a history of extracolonic cancer who were naive to IMTs (thiopurines, methotrexate, and anti-TNF agents) at the time of cancer diagnosis, regarding the further use of IMTs.

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PATIENTS AND METHODS

This was an observational, retrospective, multicenter, nationwide study, promoted by the Spanish Working Group in IBD (GETECCU).

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ENEIDA registry

Patients were identified from the GETECCU's ENEIDA registry that includes patients with IBD. After registration, physicians from IBD centers can voluntarily include their patients' data in the registry. At the time of data extraction, the registry contained 22,705 patients from 47 centers. The study was approved by the Research Board of GETECCU and by the local Ethics Committees of the participating centers. Written informed consent to participate in the ENEIDA registry was obtained from all patients. The database prospectively records clinical data, use, effectiveness, and adverse events of all immunosuppressive drugs, and also comorbidities. Among comorbidities, colonic and extracolonic neoplasms are specifically collected. (For a list of investigators of the ENEIDA registry, see Supplementary Digital Content 1, http://links.lww.com/AJG/A164.)

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Patients

Only patients with a history of extracolonic cancer who had never been exposed to thiopurines, methotrexate, or anti-TNF agents before the time of cancer diagnosis were included in the study. Patients were categorized as either exposed or nonexposed on the basis of subsequent exposure to IMT (including thiopurines and anti-TNF agents) after cancer diagnosis. Patients treated with any IMT before the diagnosis of cancer and those with a history of colorectal cancer were excluded from the analysis.

Diagnosis of IBD was based on the accepted criteria by the European Crohn's and Colitis Organization (14,15), including clinical symptoms, endoscopy, radiology, pathology, and operative reports. Basic demographic information, age at IBD diagnosis, IBD phenotype, the date of cancer diagnosis, the type of cancer, the date of last clinical encounter, and IBD medications were obtained from the ENEIDA registry (Supplementary Digital Content 2, http://links.lww.com/AJG/A165).

The date of the index cancer diagnosis was collected from medical reports or was reported by patients, which was confirmed by pathologic reports whenever possible. Lesions classified as category D (in situ neoplasms, benign neoplasms, and neoplasms of uncertain or unknown behavior) were excluded. Cancer staging was established by means of the TNM system (16) whenever possible. Cancer type was categorized into gastrointestinal (any malignancy of the gastrointestinal tract, except colorectal cancer), hematologic (any leukemia or lymphoma), dermatologic (melanoma and nonmelanoma skin cancers), or of other solid organs. Cancers were also categorized on the basis of Penn's classification for the recurrence risk of preexisting malignancies as low-risk malignancies (including incidental renal tumor, lymphoma, testicular, uterine, cervical, and thyroid carcinomas), intermediate-risk cancers (including carcinoma of the uterine body, prostate, and breast, and Wilms tumor), and high-risk malignancies (including carcinoma of the bladder, sarcomas, malignant melanoma, symptomatic renal carcinoma, nonmelanoma skin cancers, and myeloma) (17).

The primary outcome of the study was the development of incident cancers. The time to incident cancer was calculated from the date of the index cancer diagnosis to the date of the first new or recurrent malignancy diagnosis, or the date of last clinical encounter (the end of follow-up) if no recurrent or new cancer occurred. For patients with multiple cancers, the interval between the first cancer diagnosis and the first recurrence or a secondary malignancy was used for the analysis.

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Statistical analysis

Continuous variables are expressed as mean with s.d. or median and interquartile range, as needed, and compared using the Student's t test. Categorical variables were expressed as proportions with 95% confidence interval (CI) and compared by means of the χ2 test. Cox proportional hazards regression analysis was used to identify independent risk factors for the occurrence of incident cancers. Proportional hazards assumption was evaluated, assessing the Schoenfeld residuals. Event-free survival curves were plotted. A 2-sided P value of <0.05 was considered statistically significant. Statistical analyses were performed with SPSS 20 (SPSS, Chicago, IL).

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RESULTS

Characteristics of the study population

A total of 947 patients with IBD with a diagnosis of a noncolorectal cancer were identified (the date range of the diagnosis of the index cancer was between 1968 and 2014); of these, 422 were excluded because they had been exposed to an IMT before the diagnosis of the index cancer. Therefore, 520 patients nonexposed to any IMT before the cancer diagnosis were finally included. Among these, 146 patients (27%) were further treated with thiopurines and/or anti-TNF (exposed) and were compared with 374 patients (73%) who had never been exposed to any IMT during the follow-up (nonexposed) (Table 1). Eighty-nine exposed patients (62%) were treated with thiopurines in monotherapy, 52 (34%) with thiopurines and anti-TNF in combination, and 5 (4%) with anti-TNF agents alone. IMTs were started after a median of 60 months (interquartile range, 23–130) from index cancer diagnosis.

Table 1

Table 1

Table 2 summarizes the patients' baseline characteristics at the time of diagnosis of the index cancer. Both study groups were similar, except for a younger age, a greater proportion of female gender, Crohn's disease, and active smokers in exposed patients. Table 3 summarizes the features of the index cancer. There were significant differences in the type of cancers and Penn's risk for recurrence between the study groups. Exposed patients had a higher proportion of dermatologic cancers and cancers with a high risk of recurrence, compared with nonexposed patients. By contrast, nonexposed patients had a higher proportion of advanced-stage cancers compared with exposed patients, although cancer staging was available for only a smaller proportion of patients.

Table 2

Table 2

Table 3

Table 3

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Incident cancers

The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (Table 4), and no significant differences in the type or stage of incident cancers were observed between the two groups. Overall, the mean time on IMT after the index cancer in exposed patients was 64 months (s.d. ±120 months) and the mean time of exposure to IMT until new/recurrent cancer development was 48 months (s.d. ± 34 months). The most frequent individual incident cancers that differed between the study groups were dermatologic cancer (nonmelanoma skin cancer) and prostate cancer in exposed patients and breast cancer in nonexposed patients. Additionally, there were more cancer-related deaths in exposed patients compared with nonexposed patients.

Table 4

Table 4

The risk of developing an incident cancer is significantly higher in nonexposed patients (hazard ratio = 1.68; 95% CI = 1.03–2.73; P = 0.03) (Figure 1), and the incident rate of cancers (new or recurrent) was numerically higher among nonexposed patients (19.6 per 1,000 patient-years (95% CI = 12.7–28.9) vs 26.2 per 1,000 patient-years (95% CI = 20.56–33.11)). To rule out a potential bias arising from the differences in the stage or recurrence risk of index cancers among the study groups, we performed an exploratory analysis in which the exposed patients were grouped based on the time at which the IMT was started. No differences were found between the nonexposed patients and those who were exposed early (whenever considered within the first 5 or the first 2 years after index cancer diagnosis) (P = 0.49), whereas patients who started thiopurines and/or anti-TNF agents after 5 years had a significantly lower probability of developing an incident cancer than nonexposed patients (hazard ratio = 0.70; 95% CI = 0.53–0.93; P = 0.013) (Figure 2).

Figure 1

Figure 1

Figure 2

Figure 2

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).

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DISCUSSION

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.

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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.

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Study Highlights

WHAT IS KNOWN

  • ✓ There are scarce data on the use of IMTs in patients with IBD who have a history of cancer.
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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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