Journal of Crohn's and Colitis, 2015, 326–333 doi:10.1093/ecco-jcc/jjv032 Advanced access publication February 16, 2015 Original Article
Original Article
Incidence, Management, and Course of Cancer in Patients with Inflammatory Bowel Disease Alicia Algaba,a Iván Guerra,a Ignacio Marín-Jiménez,b Elvira Quintanilla, c Pilar López-Serrano,d María Concepción García-Sánchez,e Begoña Casis,f Carlos Taxonera,g Ignacio Moral,h María Chaparro,i Daniel Martín-Rodríguez,j María Dolores Martín-Arranz,k Noemí Manceñido,l Luis Menchén,b Antonio López-Sanromán,e Ángel Castaño,m Fernando Bermejoa Departments of Gastroenterology: aHospital Universitario de Fuenlabrada bHospital Universitario Gregorio Marañón c Hospital Universitario Severo Ochoa dHospital Universitario Fundación Alcorcón eHospital Universitario Ramón y Cajal fHospital Universitario 12 de Octubre gHospital Clínico San Carlos, IdISSC hHospital Príncipe de Asturias i Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa [IP] and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD] jHospital Universitario Infanta Cristina k Hospital Universitario La Paz lHospital Universitario Infanta Sofía mDepartment of Pathology. Hospital Universitario de Fuenlabrada; Madrid, Spain Corresponding author: Alicia Algaba, C/Isaac Peral, 43. Bloque D1, 1ºB. 28330 San Martín de la Vega, Madrid, Spain. Tel.: +34-699646717; Fax: +34-916006175; E-mail: [email protected]
Abstract Background and aims: Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia. Our aims were to determin the risk for cancer in patients with IBD and to describe the relationship with immunosuppressive therapies and clinical management after tumor diagnosis. Methods: Retrospective, multicenter, observational, 5-year follow-up, cohort study. Relative risk [RR] of cancer in the IBD cohort and the background population, therapeutic strategies, and cancer evolution were analyzed. Results: A total of 145 cancers were diagnosed in 133 of 9100 patients with IBD (global cumulative incidence 1.6% vs 2.4% in local population; RR = 0.67; 95% confidence interval [CI]: 0.57–0.78). Patients with IBD had a significantly increased RR of non-melanoma skin cancer [RR = 3.85; 2.53– 5.80] and small bowel cancer [RR = 3.70; 1.23–11.13]. After cancer diagnosis, IBD treatment was maintained in 13 of 27 [48.1%] patients on thiopurines, in 2 of 3 on methotrexate [66.6%], none on anti-TNF-α monotherapy [n = 6] and 4 of 12 [33.3%] patients on combined therapy. Rate of death and cancer remission during follow-up did not differ [p > 0.05] between patients who maintained the treatment compared with patients who withdrew [5% vs 8% and 95% vs 74%, respectively]. An association between thiopurines [p = 0.20] or anti-TNF-α drugs [p = 0.77] and cancer was not found. Conclusions: Patients with IBD have an increased risk for non-melanoma skin cancer and small bowel cancer. Immunosuppresive therapy is not related to a higher overall risk for cancer or worse tumor evolution in patients who maintain these drugs after cancer diagnosis. Keywords: Inflammatory bowel disease; cancer risk; thiopurines; anti-TNF-drugs
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
326
Cancer in Patients with Inflammatory Bowel Disease
1. Introduction Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia.1,2 Numerous studies have described a higher risk for colorectal cancer in patients with longstanding IBD but the relationship between IBD and extra-intestinal tumours is not well defined. Chronic inflammation associated with IBD can affect other organs besides the bowel and could be related to an increased risk for cancer in these areas. Latest publications in different populations across the world have found IBD patients to be at increased risk for different specific extra-intestinal tumors.3,4,5 In particular, it has been reported that patients with Crohn’s disease [CD] have an increased risk for developing cancer of the upper gastrointestinal tract, lung, urinary bladder, skin [squamous] and lymphoma.6,7 On the other hand, ulcerative colitis [UC] has been associated with an increased risk for hepatobiliary cancer and leukemia.6,8 IBD affects primarily young patients and the use of immunomodulators and anti-TNF drugs is frequent during the course of disease. These medications have also been associated with a variable risk for cancer. Thiopurines have been related to an increased risk for lymphoproliferative disorders and non-melanoma skin cancers.9,10 However, data regarding the relationship between anti-TNF-α drugs and cancer are more controversial on account of the frequent concomitant use of thiopurines in these patients.11,12,13 Additionally, data published regarding management and cancer evolution, and the possibility of future immunosuppressant treatment after cancer, in these patients are scarce.14 Therefore, the objectives of our study in a large series of IBD patients were: [1] to determine the incidence and characteristics of intestinal and extra-intestinal cancers affecting patients with IBD in our environment and to compare these with data in the background population; [2] to describe the clinical management of IBD patients and cancer; [3] to determine how the therapies prescribed for treatment of IBD can affect the risk for developing different cancers; and [4] to study the evolution and treatment of cancer in IBD patients.
2. Materials and Methods 2.1. Patients We conducted an observational, retrospective, 5-year follow-up, cohort study. All cases of cancer diagnosed from January 2007 to the end of December 2011 in a multicenter cohort of patients with IBD [followed in 12 tertiary university hospitals in the Community of Madrid, Spain] were retrospectively included. The study was approved by the ethics committee of the steering center [Hospital Universitario de Fuenlabrada]. In each case, cancer was diagnosed by pathologists of the participating centers who classified the lesions according to the International Classification of Diseases for Oncology [ICD-O-3 histology codes]. Diagnosis of IBD was confirmed by routine clinical, radiologic, endoscopic, and histologic criteria.15 Cumulative incidence and relative risk [RR] for the most common intestinal and extra-intestinal cancers were calculated in the IBD cohort and compared with the local background population of Madrid. Data corresponding to the baseline population were obtained using the tumor registry from the Community of Madrid. These registries contain all cases of cancer diagnosed during the 5-year follow-up period in the patients of each participating area. Demographic data, time from diagnosis of IBD to occurrence of cancer, IBD treatment at time of cancer diagnosis, and therapeutic
327 strategies for the management of patients after tumor diagnosis were collected in the IBD cohort. A possible association between IBD therapy and malignancy risk, and the treatment and evolution of cancer were also reviewed. Cancer recurrence was considered as the reappearance of cancer after treatment and after a period of time during which the tumor could not be detected, independently of the localization of the recurrent lesion. Cancer progression was defined as tumor spread or worsening clinical data.
2.2. Statistical analysis The descriptive analysis of quantitative variables calculated the mean and standard deviation or median and interquartile range [IQR], depending on whether or not the data were normally distributed. A Kolmogorov Smirnov test was used to evaluate normality of continuous variables. Qualitative variables were expressed as percentages with 95% confidence intervals [95% CIs]. Cumulative incidences for each cancer were calculated for patients with IBD and background local population and relative risks [RRs] with 95% CIs were analyzed. Comparison between quantitative variables was carried out by chisquare testing. Statistical significance was assumed for p-values < 0.05.
3. Results 3.1. Baseline characteristics of patients with inflammatory bowel disease and of the background population A total of 145 cancers were diagnosed during the study period in 133 patients from a cohort of 9100 cases of IBD [4550 CD; 4326 UC; 224 indeterminate or unclassified colitis]. According to the type of IBD, 76 tumors were diagnosed in 66 patients with CD, 66 in 64 UC patients, and 3 in 3 patients with indeterminate colitis; 12 patients [9%] were diagnosed with two or more different cancers during follow-up. At the time of cancer diagnosis, the mean age of patients with IBD was 59 ± 14 years, 59% were males, 35% smokers, 20% had a family history of cancer, and 18% had had previous cancer before the study. Only in two instances was the previous cancer type the same as the cancer developed during the study, that is two patients with previous non-melanoma skin cancer developed a new non-melanoma skin cancer in a different site from the first tumor. The mean time-course of IBD until cancer development was 125 ± 113 months [IQR 27–192]. Tumors were extra-intestinal in 82% of patients [n = 120]. Compared with the whole IBD population, mean age was higher in patients who developed cancer [59 ± 14 years vs 44 ± 14 years; p 40] Disease location CDa -L1 [ileal] -L2 [colic] -L3 [ileocolic] -L4 [upper gastrointestinal tract] -L1 + L4 -L3 + L4 Behavior CD a -B1 [non-stricturing non-penetrating] -B2 [stricturing] -B3 [penetrating] -B1 + peri-anal disease -B2 + peri-anal disease -B3 + peri-anal disease
Numbers in brackets are percentages. CD, Crohn’s disease; UC, ulcerative colitis; SD, standard deviation. a According to Montreal classification.
the cumulative incidences in CD and UC patients were compared, we found that the cumulative incidence in patients with CD was 1.7% vs 1.5% in the UC group; RR = 1.1; 0.79–1.52. The most frequent neoplasms observed in the IBD cohort were skin, colorectal, breast, and lung tumors [Table 2]. Compared with the background population, patients with IBD had a significantly increased RR for skin [non-melanoma type: 82% basal cell carcinoma; 18% squamous cell carcinoma; and 50% of lesions larger than 5 mm] and small bowel cancer [1 carcinoid and 2 adenocarcinomas]. However, the risk for colorectal, breast, lung, and prostate cancer was lower [p< 0.05] in patients with IBD than in the background population. The percentage of smokers in the group of patients who developed lung cancer was 50% smokers and 50% former smokers, and in the group who developed urinary bladder cancer was 37.5 smokers and 62.5% former smokers. Only one case of melanoma was observed in the cohort of patients with IBD [RR = 0.33; 0.076–3.82]. When the two different groups of IBD patients were compared separately with the background population, we found that patients with CD also had a significantly increased RR for non-melanoma
skin and small bowel cancer [two CD patients with ileal involvement and diagnosis of small bowel adenocarcinoma, mean IBD duration: 108 months], and a significantly decreased RR for colorectal cancer [Table 2]. On the other hand, patients with UC maintained an increased RR for non-melanoma skin cancer, but no further differences between UC patients and the local population were found for the remaining cancers [Table 2]. Regarding hematological cancers, only one case each of nonHodgkin lymphoma; [RR = 0.13; 0.02–0.93] and myelodysplastic syndrome were observed in this series. None of these patients had received previously or were currently receiving immunosuppressive or anti-TNF-α drug therapy at the time of cancer diagnosis.
3.3. Management and course of inflammatory bowel disease patients with associated cancer A total of 27 tumors [18.6% of all tumors] were diagnosed in patients receiving treatment with thiopurines, 3 in patients on methotrexate [2.1%], 6 during anti-TNF-α monotherapy [4.2%], and 12 were identified in patients on combined therapy with an immunosuppressive [10 thiopurines and 2 methotrexate] with an antiTNF-α drug [8.4%]. The median duration of treatments until cancer diagnosis was: 57 months for thiopurines [IQR 8–87], 19 months for methotrexate [IQR 3–39], and 9 months for anti-TNF-α [IQR 2–13]. Mean dose for azathioprine was 129 ± 52 mg and mean dose for mercaptopurine was 67 ± 27 mg. Five [27.8%] of the 18 patients on treatment with anti-TNF-α had dose escalation before the cancer diagnosis. The remaining tumors were diagnosed in patients: not receiving any treatment for IBD; or on mesalazine therapy; or on other treatment different from immunosuppressive/anti-TNF-α drugs at time of cancer diagnosis [n = 97; 66.7%]. Nine of these patients [9.3%] had previously been exposed to thiopurines and five [5.1%] had been on anti-TNF-α therapy at some time before cancer diagnosis. After the diagnosis of cancer, IBD treatment was maintained in 13 [48.1%] of 27 patients on thiopurines, in 2 [66.7%] of 3 of those on methotrexate, and in 4 [33.3%] of 12 patients receiving combined therapy [Figure 1]. Globally, immunosuppressive IBD treatment was maintained in 19 of 48 patients after cancer diagnosis [39.6%]. The reason for continuing or discontinuing the therapy with immunosuppressant and/or anti-TNF-α drugs was in all cases determined by medical criteria, individualized based on the type of cancer and the evolution of IBD and in agreement with the oncology team. In patients in whom immunosuppressive therapy was maintained, different types of tumors were observed. The most common cancers were: non-melanoma skin cancer [n = 4]; urinary bladder cancer [n = 4]; cervical cancer [n = 3]; and ovarian cancer [n = 2]. The characteristics of these patients, type of treatment maintained, and tumor evolution are shown in Table 3. There were two cases on azathioprine therapy in which lung cancer was diagnosed, both patients dying a short period after the tumor diagnosis. In the remaining patients on immunosuppressive and/or anti-TNF-α drugs [n = 27], the treatment was withdrawn, and in three of these cases a therapy was reintroduced or incorporated later in agreement with the oncology team. The evolution of these three cases was as follows: a breast carcinoma with azathioprine reintroduction 3 years after tumor with no cancer progression; a non-melanoma skin tumor in remission for more than 3 years after thiopurine introduction; and a breast ductal carcinoma [with previous IBD therapy with adalimumab before cancer diagnosis] in whom methotrexate was prescribed, maintaining cancer remission after 5 years’ follow-up.
Cancer in Patients with Inflammatory Bowel Disease
329
Table 2. Relative risk for developing different types of cancers in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis, compared with the background population. Location of cancer
IBD
Skin [non-melanoma] Colorectal Breast Lung Prostate Kidney Urinary bladder Cervix Ovary Liver and biliary system Small bowel Stomach
CD
UC
N
RR [95% CI]
N
RR [95% CI]
N
RR [95% CI]
23 18 15 12 11 10 8 5 5 4 3 3
3.85 [2.53–5.80]* 0.36 [0.34–0.71]* 0.63 [0.32–0.89]* 0.52 [0.30–0.90]* 0.46 [0.26–0.83]* 1.83 [0.90–3.19] 0.56 [0.28–1.11] 1.83 [0.75–4.40] 1.37 [0.51–2.97] 0.90 [0.32–2.30] 3.70 [1.23–11.13]* 0.37 [0.12–1.13]
11 5 9 7 5 6 5 2 3 2 2 1
3.70 [2.05–6.68]* 0.30[0.06–0.73]* 0.67 [0.35–1.28] 0.60 [0.29–1.26] 0.42 [0.17–1.00] 2.00 [0.90–4.48] 0.69 [0.29–1.63] 1.50 [0.38–5.80] 1.65 [0.56–4.90] 0.70 [0.23–3.57] 4.90 [1.20–19.90]* 0.24 [0.03–1.70]
11 13 6 5 6 4 3 2 2 2 1 1
3.90 [2.15–7.05]* 0.81 [0.14–4.53] 0.47 [0.21–1.05] 0.44 [0.18–1.06] 0.54 [0.24–1.52] 1.41 [0.53–3.74] 0.43 [0.14–1.30] 1.50 [0.37–5.99] 1.24 [0.30–4.95] 0.94 [0.23–3.78] 2.50 [0.36–18.17] 0.25 [0.04–1.82]
IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR: relative risk; 95% CI; 95% confidence interval. *p
Original Article
Incidence, Management, and Course of Cancer in Patients with Inflammatory Bowel Disease Alicia Algaba,a Iván Guerra,a Ignacio Marín-Jiménez,b Elvira Quintanilla, c Pilar López-Serrano,d María Concepción García-Sánchez,e Begoña Casis,f Carlos Taxonera,g Ignacio Moral,h María Chaparro,i Daniel Martín-Rodríguez,j María Dolores Martín-Arranz,k Noemí Manceñido,l Luis Menchén,b Antonio López-Sanromán,e Ángel Castaño,m Fernando Bermejoa Departments of Gastroenterology: aHospital Universitario de Fuenlabrada bHospital Universitario Gregorio Marañón c Hospital Universitario Severo Ochoa dHospital Universitario Fundación Alcorcón eHospital Universitario Ramón y Cajal fHospital Universitario 12 de Octubre gHospital Clínico San Carlos, IdISSC hHospital Príncipe de Asturias i Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa [IP] and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD] jHospital Universitario Infanta Cristina k Hospital Universitario La Paz lHospital Universitario Infanta Sofía mDepartment of Pathology. Hospital Universitario de Fuenlabrada; Madrid, Spain Corresponding author: Alicia Algaba, C/Isaac Peral, 43. Bloque D1, 1ºB. 28330 San Martín de la Vega, Madrid, Spain. Tel.: +34-699646717; Fax: +34-916006175; E-mail: [email protected]
Abstract Background and aims: Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia. Our aims were to determin the risk for cancer in patients with IBD and to describe the relationship with immunosuppressive therapies and clinical management after tumor diagnosis. Methods: Retrospective, multicenter, observational, 5-year follow-up, cohort study. Relative risk [RR] of cancer in the IBD cohort and the background population, therapeutic strategies, and cancer evolution were analyzed. Results: A total of 145 cancers were diagnosed in 133 of 9100 patients with IBD (global cumulative incidence 1.6% vs 2.4% in local population; RR = 0.67; 95% confidence interval [CI]: 0.57–0.78). Patients with IBD had a significantly increased RR of non-melanoma skin cancer [RR = 3.85; 2.53– 5.80] and small bowel cancer [RR = 3.70; 1.23–11.13]. After cancer diagnosis, IBD treatment was maintained in 13 of 27 [48.1%] patients on thiopurines, in 2 of 3 on methotrexate [66.6%], none on anti-TNF-α monotherapy [n = 6] and 4 of 12 [33.3%] patients on combined therapy. Rate of death and cancer remission during follow-up did not differ [p > 0.05] between patients who maintained the treatment compared with patients who withdrew [5% vs 8% and 95% vs 74%, respectively]. An association between thiopurines [p = 0.20] or anti-TNF-α drugs [p = 0.77] and cancer was not found. Conclusions: Patients with IBD have an increased risk for non-melanoma skin cancer and small bowel cancer. Immunosuppresive therapy is not related to a higher overall risk for cancer or worse tumor evolution in patients who maintain these drugs after cancer diagnosis. Keywords: Inflammatory bowel disease; cancer risk; thiopurines; anti-TNF-drugs
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
326
Cancer in Patients with Inflammatory Bowel Disease
1. Introduction Patients with inflammatory bowel disease [IBD] are at increased risk for developing some types of neoplasia.1,2 Numerous studies have described a higher risk for colorectal cancer in patients with longstanding IBD but the relationship between IBD and extra-intestinal tumours is not well defined. Chronic inflammation associated with IBD can affect other organs besides the bowel and could be related to an increased risk for cancer in these areas. Latest publications in different populations across the world have found IBD patients to be at increased risk for different specific extra-intestinal tumors.3,4,5 In particular, it has been reported that patients with Crohn’s disease [CD] have an increased risk for developing cancer of the upper gastrointestinal tract, lung, urinary bladder, skin [squamous] and lymphoma.6,7 On the other hand, ulcerative colitis [UC] has been associated with an increased risk for hepatobiliary cancer and leukemia.6,8 IBD affects primarily young patients and the use of immunomodulators and anti-TNF drugs is frequent during the course of disease. These medications have also been associated with a variable risk for cancer. Thiopurines have been related to an increased risk for lymphoproliferative disorders and non-melanoma skin cancers.9,10 However, data regarding the relationship between anti-TNF-α drugs and cancer are more controversial on account of the frequent concomitant use of thiopurines in these patients.11,12,13 Additionally, data published regarding management and cancer evolution, and the possibility of future immunosuppressant treatment after cancer, in these patients are scarce.14 Therefore, the objectives of our study in a large series of IBD patients were: [1] to determine the incidence and characteristics of intestinal and extra-intestinal cancers affecting patients with IBD in our environment and to compare these with data in the background population; [2] to describe the clinical management of IBD patients and cancer; [3] to determine how the therapies prescribed for treatment of IBD can affect the risk for developing different cancers; and [4] to study the evolution and treatment of cancer in IBD patients.
2. Materials and Methods 2.1. Patients We conducted an observational, retrospective, 5-year follow-up, cohort study. All cases of cancer diagnosed from January 2007 to the end of December 2011 in a multicenter cohort of patients with IBD [followed in 12 tertiary university hospitals in the Community of Madrid, Spain] were retrospectively included. The study was approved by the ethics committee of the steering center [Hospital Universitario de Fuenlabrada]. In each case, cancer was diagnosed by pathologists of the participating centers who classified the lesions according to the International Classification of Diseases for Oncology [ICD-O-3 histology codes]. Diagnosis of IBD was confirmed by routine clinical, radiologic, endoscopic, and histologic criteria.15 Cumulative incidence and relative risk [RR] for the most common intestinal and extra-intestinal cancers were calculated in the IBD cohort and compared with the local background population of Madrid. Data corresponding to the baseline population were obtained using the tumor registry from the Community of Madrid. These registries contain all cases of cancer diagnosed during the 5-year follow-up period in the patients of each participating area. Demographic data, time from diagnosis of IBD to occurrence of cancer, IBD treatment at time of cancer diagnosis, and therapeutic
327 strategies for the management of patients after tumor diagnosis were collected in the IBD cohort. A possible association between IBD therapy and malignancy risk, and the treatment and evolution of cancer were also reviewed. Cancer recurrence was considered as the reappearance of cancer after treatment and after a period of time during which the tumor could not be detected, independently of the localization of the recurrent lesion. Cancer progression was defined as tumor spread or worsening clinical data.
2.2. Statistical analysis The descriptive analysis of quantitative variables calculated the mean and standard deviation or median and interquartile range [IQR], depending on whether or not the data were normally distributed. A Kolmogorov Smirnov test was used to evaluate normality of continuous variables. Qualitative variables were expressed as percentages with 95% confidence intervals [95% CIs]. Cumulative incidences for each cancer were calculated for patients with IBD and background local population and relative risks [RRs] with 95% CIs were analyzed. Comparison between quantitative variables was carried out by chisquare testing. Statistical significance was assumed for p-values < 0.05.
3. Results 3.1. Baseline characteristics of patients with inflammatory bowel disease and of the background population A total of 145 cancers were diagnosed during the study period in 133 patients from a cohort of 9100 cases of IBD [4550 CD; 4326 UC; 224 indeterminate or unclassified colitis]. According to the type of IBD, 76 tumors were diagnosed in 66 patients with CD, 66 in 64 UC patients, and 3 in 3 patients with indeterminate colitis; 12 patients [9%] were diagnosed with two or more different cancers during follow-up. At the time of cancer diagnosis, the mean age of patients with IBD was 59 ± 14 years, 59% were males, 35% smokers, 20% had a family history of cancer, and 18% had had previous cancer before the study. Only in two instances was the previous cancer type the same as the cancer developed during the study, that is two patients with previous non-melanoma skin cancer developed a new non-melanoma skin cancer in a different site from the first tumor. The mean time-course of IBD until cancer development was 125 ± 113 months [IQR 27–192]. Tumors were extra-intestinal in 82% of patients [n = 120]. Compared with the whole IBD population, mean age was higher in patients who developed cancer [59 ± 14 years vs 44 ± 14 years; p 40] Disease location CDa -L1 [ileal] -L2 [colic] -L3 [ileocolic] -L4 [upper gastrointestinal tract] -L1 + L4 -L3 + L4 Behavior CD a -B1 [non-stricturing non-penetrating] -B2 [stricturing] -B3 [penetrating] -B1 + peri-anal disease -B2 + peri-anal disease -B3 + peri-anal disease
Numbers in brackets are percentages. CD, Crohn’s disease; UC, ulcerative colitis; SD, standard deviation. a According to Montreal classification.
the cumulative incidences in CD and UC patients were compared, we found that the cumulative incidence in patients with CD was 1.7% vs 1.5% in the UC group; RR = 1.1; 0.79–1.52. The most frequent neoplasms observed in the IBD cohort were skin, colorectal, breast, and lung tumors [Table 2]. Compared with the background population, patients with IBD had a significantly increased RR for skin [non-melanoma type: 82% basal cell carcinoma; 18% squamous cell carcinoma; and 50% of lesions larger than 5 mm] and small bowel cancer [1 carcinoid and 2 adenocarcinomas]. However, the risk for colorectal, breast, lung, and prostate cancer was lower [p< 0.05] in patients with IBD than in the background population. The percentage of smokers in the group of patients who developed lung cancer was 50% smokers and 50% former smokers, and in the group who developed urinary bladder cancer was 37.5 smokers and 62.5% former smokers. Only one case of melanoma was observed in the cohort of patients with IBD [RR = 0.33; 0.076–3.82]. When the two different groups of IBD patients were compared separately with the background population, we found that patients with CD also had a significantly increased RR for non-melanoma
skin and small bowel cancer [two CD patients with ileal involvement and diagnosis of small bowel adenocarcinoma, mean IBD duration: 108 months], and a significantly decreased RR for colorectal cancer [Table 2]. On the other hand, patients with UC maintained an increased RR for non-melanoma skin cancer, but no further differences between UC patients and the local population were found for the remaining cancers [Table 2]. Regarding hematological cancers, only one case each of nonHodgkin lymphoma; [RR = 0.13; 0.02–0.93] and myelodysplastic syndrome were observed in this series. None of these patients had received previously or were currently receiving immunosuppressive or anti-TNF-α drug therapy at the time of cancer diagnosis.
3.3. Management and course of inflammatory bowel disease patients with associated cancer A total of 27 tumors [18.6% of all tumors] were diagnosed in patients receiving treatment with thiopurines, 3 in patients on methotrexate [2.1%], 6 during anti-TNF-α monotherapy [4.2%], and 12 were identified in patients on combined therapy with an immunosuppressive [10 thiopurines and 2 methotrexate] with an antiTNF-α drug [8.4%]. The median duration of treatments until cancer diagnosis was: 57 months for thiopurines [IQR 8–87], 19 months for methotrexate [IQR 3–39], and 9 months for anti-TNF-α [IQR 2–13]. Mean dose for azathioprine was 129 ± 52 mg and mean dose for mercaptopurine was 67 ± 27 mg. Five [27.8%] of the 18 patients on treatment with anti-TNF-α had dose escalation before the cancer diagnosis. The remaining tumors were diagnosed in patients: not receiving any treatment for IBD; or on mesalazine therapy; or on other treatment different from immunosuppressive/anti-TNF-α drugs at time of cancer diagnosis [n = 97; 66.7%]. Nine of these patients [9.3%] had previously been exposed to thiopurines and five [5.1%] had been on anti-TNF-α therapy at some time before cancer diagnosis. After the diagnosis of cancer, IBD treatment was maintained in 13 [48.1%] of 27 patients on thiopurines, in 2 [66.7%] of 3 of those on methotrexate, and in 4 [33.3%] of 12 patients receiving combined therapy [Figure 1]. Globally, immunosuppressive IBD treatment was maintained in 19 of 48 patients after cancer diagnosis [39.6%]. The reason for continuing or discontinuing the therapy with immunosuppressant and/or anti-TNF-α drugs was in all cases determined by medical criteria, individualized based on the type of cancer and the evolution of IBD and in agreement with the oncology team. In patients in whom immunosuppressive therapy was maintained, different types of tumors were observed. The most common cancers were: non-melanoma skin cancer [n = 4]; urinary bladder cancer [n = 4]; cervical cancer [n = 3]; and ovarian cancer [n = 2]. The characteristics of these patients, type of treatment maintained, and tumor evolution are shown in Table 3. There were two cases on azathioprine therapy in which lung cancer was diagnosed, both patients dying a short period after the tumor diagnosis. In the remaining patients on immunosuppressive and/or anti-TNF-α drugs [n = 27], the treatment was withdrawn, and in three of these cases a therapy was reintroduced or incorporated later in agreement with the oncology team. The evolution of these three cases was as follows: a breast carcinoma with azathioprine reintroduction 3 years after tumor with no cancer progression; a non-melanoma skin tumor in remission for more than 3 years after thiopurine introduction; and a breast ductal carcinoma [with previous IBD therapy with adalimumab before cancer diagnosis] in whom methotrexate was prescribed, maintaining cancer remission after 5 years’ follow-up.
Cancer in Patients with Inflammatory Bowel Disease
329
Table 2. Relative risk for developing different types of cancers in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis, compared with the background population. Location of cancer
IBD
Skin [non-melanoma] Colorectal Breast Lung Prostate Kidney Urinary bladder Cervix Ovary Liver and biliary system Small bowel Stomach
CD
UC
N
RR [95% CI]
N
RR [95% CI]
N
RR [95% CI]
23 18 15 12 11 10 8 5 5 4 3 3
3.85 [2.53–5.80]* 0.36 [0.34–0.71]* 0.63 [0.32–0.89]* 0.52 [0.30–0.90]* 0.46 [0.26–0.83]* 1.83 [0.90–3.19] 0.56 [0.28–1.11] 1.83 [0.75–4.40] 1.37 [0.51–2.97] 0.90 [0.32–2.30] 3.70 [1.23–11.13]* 0.37 [0.12–1.13]
11 5 9 7 5 6 5 2 3 2 2 1
3.70 [2.05–6.68]* 0.30[0.06–0.73]* 0.67 [0.35–1.28] 0.60 [0.29–1.26] 0.42 [0.17–1.00] 2.00 [0.90–4.48] 0.69 [0.29–1.63] 1.50 [0.38–5.80] 1.65 [0.56–4.90] 0.70 [0.23–3.57] 4.90 [1.20–19.90]* 0.24 [0.03–1.70]
11 13 6 5 6 4 3 2 2 2 1 1
3.90 [2.15–7.05]* 0.81 [0.14–4.53] 0.47 [0.21–1.05] 0.44 [0.18–1.06] 0.54 [0.24–1.52] 1.41 [0.53–3.74] 0.43 [0.14–1.30] 1.50 [0.37–5.99] 1.24 [0.30–4.95] 0.94 [0.23–3.78] 2.50 [0.36–18.17] 0.25 [0.04–1.82]
IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR: relative risk; 95% CI; 95% confidence interval. *p
