As more children diagnosed with cancer are surviving long-term, it is increasingly important to recognize the long-term consequence of their cancer and its therapy. This analysis demonstrates that survivors of childhood cancer have a higher incidence of self-reported GI complaints compared with their siblings. Risks for colostomy/ileostomy, cirrhosis or liver biopsy were highest. Older age at diagnosis, exposure to abdominal radiation, and certain chemotherapy treatments increase that risk.
Over 40% of childhood cancer survivors reported a late GI complication by 20 years after cancer therapy. Studies of adult onset cancer survivors support that late GI complications are relatively common. This is particularly true in patients with abdominal or pelvic carcinomas treated with radiation. These GI conditions can have a significant impact on quality of life.13–15
Up to 50% of adult onset cancer patients treated with pelvic radiation report that quality of life is impacted by GI symptoms. Information regarding late GI consequences in childhood cancer is limited. In a study of females treated for pelvic rhabdomyosarcoma, 41 GI late-effects were identified in 18 of 26 patients studied.16
Intestinal complications included strictures, gastritis, incontinence, enteritis, perforation, constipation, and liver conditions. Thus, the CCSS data and other data indicate that late GI complications are a relatively common, and perhaps under-investigated, problem.
The probability of experiencing a late GI consequence was greater in survivors compared to siblings in 16 out the 17 categories evaluated. Cancer therapy has well known acute GI toxicities, including nausea, vomiting, esophagitis, mucositis, enteritis, diarrhea, and liver dysfunction. The survivor’s prior experience may increase their sensitivity to GI related symptoms, but cancer treatments may cause direct damage to the GI organ system. Late GI toxicity may result from repeated injury and scarring of the tissue from chemotherapy or gastrointestinal infections related to chemotherapy-related myelosuppression. Blood products needed during therapy increase the risk of hepatitis.17, 18
Radiation can cause vascular injury and result in intestinal ischemia and/or fibrosis.19, 20
The incidence of intestinal fibrosis is dose dependent, 5% at 40Gy and up to 40% at 60Gy.20
Radiation can also damage abdominal blood vessels and cause clinically significant vascular compromise including impaired growth and stenosis of the abdominal aorta.21
Radiation can also cause long-standing liver damage that is dose and volume dependent.22
Thus, it is not surprising that survivors of childhood cancer have long-term GI complications.
Some of the factors that influenced risk for late GI toxicity were expected and others were not. As expected, exposure to abdominal radiation increased the risk of upper and lower GI complications. However, abdominal radiation did not increase the risk of liver complications. This may reflect the fact that most patients needing abdominal radiation (i.e, neuroblastoma, Wilms tumor) may have had the liver spared from direct and/or high doses of radiation. The liver seems to tolerate relatively smaller doses (<20 Gy) to larger areas of the liver or higher doses to smaller areas of the liver. 23
Patients undergoing BMT with TBI did have a high rate of liver conditions. This may reflect the overall intensity of the therapy and associated increased risk of VOD, infectious complications (including viral hepatitis), and/or GVHD.
Chemotherapy, like radiation, causes toxicity in organs with rapid cell turnover. Alkylators are mutagenic and may cause long-term genetic changes in tissues of organs like the gastrointestinal tract.24
Anthracyclines have a well known association with early and late cardiac damage.25
They also cause significant acute GI toxicities.26
Therefore, it is understandable why alkylators and anthracyclines influenced the risk of late hepatic and lower GI consequences. Consistent with this finding, concurrent chemotherapy in adult patients with cervical carcinoma have a higher risk of bowel damage and late GI toxicity.27
Abdominal surgery may predispose survivors to the development of adhesions and late GI complications. Based on anecdotal long-term reports, small bowel obstruction can be a late sequlae of abdominal surgery.23
However, on multivariate analysis in this study, abdominal surgery was only associated with late hepatic consequences.
The association between older age at diagnosis and increased risk of developing late GI complications was unanticipated. The increasing incidence with increasing age may reflect less resiliency of the GI tissue with age. Alternatively, older patients develop different cancers (e.g., Hodgkin disease, bone sarcoma) that may employ treatments with greater potential for GI toxicity or a greater tendency to use radiation in older children.
The large size of the CCSS cohort and the high participation rates are strengths of our study. Several limitations should also be discussed. The first limitation relates to the self-reported nature of the data and the potential for under- or over-reporting outcomes. While CCSS investigators have had excellent success in validating selected outcomes, such as second malignancies, our success in obtaining complete medical records on a high proportion of survivors for validation of other major outcomes has been limited.28
Previous reports have demonstrated that survivors of stem cell transplantation have the ability to recall many medical outcomes with a relatively good level of sensitivity and specificity 29
. Additionally, using siblings as a control could introduce bias. Siblings might be predicted to have more GI complaints than the general populations; if so this would make the results somewhat conservative. Another limitation of this study is that some reported late-effects could be related to recurrence or progression of their cancer. Patients who were alive, but had active disease at 5-years after diagnosis, were included. However, when we added an indicator variable of recurrence to the multivariable model, we found that there were no significant differences in the three outcomes’ rates by recurrence (data not shown). Although this was likely a small number of patients, the methods of data capture do not allow separate analysis of disease state at time of entry. Lastly, it is not possible to distinguish between the direct effects of the cancer treatment and indirect effects (such as hepatitis C infection from transfusion on the liver).
In conclusion, survivors are at elevated risk for ongoing GI complications after therapy. As these GI complications may impact quality of life, health care providers should be aware of potential GI problems in this population as they evaluate acute complaints and plan ongoing follow-up care. Longitudinal follow-up survivors of childhood cancer will help determine the effects of aging on GI symptoms and disease. In addition, the risks of late GI complications may change, as therapy for childhood and adolescent cancer continues to evolve, and will require studies of more recently treated patients.