TY - JOUR
AU - Farraye, Francis, A.
AB - Abstract The medical treatment for inflammatory bowel disease (IBD) has improved over the past 20 years. Although the routine use of immunomodulators and biologic agents in the treatment of IBD in the modern era has been a great achievement, these medicines are associated with rare but serious adverse events. In addition to the infectious complications, there are data to suggest that some of these agents are associated with higher rates of malignancy. In a patient with a history of cancer, or a family history of cancer, the gastroenterologist must be prepared to answer questions about the oncogenic potential of these agents. Thiopurines have been associated with a small increased risk of lymphoma in patients with IBD. In addition, an association with skin cancer has been established. Methotrexate is generally considered safe in patients with a history of cancer. There may be a small risk of lymphoma and possibly skin cancer with anti-tumor necrosis factor agents, but determining the cancer risk of these medications is difficult as they are often used in combination with thiopurines. In general, a family history of cancer should not influence a patient's medical regimen. Treatment for a patient with a personal history of cancer must be individualized and take into account the type and stage of cancer, time since completion of therapy, and the opinion of an oncologist. inflammatory bowel disease, malignancy, lymphoma, skin cancer, biologics, thiopurines, methotrexate Before any conversation about the risk of using immunomodulators and biologics for the treatment of Inflammatory Bowel Disease (IBD) in a patient with a personal or family history of cancer, it is important to note that there is a well-established increased risk of certain malignancies in patients with Crohn's disease (CD) and ulcerative colitis (UC) independent of treatment (Fig. 1).1,2 The malignancies with the strongest link to IBD are colorectal cancer (CRC) and biliary cancer in patients with primary sclerosing cholangitis (PSC). A slight increased risk of lymphoma is likely; although, as we show below, this risk seems to be increased by thiopurines or the combination of thiopurines and anti-tumor necrosis factor (TNF) agents. Additionally, there is evidence of a higher incidence of small bowel cancer in patients with CD, although the absolute risk was 0.07% (95% CI 0.03–0.15).2 In a population-based control study from the Surveillance, Epidemiology, and End Results (SEER) database of patients with small bowel cancer, there was a strong association between small bowel cancer and CD (odds ratio [OR] 12.1, 95% CI 6.07–20.80), although the prevalence of CD in patients with small bowel cancer was very small (1.6%).3 There are limited data to support an increased risk of leukemia and cancers of the endometrium, lung, testicles, bladder, and gallbladder among others. Figure 1. Open in new tabDownload slide Breakdown by site of cancers occurring 1–11 years after IBD diagnosis, Denmark 1978–2010. Data used from Kappelman et al.2 Figure 1. Open in new tabDownload slide Breakdown by site of cancers occurring 1–11 years after IBD diagnosis, Denmark 1978–2010. Data used from Kappelman et al.2 The increased risk of CRC in patients with UC was first recognized early in the 20th century, and in the most recent studies accounts for 10% to 15% of all deaths related to IBD.4 Compared with the general population, although IBD-associated CRC tends to affect a younger population, outcomes are similar.5 A meta-analysis of 116 studies published in 2001 on over 50,000 patients with UC found an overall prevalence of CRC of 3.7% (5.4% in pancolitis).6 A more recent population-based study reported cumulative risks of CRC of 1%, 2%, and 5% after 10, 20, and greater than 20 years of disease duration, respectively.7 A population-based study from Sweden of over 7500 patients with IBD found an overall incidence of 85 cases of CRC per 100,000 person-years, corresponding to a standardized incidence ratio of 2.3 (95% CI 2.0–2.6) when compared with the general population.8 A similar risk of CRC in patients with colonic CD has been established, but patients with isolated small bowel CD have a risk that more closely resembles the general population.9 Perhaps, the subset of patients with IBD with the greatest risk of developing cancer are those with PSC. In addition to an increased risk of CRC and gallbladder cancer, there is a markedly elevated risk of cholangiocarcinoma.10 The lifetime prevalence of cholangiocarcinoma in patients with PSC is felt to be 5% to 10% and is associated with a very poor prognosis.11 In comparison with the general population, the relative risk (RR) is 1560 (95% CI 780–2793) of cholangiocarcinoma in PSC.12 The data supporting an association between IBD and lymphoma are less robust. In contrast, there is a more convincing association of lymphoma in rheumatoid arthritis (RA), especially when poorly controlled.13 The association between lymphoma and IBD has been most widely studied in Europe. A study from the United Kingdom comparing 6605 patients with CD and 10,391 patients with UC with controls found a RR of 1.2 (95% CI 0.67–2.06) with CD or UC compared with the controls, but this did not reach statistical significance.14 A Swedish prospective study noted a RR of lymphoma of 1.0 (95% CI 0.8–1.3) in patients with UC and 1.3 (95% CI 1.0–1.6) in patients with CD, with statistical significance in CD.15 More recently, a Dutch retrospective study of 17,000 patients with IBD revealed total of 44 lymphomas in this population between 1997 and 2004, giving a RR of 1.27 (95% CI 0.92–1.68) which the authors concluded did not suggest an increased risk over the general population.16 Overall, the data seem to suggest a small but elevated baseline risk of lymphoma in patients with IBD. Individual IBD Treatments and Cancer Risk Thiopurines Thiopurines (azathioprine and 6-mercaptopurine) are commonly used in the treatment of IBD because of their potent anti-inflammatory properties. Given the recent studies demonstrating the benefit of combination therapy of thiopurines and anti-TNF agents,17 more patients are being started on thiopurines and receiving them for longer periods of time. Thiopurines have been shown to cause dose-dependent increases in somatic mutations in vivo and interfere with DNA repair mechanisms, supporting the concept that thiopurines are indeed mutagenic.18,19 As these changes are not limited to one organ system, thiopurines can increase the risk of many different cancers.20 The initial clinical data suggesting a cancer risk for thiopurines came from the renal transplant population, suggesting an association with nonmelanoma skin cancer (NMSC), Kaposi sarcoma, and lymphoma.21,–23 Lymphoma is one of the most feared complications of thiopurine use. In addition to the mutagenic risk noted above, thiopurines may decrease the immune system's ability to recognize B cells infected by Epstein–Barr virus (EBV) leading to a risk of EBV-related lymphoproliferative disorders.16,24 Some studies have suggested an increased risk of lymphoma in patients without IBD, such as in patients with RA where the risk seems to be most correlated with severity of inflammation.13 Several small studies with inconsistent results suggested a small risk of lymphoma in patients with IBD treated with thiopurines, and a meta-analysis published in 2005 demonstrated a small but statistically significant association between lymphoma and thiopurine use in patients with IBD.25 In this meta-analysis, which included 6 studies published between 1985 and 2001, a total of 11 cases of lymphoma were reported, increased from the expected value of 2.63. The pooled RR was 4.18 (95% CI 2.07–7.51), but the absolute risk was quite small; 4357 persons would have to be treated per year to cause one additional lymphoma in the 20- to 29-year age group and 355 in the 70- to 79-year age group.25 A French prospective study confirmed the association suggested by this meta-analysis.26 This study of 19,486 patients with IBD noted a lymphoma incidence rate of 0.9 per 1000 patient-years in patients receiving thiopurines compared with 0.20 per 1000 patient-years in those who discontinued thiopurines and 0.26 per 1000 patient-years in those without a previous exposure to thiopurines.26 Overall, the adjusted hazard ratio of lymphoproliferative disorders in this study was 5.28 (95% CI 2.01–13.90) in patients exposed to thiopurines compared with those who were thiopurine-naive, and older age, male gender, and duration of IBD were associated with increased risk.26 Another large study from the United Kingdom (a nested case–control study of 15,471 patients with IBD) suggested a small increase in lymphoma in patients with IBD with an OR of 3.22 (95% CI 1.01–10.18), although this did not reach statistical significance when corrected for age and smoking status.27 Taken together, the literature does suggest an increased risk of lymphoma in patients with IBD treated with thiopurines. In addition to an increased risk of lymphoma, there are data that thiopurine use may be associated with an increase in the development of skin cancer. In addition to the aforementioned mechanisms of carcinogenesis, thiopurines may affect DNA sensitivity to ultraviolet light.28 Some studies have shown no increased risk of NMSCs,27 whereas others show an increased risk of NMSCs in patients with IBD treated with thiopurines.29,30 A recent meta-analysis of 8 studies involving over 60,000 patients with IBD on thiopurines found a pooled hazard ratio of 2.28 (95% CI, 1.5–3.45) suggesting a modestly elevated risk of NMSC in patients with IBD on thiopurines, but the statistical significance was lost when only studies with more than 3 years of follow-up were included.31 Although patients with IBD may have a higher risk of NMSC in general, thiopurines have also been shown to have an increased risk of basal cell carcinoma and squamous cell carcinomas in the organ transplant and RA population.32,33 Although NMSCs are rarely lethal, they may require surgery and squamous cell carcinomas can metastasize; therefore, these risks must be discussed with any patient with IBD starting on a thiopurine medicine. Although there may be an increased risk of melanoma in patients with IBD,2,34 no study has specifically shown an increase in melanoma with thiopurine use. In addition to lymphoma and NMSC, thiopurines have been associated with an increased rate or other malignancies such as urinary tract cancers, CRC, and cervical cancer, but the data are less compelling.20,35 Methotrexate Methotrexate (MTX) is a therapeutic agent used in the treatment of IBD and other autoimmune disorders such as RA and psoriasis. Methotrexate functions as a folate antimetabolite that inhibits DNA synthesis thereby reducing cellular proliferation and is highly teratogenic. There is also some data which suggest that MTX is carcinogenic, but overall this literature is rather weak. As MTX can reduce the immune system's ability to recognize EBV-infected B lymphocytes, there is concern that MTX may increase the risk of EBV-related lymphoproliferative disorders. Although there are case reports of this association,36 population-based studies have shown conflicting results37,–39 in the RA and psoriasis populations. A meta-analysis in the RA population showed no increase in lymphoma.40 In the IBD population, there are very little data supporting an association between MTX use and lymphoma although 1 single center study in Ireland that did reveal 4 lymphomas among 238 patients with IBD, of whom 2 were taking MTX.41 The authors conclude that MTX may increase the risk of lymphoma, but the risk is likely very small. There is some evidence of an increase in skin cancers with MTX. In the rheumatologic literature, a systematic review in 2010 reported an increase in melanoma in patients receiving MTX monotherapy for RA and an increase in NMSC in patients with psoriasis.42 However, there are no data to support the association between melanoma and MTX use in the IBD population. Similarly, studies in the IBD population do not reveal an increased risk of NMSC in patients receiving MTX.34,43 Biologics Although anti-TNF agents have no direct carcinogenic effect, there may be an increased cancer risk due to reduced immune surveillance of tumors.24 In addition, TNF has the ability to trigger tumor apoptosis through the caspase pathway but can also promote tumor growth through the NF-kB cascade; therefore, it is unclear whether anti-TNFs would generally be expected to increase or reduce cancer risk.44 In the rheumatologic literature, a recent meta-analysis did not reveal any increase in cancer, notably lymphoma, in patients with RA being treated with anti-TNF agents over those with RA treated with classic disease-modifying antirheumatic drugs (DMARDs, such as methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine, and azathioprine) other than skin cancers, with a 45% increase in NMSC and 79% increase in melanoma.45 An earlier meta-analysis published in 2006 of patients with RA being treated with infliximab or adalimumab found a pooled OR of 3.3 (95% CI, 1.2–9.1) for increased risk of malignancy over placebo with a number needed to harm of 154.46 The number needed to harm refers to the number of patients who would need to be exposed to a certain risk factor, anti-TNF exposure in this case, over a specific period to cause harm in one patient.46 As these 2 meta-analyses are conflicting, the true risk of cancer in patients with RA being treated with anti-TNF agents is unclear. Determining the risk of anti-TNF therapy and cancer in the IBD population is more difficult to study as research is limited by the fact that many patients receive simultaneous treatment with anti-TNF therapy and thiopurines. After infliximab was approved in 1998, case reports were published suggesting an association between anti-TNF therapy and lymphoproliferative disorders in the IBD population.47,48 A postmarketing study published in 2002 evaluating patients with RA and CD treated with etanercept or infliximab revealed 8 cases of lymphoma in patients treated with infliximab (5 of whom were treated for CD) and several other cases that were considered “possible” or “probable” associations.49 As such, the infliximab package insert now includes an increased risk of lymphoma 4 times than that of the general population with an increase of 0.10 cases per 100 patient-years.50 A meta-analysis on anti-TNF therapy (infliximab, adalimumab, and certolizumab) in patients with IBD found a 3-fold increase in lymphoma over the general population, but there was no statistically significant increase in lymphoma in patients treated with anti-TNF therapy over immunomodulators alone.51 Of note, 66% of patients on anti-TNF agents were on concomitant immunomodulators. The overall rate of lymphoma was very small (6.1 per 10,000 patient-years in the anti-TNF subgroup, 4 per 10,000 patient-years in the immunomodulator subgroup, and 1.9 per 10,000 patient-years in the general population).51 More recent data have called the lymphoma risk associated with anti-TNF agents into question. A retrospective review of 1594 patients with CD treated with adalimumab monotherapy and combination therapy found no increase in lymphoma in patients in the adalimumab monotherapy group over the general population, but an 8-fold increase in lymphoma in the combination group over the general population.52 A recent review of all lymphomas reported to the Food and Drug Administration (FDA) from 2003 to 2010 in patients receiving anti-TNF therapy for approved indications revealed a total of 100 cases (36 CD, 9 UC) and found no increase in lymphoma in patients on anti-TNF monotherapy, but a 5-fold increase in patients on anti-TNF therapy combined with thiopurines.53 A large prospective cohort study of patients with CD treated with infliximab found similar rates of malignancy in the infliximab versus non-infliximab group (0.16 per 100 patient-years vs 0.18 per 100 patient-years).54 A larger nationwide cohort study of 56,146 patients with IBD in Denmark (8.1% of whom were on anti-TNF agents) followed for a median of 3.7 years in the exposed group revealed no increase in overall malignancy in those with IBD exposed to anti-TNF agents (RR 1.07, 95% CI 0.85–1.36, when adjusted for age and thiopurine use) and no increase in the specific risk of lymphoma (adjusted RR 0.90, 95% CI 0.42–1.91).55 The most recent meta-analysis on the subject of malignancy and anti-TNF therapy in the IBD population, which included 22 randomized controlled trials, found no increase in lymphomas in patients treated with anti-TNF therapy over the control group.56 Overall, the risk of lymphoma in patients taking anti-TNF monotherapy may be only marginally elevated over the general population of patients with IBD and is much less conclusive than the data available for thiopurines. However, patients on combination therapy with an immunomodulator may have a more substantial risk of lymphoma over the general IBD population as has been shown in several trials and in large registries, including experiences from the Mayo clinic and Kaiser Permanente.57,58 One of the most feared complications of immunosuppressive therapy is hepatosplenic T-cell lymphoma (HSTCL), a very rare but typically fatal lymphoma. The median survival is less than a year, and patients may clinically present with severe hepatosplenomegaly on examination in the absence of lymphadenopathy.59 It is also noteworthy that this disorder tends to afflict young males.60 Of the 200 cases of HSTCL reported in the literature, most have occurred without a known risk factor, but 20% to 30% have been in the setting of immunosuppression.60 Of the 36 cases reported in patients with IBD, 20 patients were on combined thiopurine and anti-TNF therapy and most were men under age 35 years.60 In a review of all cases that were reported to the FDA in patients with HSTCL taking anti-TNF inhibitors, 22 of 25 cases were in patients with IBD.61 Of the IBD cases reported, 96% were on an immunomodulator and no cases were identified from patients on anti-TNF monotherapy.61 The aforementioned study by Deepak et al53 reviewing all cases of lymphoma reported to the FDA attributed to anti-TNF therapy used for both rheumatologic and IBD indications from 2003 to 2010 revealed 29 HSTCL cases in patients on combination therapy and only 1 case in a patient on anti-TNF monotherapy. At this time, both infliximab and adalimumab package inserts contain black box warnings regarding HSTCL, but both suggest that the risk is mainly attributed to combination therapy with thiopurines.50,62 The risk of melanoma and NMSCs with anti-TNF therapy is also incompletely understood for the same reason as lymphoma; thiopurines are associated with skin cancers and frequently used in combination with anti-TNF agents.43 Additionally, IBD in and of itself may be associated with an increase in skin cancers.1 A recent retrospective cohort of 108,579 patients with IBD and nested case–control studies published by Long suggested an increased incidence of melanoma and NMSCs, but in the nested case–control portion of the study, anti-TNF agents were associated with an increase in melanoma (adjusted OR 1.88, 95% CI 1.08–3.29) but there was no increase in NMSCs in these patients (adjusted OR 1.14, 95% CI 0.95–1.36).34 It should also be stated that in this study no data were provided regarding exposure to anti-TNF therapy alone versus combination therapy. In the TREAT registry cohort, no increased incidence of melanoma or NMSC was noted in patients treated with biologics.54 In a retrospective cohort from the Netherlands, 147 patients were followed over 9 years and 2 with NMSC and 1 with melanoma were found, all 3 in the setting of combination therapy with thiopurines.63 A Spanish study of 152 patients followed over 9 years on infliximab revealed no skin cancers.64 A recent meta-analysis on anti-TNF agents in IBD found no increase in skin cancers over the general populations.56 Overall, the true risk of skin cancer attributable to anti-TNF therapy is unknown but it is reasonable to consider periodic skin checks and skin barrier protection in all patients with IBD, including those on anti-TNF therapy. There are two integrin receptor antagonists approved to treat IBD. Natalizumab, approved for multiple sclerosis (MS) in 2004 and in 2008 for Crohn's disease, is a humanized monoclonal antibody that binds to alpha-4 integrin subunit leading to reduced migration of leukocytes to areas of inflammation. Vedolizumab is a humanized monoclonal antibody recently approved for the treatment of both UC and CD that specifically blocks the α4β7 cell-surface glycoprotein expressed on circulating B and T lymphocytes. There are little data suggesting an association between natalizumab and malignancy, though there is ongoing debate around this issue.65 In the MS literature, several case reports have been published on patients treated with natalizumab who developed melanoma,66,–69 CNS lymphoma,70 and peripheral T cell lymphoma.71 Although there are no reported cases of malignancy associated with natalizumab in IBD patients published in the literature after its approval, in placebo controlled trials of natalizumab for CD there was a slightly higher rate of malignancy in patients treated with natalizumab (six patients in the natalizumab arm vs one in the placebo arm).72 However, as there were a variety of neoplasms (adenocarcinoma, breast cancer, melanoma and bladder cancer), a brief time between administration of the study drug and diagnosis of cancer, and variable exposure to the drug, it is unclear if there truly is an association between natalizumab and malignancy. For vedolizumab, published data regarding the risk of developing cancer is limited to clinical trials with follow-up of 52 weeks. Of the 1434 patients treated with vedolizumab, 17 patients were diagnosed with a cancer.73 Several different malignancies were identified, with CRC being the most common cancer (4 of 17); the overall CRC incidence rate of 0.66 per 1000 person-years, however, is actually lower than the risk associated with underlying IBD (0.88 per 1000 person-years).8 At this time there are no convincing data to support an increased cancer risk with natalizumab or vedolizumab. In addition, as vedolizumab selectively blocks gut lymphocyte trafficking, it theoretically might decrease the risk of systemic adverse events including malignancy. As such, vedolizumab may become an attractive option in the future for IBD management in patients with a history of cancer. Treating a Patient With a Cancer History Treatment-related cancers in IBD patients are of great concern among gastroenterologists. Although treatment-associated cancers are rare, it is appropriate to try and reduce the risk by as much as possible. Although there may be an increased concern of malignancy in patients with a family history of cancer, there are no data to support altering IBD management based on a family history of any cancer. As previously discussed, if there is any risk of cancer with IBD treatments, the risk is very small and changing treatment modalities based on a family history is not warranted. In our practice, we do not alter IBD management based on a family history of cancer. A personal history of cancer, however, can impact IBD management significantly. Given a lack of evidence, the decision to initiate immunosuppressant medication in a patient with a history of cancer needs to be weighed carefully on a case-by-case basis and with consultation from an oncologist. Expert opinion in this area involves taking a myriad of clinical factors into consideration including natural history of the previous cancer, degree that the primary cancer is controlled, remoteness of the cancer itself, IBD severity, concern for drug-induced immunosuppression affecting that particular cancer, and lack of other cancers.24,74 Indeed some cancers seem to have a higher risk of recurrence, as noted in the posttransplant setting, but there is not enough data in the IBD setting to dictate what cancers are at higher risk of recurrence with IBD treatment. From the posttransplant literature, tumors with lower risk of recurrence include lymphomas and uterine/cervical cancer, whereas higher risk tumors include melanoma, NMSC, and myelomas.44,75 Expert opinion suggests that at least 2 years should pass between the completion of cancer treatment and the resumption of immunosuppressive therapy, with the possible exception of NMSCs and high-grade dysplasia of the cervix.24 IBD treatment during this 2-year window should consist of surgery, if necessary, corticosteroids, 5-ASA agents, and antibiotics.24 In the setting of uncontrolled IBD in a patient with active malignancy, biologic agents can be considered as a second-line therapy.44 As most prospective randomized trials with anti-TNF agents and immunomodulators exclude patients with a history of malignancy, it is hard to determine the exact risk of IBD-related treatment on patients with a cancer history. In a prospective cohort study of 5120 German patients with RA followed over 5 years, the likelihood of developing a cancer during the study period if treated with an anti-TNF agent was not higher in patients with a previous malignancy versus those without a previous cancer.76 In this cohort, 122 patients had a previous cancer, 58 of whom were treated with anti-TNF agents. Eight patients had recurrences with anti-TNF agents and a previous malignancy, with a crude incidence rate of 45.5 per 1000 patient-years. This incidence ratio was not statistically significantly different compared with patients with a cancer history and treated with DMARDs (31 per 1000 patient-years, P = 0.63). In a British study of RA, 177 of 293 patients were identified as having a previous malignancy and treated with anti-TNF agents (the rest were on classic DMARDs).77 In the anti-TNF group, a rate of malignancy was noted to be 25.3 per 1000 patient-years compared with 38.3 per 1000 patient-years in the DMARD group. One noteworthy finding from this study was that 3 of 17 patients (18%) with melanoma in the anti-TNF group had a recurrence suggesting that there may be a higher risk for anti-TNF use in patients with a history of melanoma. With regard to skin cancer, expert opinion suggests that anti-TNFs are safe to use if there is a history of NMSCs.78 In the setting of melanoma, anti-TNF agents may be safe to use if the lesion has been resected with intent to cure, but anti-TNF should be stopped in the setting of metastatic or recurrent melanoma.78 In patients with a history of cancer, some authors propose consideration of MTX as the preferred immunomodulator.78 As MTX has chemotherapeutic properties, it is felt to have a low recurrence risk as a treatment option for IBD. As mentioned previously, if there is an increased risk of lymphoma and skin cancer with MTX use, it is felt to be very small. In our practice, we consider MTX use when an immunomodulator is needed in a patient with IBD with a history of cancer. Thiopurines, overall, are felt to be safe in the treatment of patients with a history of cancer. The best supporting data come from a subgroup analysis of the French CESAME cohort. In this study population enrolled from 2004 to 2005 and followed through 2007, 17,047 patients were followed including 405 patients with a history of cancer.79 Of the 405 patients with a history of cancer, 93 were treated with an immunosuppressant (most of which were on thiopurine monotherapy). The rate of incident cancers in the patients exposed to immunosuppressants (27 per 1000 patient-years) and those not exposed to immunosuppressants (19.2 per 1000 patient-years) were not statistically different.79 A nested case–control study on this population found that exposure to immunosuppressants and a short period of less than 2 years from cancer diagnosis to the study period were both not associated with an increased risk of new or recurrent cancer.79 It is relevant to note that the most common type of recurrent cancer in patients with a history of cancer on thiopurines in this study was NMSC. Regarding skin cancer and thiopurines, expert opinion suggests that thiopurines can be continued in the setting of NMSCs as long as they are not numerous or disfiguring.78 Like anti-TNF agents, thiopurines can be continued in the setting of melanoma as long as disease has been cured and there is a very low concern for recurrence or metastasis; however it is of paramount importance that this decision be made with the input of an oncologist.78 In patients with a history of EBV-related lymphoproliferative disease, thiopurines should be avoided and anti-TNF monotherapy or methotrexate should be considered,24 given the substantially elevated risk of lymphoma with combination therapy including a biologic agent and immunomodulator.57,58 At this time, guidelines do not specifically address how best to manage patients with a history of cancer and IBD. The 2009 American College of Gastroenterology and 2010 World Gastroenterology Organization guidelines do not have any recommendations in this clinical setting.80,81 The European Crohn's and Colitis Organization guidelines consider anti-TNF therapy as contraindicated in patients with a lymphoma history and advise caution when using anti-TNF agents in solid tumors.82 As such, the practitioner is truly limited to expert opinion in this clinical scenario. We would advise considering the approach advocated by Bernheim et al,74 which suggests that patients with a previous cancer should be divided into 2 categories: more than 2 years or less than 2 since completion of treatment.74 Patients with IBD less than 2 years from cancer treatment who are poorly controlled despite 5-aminosalicylic acid (5-ASA) agents and antibiotics should have flares treated with steroids; biologics should only be considered if these treatments are ineffective (Fig. 2). Generally, we prefer to avoid immunomodulators in this subgroup of patients. A step-up approach should be considered in patients with a history of cancer more than 2 years since completion of therapy.65 If an immunomodulator is necessary in this category of patients, we favor MTX over a thiopurine. Although this generalization of dividing patients into those more or less than 2 years removed from cancer treatment is useful to keep in mind when the IBD practitioner is evaluating an individual patient, one should be sure to recognize that some cancers such as breast cancer, melanoma, and renal cell carcinoma are more likely to recur even after more than 2 years of follow-up. Figure 2. Open in new tabDownload slide General approach to IBD treatment in a patient with a history of cancer. Figure 2. Open in new tabDownload slide General approach to IBD treatment in a patient with a history of cancer. Those patients with poorly controlled IBD who have a high risk malignancy or metastatic disease for whom chemotherapy is recommended should proceed with cancer treatment as chemotherapy itself may have a beneficial effect on their IBD. Chemotherapy drugs vary in their immunosuppressive activity and further study on the immunological effects of drugs commonly used to treat bowel cancers (e.g., 5-fluorouracil, oxaliplatin, irinotecan) would be of interest. If IBD is not well controlled despite chemotherapy, 5-ASA agents, antibiotics, and steroids should be considered first-line therapy and anti-TNF agents or other biologics should be considered second-line therapy.74 In summary, managing IBD in a patient with a history of cancer requires a thorough discussion with the patient regarding the lack of firm recommendations in the literature, consideration of the type and stage of their cancer and the severity of the IBD. Consultation with an oncologist is crucial in managing these patients. References 1. Hudesman D , Lichtiger S , Sands B . Risk of extraintestinal solid cancer with anti-TNF therapy in adults with inflammatory bowel disease: review of the literature . Inflamm Bowel Dis . 2013 ; 19 : 644 – 649 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Kappelman MD , Farkas DK , Long MD , et al. . Risk of cancer in patients with inflammatory bowel disease: a nationwide population-based cohort study with 30 years of follow up evaluation . Clin Gastroenterol Hepatol . 2014 ; 12 : 265 – 273 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Shaukat A , Virnig DJ , Howard D . Crohns disease and small bowel adenocarcinoma: a population-based case-control study . Cancer Epidemiol Biomarkers Prev . 2011 ; 20 : 1120 – 1123 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Munkholm P . Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003 ; 18 (suppl 2):1–5. WorldCat 5. Dyson JK , Rutter MD . Colorectal cancer in inflammatory bowel disease: what is the real magnitude of risk? . World J Gastroenterol . 2012 ; 18 : 3839 – 3848 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Eaden JA , Abrams KR , Mayberry JF . The risk of colorectal cancer in ulcerative colitis: a meta-analysis . Gut . 2001 ; 48 : 526 – 535 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Lutgens W , Van Oijen MG , Van der Heijden GJ , et al. . Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies . Inflamm Bowel Dis . 2013 ; 19 : 789 – 799 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Söderlund S , Brandt L , Lapidus A , et al. . Decreasing time-trends of colorectal cancer in a large cohort of patients with inflammatory bowel disease . Gastroenterology. 2009 ; 136 : 1561 – 1567 ; quiz 1818–1819. Google Scholar Crossref Search ADS PubMed WorldCat 9. Ekbom A , Helmick C , Zack M , et al. . Increased risk of large-bowel cancer in Crohn's disease with colonic involvement . Lancet . 1990 ; 336 : 357 – 359 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Singh S , Talwalkar JA . Primary sclerosing cholangitis: diagnosis, prognosis, and management . Clin Gastroenterol Hepatol . 2013 ; 11 : 898 – 907 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Razumilava N , Gores GJ , Lindor KD . Cancer surveillance in patients with primary sclerosing cholangitis . Hepatology . 2011 ; 54 : 1842 – 1852 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Burak K , Angulo P , Pasha TM , et al. . Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis . Am J Gastroenterol . 2004 ; 99 : 523 – 526 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Baecklund E , Iliadou A , Askling J , et al. . Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis . Arthritis Rheum . 2006 ; 54 : 692 – 701 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Lewis JD , Bilker WB , Brensinger C , et al. . Inflammatory bowel disease is not associated with an increased risk of lymphoma . Gastroenterology . 2001 ; 121 : 1080 – 1087 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Askling J , Brandt L , Lapidus A , et al. . Risk of haematopoietic cancer in patients with inflammatory bowel disease . Gut . 2005 ; 54 : 617 – 622 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Vos AC , Bakkal N , Minnee RC , et al. . Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study . Inflamm Bowel Dis . 2011 ; 17 : 1837 – 1845 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Colombrel JF , Sandborn W , Reinisch W , et al. . Infliximab, azathioprine or combination therapy for Crohn's disease . N Engl J Med . 2010 ; 362 : 1383 – 1395 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Ngueyn T , Vacek PM , O'Neil P , et al. . Mutagenicity and potential carcinogenesis of thiopurine treatment in patients with inflammatory bowel disease . Cancer Res . 2009 ; 69 : 7004 – 7012 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Karran P . Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull. 2006 ; 79-80 : 153 – 170 . Google Scholar Crossref Search ADS PubMed WorldCat 20. Pasternak B , Svanstrom H , Schmiegelow K , et al. . Use of azathioprine and the risk of cancer in inflammatory bowel disease . Am J Epidemiol . 2013 ; 177 : 1296 – 1305 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Kauffman HM , Cherikh WS , McBride MA , et al. . Post-transplant de novo malignancies in renal transplant recipients: the past and present . Transpl Int . 2006 ; 19 : 607 – 620 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Opelz G , Dohler B . Lymphomas after solid organ transplantation: a collaborative transplant study report . Am J Transplant . 2004 ; 4 : 222 – 230 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Marcen R , Pascual J , Tato AM , et al. . Influence of immunosuppression on the prevalence of cancer after kidney transplantation . Transplant Proc . 2003 ; 35 : 1714 – 1716 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Beaugerie L . Use of immunosuppressants and biologics in patients with previous cancer . Dig Dis . 2013 ; 31 : 254 – 259 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Kandiel A , Fraser AG , Korelitz BI , et al. . Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine . Gut. 2005:54:1121–1125. WorldCat 26. Beaugerie L , Brousse N , Bouvier AM , et al. . Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observation cohort study . Lancet. 2009 ; 364 : 1617 – 1625 . Google Scholar Crossref Search ADS WorldCat 27. Armstrong RG , West J , Card TR . Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study . Am J Gastroenterol . 2010 ; 105 : 1604 – 1609 . Google Scholar Crossref Search ADS PubMed WorldCat 28. O'Donovan P , Perrett CM , Zhang X , et al. . Azathioprine and UVA light generate mutagenic oxidative DNA damage . Science . 2005 ; 309 : 1871 – 1874 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Peyrin-Biroulet L , Khosrotehrani K , Carrat F , et al. . Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease . Gastroenterology. 2011:141:1621–1628 e1–5. WorldCat 30. Setshedi M , Epstein D , Winter T , et al. . Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study . J Gastroenterol Hepatol. 2012 ; 27 : 385 – 389 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Ariyaratnam J , Subramanian V . Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis . Am J Gastroenterol . 2014 ; 109 : 163 – 169 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Euvrard S , Kanitakis J , Claudy A . Skin cancers after organ transplantation . N Engl J Med . 2003 ; 2003 : 1681 – 1691 . Google Scholar Crossref Search ADS WorldCat 33. van den Reek J , van Lümig P , Janssen M , et al. . Increased incidence of squamous cell carcinoma of the skin after long term treatment with azathioprine in patients with auto-immune inflammatory rheumatic diseases . J Eur Acad Dermatol Venereol . 2014 ; 28 : 27 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Long MD , Martin CF , Pipkin CA , et al. . Risk of melanoma and non-melanoma skin cancer among patients with inflammatory bowel disease . Gastroenterology . 2012 ; 143 : 390 – 399 . Google Scholar Crossref Search ADS PubMed WorldCat 35. Smith MA , Irving PM , Marinaki AM , et al. . Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease . Aliment Pharmacol Ther . 2010 ; 32 : 119 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat 36. Kamel OW , Van De Rijn M , Weiss LM , et al. . Brief report: reversible lymphomas associated with Epstein Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis . N Engl J Med . 1993 ; 328 : 1317 – 1321 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Hannuksela-Svhan A , Pukkala E , Laara E , et al. . Psoriasis, its treatment, and cancer in a cohort of Finish patients . J Invest Dermatol . 2000 ; 114 : 587 – 590 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Mariette X , Casals-Hatem D , Warszawki J , et al. . Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3 year prospective study in France . Blood . 2002 ; 99 : 3909 – 3915 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Buchbinder R , Barber M , Heuzenroeder L , et al. . Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate . Arthritis Rheum . 2008 ; 59 : 794 – 799 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Salliot C , van der-Heijde D . Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research . Ann Rheum Dis . 2009 ; 68 : 1100 – 1104 . Google Scholar Crossref Search ADS PubMed WorldCat 41. Farrell RJ , Ang Y , Kileen P , et al. . Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low . Gut . 2000 ; 47 : 514 – 519 . Google Scholar Crossref Search ADS PubMed WorldCat 42. Krathen MS , Gottlieb AB , Mease PJ . Pharmacologic immunomodulation and cutaneous malignancy in rheumatoid arthritis, psoriasis, and psoriatic arthritis . J Rheumatol . 2010 ; 37 : 2205 – 2215 . Google Scholar Crossref Search ADS PubMed WorldCat 43. Singh H , Nugent Z , Demers AA , et al. . Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease . Gastroenterology . 2011 ; 141 : 1612 – 1620 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Beaugerie L . Inflammatory bowel disease therapies and cancer risk: where are we and where are we going? Gut. 2012 ; 61 : 476 – 483 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Mariette X , Matucci M , Pavelka K , et al. . Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis . Ann Rheum Dis . 2011 ; 70 : 1895 – 1904 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Bongartz T , Sutton AJ , Sweeting MJ , et al. . Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials . JAMA . 2006 ; 295 : 2275 – 2285 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Bickston SJ , Lichtenstein GR , Arseneau KO , et al. . The relationship between infliximab treatment and lymphoma in Crohn's disease . Gastroenterology . 1999 ; 177 : 1433 – 1437 . Google Scholar Crossref Search ADS WorldCat 48. Alcaín G , Andrade RJ , Queipo de Llano MP , et al. . Acute leukemia after infliximab therapy . Am J Gastroenterol. 2003 ; 98 : 2577 . Google Scholar Crossref Search ADS PubMed WorldCat 49. Brown SL , Greene MH , Gershon SK , et al. . Tumor necrosis factor antagonist therapy and lymphoma development: twenty six cases reported to the Food and Drug Administration . Arthritis Rheum. 2002:46;3151–3158. WorldCat 50. Remicade: Full Prescribing Information. Available at: http://www.remicade.com/shared/product/remicade/prescribing-information.pdf. Accessed September 10, 2014. 51. Siegel CA , Marden SM , Persing SM , et al. . Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis . Clin Gastroenterol Hepatol. 2009 ; 7 : 874 – 881 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Osterman M , Sandborn WJ , Colombel J , et al. . Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn's disease . Gastroenterology . 2014 ; 146 : 941 – 946 . Google Scholar Crossref Search ADS PubMed WorldCat 53. Deepak P , Sifuentes H , Sherid M , et al. . T cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha inhibitors: results of the REFURBISH study . Am J Gastroenterol . 2013 ; 108 : 99 – 105 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Lichtenstein GR , Feagan BG , Cohen RC , et al. . Drug therapies and the risk of malignancy in Crohn's disease: results from the TREAT registry . Am J Gastroenterol . 2014 ; 109 : 212 – 223 . Google Scholar Crossref Search ADS PubMed WorldCat 55. Andersen NN , Pasternak N , Basit S , et al. . Association between tumor necrosis factor-alpha antagonists and risk of cancer in patients with inflammatory bowel disease . JAMA . 2014 ; 311 : 2406 – 2413 . Google Scholar Crossref Search ADS PubMed WorldCat 56. Williams CJM , Peyrin-Biroulet L , Ford AC . Systematic review with meta-analysis: malignancies with anti-tumor necrosis factor alpha therapy in inflammatory bowel disease . Aliment Pharmacol Ther . 2014 ; 39 : 447 – 458 . Google Scholar Crossref Search ADS PubMed WorldCat 57. Colombel JF , Loftus EV Jr , Tremaine WJ , et al. . The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients . Gastroenterology . 2004 ; 126 : 19 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat 58. Herrinton LJ , Liu L , Weng X , et al. . Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease . Am J Gastroenterol . 2011 ; 106 : 2146 – 2153 . Google Scholar Crossref Search ADS PubMed WorldCat 59. Subramanian K , D'Rozario J , Pavli P . Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: a review . J Gastroenterol Hepatol . 2013 ; 28 : 24 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Subramanian K , Yeng D , Grimpen F , et al. . Hepatosplenic T-cell lymphoma, immunosuppressive agents and biological: what are the risks? . Intern Med J . 2014 ; 44 : 287 – 290 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Parakkal D , Sifuentes H , Semer R , et al. . Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk . Eur J Gastroenterol Heptaol . 2011 ; 23 : 1150 – 1156 . Google Scholar Crossref Search ADS WorldCat 62. Abbvie. Humira: Full Prescribing Information. Available at: http://www.rxabbvie.com/pdf/humira.pdf. Accessed September 10, 2014. 63. De Vries HS , van Oijen GH , de Jong DJ . Serious events with infliximab in patients with inflammatory bowel disease: a 9 year cohort study in the Netherlands . Drug Saf. 2008 ; 31 : 1135 – 1144 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Zabana Y , Domenech E , Manosa M , et al. . Infliximab safety profile and long term applicability in inflammatory bowel disease: a 9 year experience in clinical practice . Aliment Pharmacol Ther . 2010 ; 31 : 553 – 560 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Planas R , Martin R , Sospedra M . Long-term safety and efficacy of natalizumab in relapsing-remitting multiple sclerosis: impact on quality of life . Patient Relat Outcome Meas . 2014 ; 5 : 25 – 33 . Google Scholar PubMed WorldCat 66. Bergamaschi R , Montomoli C . Melanoma in multiple sclerosis treatedwith natalizumab: causal association or coincidence? Mult Scer. 2009 ; 15 : 1532 – 1533 . Google Scholar Crossref Search ADS WorldCat 67. Mullen JT , Vartanian TK , Atkins MB . Melanoma complicating treatment with natalizumab for multiple sclerosis . N Engl J Med . 2008 ; 358 : 647 – 648 . Google Scholar Crossref Search ADS PubMed WorldCat 68. Ismail A , Kemp J , Sharrack B . Melanoma complicating treatment with natalizumab (tysabri) for multiple sclerosis . J Neurol . 2009 ; 256 : 1771 – 1772 . Google Scholar Crossref Search ADS PubMed WorldCat 69. Laroni A , Bedognetti M , Uccelli A , et al. . Association of melanoma and natalizumab therapy in the Italian MS population: a second case report . Neurol Sci . 2011 ; 32 : 181 – 182 . Google Scholar Crossref Search ADS PubMed WorldCat 70. Schweikert A , Kremer M , Ringel F , et al. . Primary central nervous system lymphoma in a patient treated with natalizumab . Ann Neurol . 2009 ; 66 : 403 – 406 . Google Scholar Crossref Search ADS PubMed WorldCat 71. Schowinsky J , Corboy J , Vollmer T , et al. . Natalizumab-associated complication? First case of peripheral T cell lymphoma . Acta Neuropathol . 2012 ; 123 : 751 – 752 . Google Scholar Crossref Search ADS PubMed WorldCat 72. Sanborn WJ , Colombel JF , Enns R , et al. . Natalizumab induction and maintenance therapy for Crohn's disease: the ENACT-1 and ENACT-2 trials . N Eng J Med . 2005 ; 353 : 1912 – 1925 . Google Scholar Crossref Search ADS WorldCat 73. Takeda Pharmaceuticals U.S.A., Inc . Vedolizumab: advisory committee briefing document. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/gastrointestinaldrugsadvisorycommittee/ucm377621.pdf. Accessed September 10, 2014. 74. Bernheim O , Colombel JF , Ullman TA , et al. . The management of immunosuppression in patients with inflammatory bowel disease and cancer . Gut. 2013 ; 62 : 1523 – 1528 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Penn I . The effect of immunosuppression on pre-existing cancers. Transplantation. 1993 ; 55 : 742 . Google Scholar Crossref Search ADS PubMed WorldCat 76. Strangfeld A , Hierse F , Rau R , et al. . Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT . Arthritis Res Ther. 2010 ; 12 : R5 . Google Scholar Crossref Search ADS PubMed WorldCat 77. Dixon WG , Watson KD , Lunt M , et al. . Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register . Arthritis Care Res . 2010 ; 62 : 755 – 763 . Google Scholar Crossref Search ADS WorldCat 78. Swoger JM , Regueiro M . Stopping, continuing, or restarting immunomodulators and biologics when an infection or malignancy develops . Inflamm Bowel Dis . 2014 ; 20 : 926 – 935 . Google Scholar Crossref Search ADS PubMed WorldCat 79. Beaugerie L , Carrat F , Colobmel JF , et al. . Risk of new or recurrent cancer under immunosuppressive therapy in patients with IBD and previous cancer . Gut . 2014 ; 63 : 1416 – 1423 . Google Scholar Crossref Search ADS PubMed WorldCat 80. Lichtenstein GR , Hanauer SB , Sandborn WJ , et al. . Management of Crohn's disease in adults . Am J Gastroenterol . 2009 ; 104 : 465 – 483 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Bernstein CN , Fried M , Krabshuis JH , et al. . World Gastroenterology Organization Practice Guidelines for diagnosis and management of IBD in 2010 . Inflamm Bowel Dis . 2010 ; 16 : 112 – 124 . Google Scholar Crossref Search ADS PubMed WorldCat 82. Dignass A , Van Assche G , Lindsay JO , et al. . The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management . J Crohns Colitis . 2010 ; 4 : 28 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Reprints: Richard S. Kalman, MD, Section of Gastroenterology, Boston University Medical Center, Boston, MA (e-mail: richard.kalman@bmc.org). The authors have no conflicts of interest to disclose. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.
TI - Does a Personal or Family History of Malignancy Preclude the Use of Immunomodulators and Biologics in IBD
JF - Inflammatory Bowel Diseases
DO - 10.1097/MIB.0000000000000211
DA - 2015-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/does-a-personal-or-family-history-of-malignancy-preclude-the-use-of-EGeMkpHu0q
SP - 428
VL - 21
IS - 2
DP - DeepDyve
ER -