Inflammatory bowel disease (IBD) in children is associated with chronic inflammation, and such inflammation increases the risk of cancer development. Since IBD incidence is increasing in children, the authors of this study performed a meta-analysis regarding the potential cancer risk in children with IBD using PRISMA guidelines. Potential articles and abstracts evaluating the risk of cancer in pediatric patients with IBD (defined as occurring under 25 years of age) were obtained from PubMed, Google Scholar, Scopus, Cochrane Central Register of Controlled Trials as well as from major cancer and gastroenterology meetings. IBD terms such as “Crohn’s disease”, “ulcerative colitis”, and “inflammatory bowel disease” combined with various potential cancer terms including “childhood”, “cancer”, “malignancy”, as well as several types of malignancy were searched via these databases. Each potential data source was reviewed by 2 authors, and the Jadad score and the Cochrane Risk of Bias Assessment Instrument were used to determine randomized controlled trial quality. The NewcastleOttawa Scale was used to assess observational study quality. GRADE criteria (Grading of Recommendations, Assessment, Development and Evaluation) were used to determine risk of bias. The primary outcome was to determine the risk of cancer noted in studies using standardized incidence ratios. Secondary outcomes included the pooled incidence rates of all cancers as well as site-specific cancers. Meta-regression analysis was performed to determine if medication type influenced cancer development.
A large number of potential studies (total of 969,127) was initially identified; however, only 66 studies including 38,092 patients were included in the final analysis. A total of 44 studies evaluated patients with Crohn’s disease; 31 studies evaluated patients with ulcerative colitis; and 5 studies evaluated patients with IBD (no distinction given). Patients less than 18 years of age were included in 50 studies (75.76%) while the remainder of the studies included patients 18 to 24 years of age. A total of 14 of the 62 observational studies had a Newcastle-Ottawa score of 6 or higher. All randomized controlled trials had a Jadad score of 2 or 3. No inter-rater disagreement for data scoring was noted between the study authors.
A total of six retrospective observational studies including 17,450 patients evaluated the standardized incidence ratio of cancer occurrence. At least 125 patients developed a malignancy although the final number of patients with a malignancy was not clear. Four of these studies evaluated patients with Crohn’s disease and noted a 2.4-fold increased risk of cancer (pooled SIR 2.42, P < .0001, 95% CI 1.90-3.06; meta-analysis heterogeneity score (I2) = 0%) while five of these studies evaluated patients with ulcerative colitis and noted a 2.1-fold increased risk of cancers (pooled SIR 2.10, P < .0001, 95% CI 1.51-2.90; I2 = 41.54%). A pooled standardized risk ratio for all pediatric patients with IBD was 2.39 (P < .0001, 95% CI 2.00-2.86; I2 = 0%). The pooled incidence of overall pediatric cancers came from 9 prospective and 44 retrospective studies. The pooled incidence rate of overall cancers in patients with Crohn’s disease was 0.014 (95% CI 0.0087- 0.021; I2 = 78.90%) while the pooled incidence rate of overall cancers in patients with ulcerative colitis was 0.031(95% CI 0.018-0.052; I2 = 91.59%) and the pooled incidence rate of overall cancers in all of the included studies was 0.018 (95% CI 0.013-0.025; I2 = 89.10%). A metaregression analysis determined that follow-up study duration positively correlated with cancer development risk, and this finding was statistically significant. No such association was seen with various medications used to treat pediatric IBD including use of steroids, immunomodulators, and anti-tumor necrosis factor medications.
Regarding specific cancer development, not enough data was available to perform a metaanalysis for the development of colorectal cancer. However, the pooled incidence rate of colorectal cancer in CD was 0.0075 (95% CI 0.0049-0.011; I2 = 41.30%) while the pooled incidence rate of colorectal cancer in ulcerative colitis was 0.020 (95% CI 0.012-0.034; I2 = 87.95%) and the pooled incidence rate in all pediatric IBD patients was 0.010 (95% CI 0.0074-0.014; I2 = 81.30%). There appeared to be a statistically significant and positive correlation between male patients and the risk of colorectal cancer while a statistically significant and negative correlation was seen between age of IBD diagnosis / onset and risk of colorectal cancer with younger patients at time of diagnosis having an increased risk of colorectal cancer long term. Only one study provided standardized incidence ratio data on hematologic cancers in the setting of IBD. However, enough studies were present to determine the pooled incidence rate of pediatric patients with Crohn’s disease and ulcerative colitis. Patients with Crohn’s disease had a pooled incidence rate of 0.0061 (95% CI 0.0040-0.0090; I2 = 27.14%) while patients with ulcerative colitis having a pooled incidence rate of 0.0045 (95% CI 0.0040-0.0090; I2 = 31.66%).
The pooled incidence rate of all pediatric patients with IBD was 0.0054 (95% CI 0.0039-0.0075; I2 = 35.25%). Meta-regression analysis showed no risk of hematologic cancers in patients having received steroids, immunomodulators, or antitumor necrosis factor medications. Finally, cumulative meta-analyses showed that all cancer types had a decreasing incidence over time.
This study shows that pediatric patients with IBD do have an inherent cancer risk, but it is reassuring that the risk of cancer is not associated with standard IBD therapy. It also is helpful to know that the incidence of cancer in this study decreased over time suggesting pediatric patients with IBD may be maintaining good disease control over time. However, the range of heterogeneity of meta-analyses in this study suggests that better data is needed to answer this question more clearly.
Komaki Y, Komaki F, Yamada A, Micic D, Ido A, Sakuraba A. Risk of cancers in patients with pediatric inflammatory bowel diseases: a systemic review and meta-analysis. Journal of Pediatrics 2021; 229: 102-117.