Late Effects of the Digestive System
Chemotherapy, radiation therapy, and local surgery can cause multiple cosmetic and functional abnormalities of the oral cavity and dentition. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Oral and dental complications reported in childhood cancer survivors include the following:
Abnormalities of tooth development
Abnormalities of dental development reported in childhood cancer survivors include adontia, hypodontia, microdontia, enamel hypoplasia, and root malformation.[1-9] The prevalence of hypodontia has varied widely in series depending on age at diagnosis, treatment modality, and method of ascertainment. Cancer treatments that have been associated with dental maldevelopment include head and neck radiation, any chemotherapy, and hematopoietic stem cell transplantation (HSCT). Children younger than 5 years are at greatest risk for dental anomalies, such as root agenesis, delayed eruption, enamel defects, and/or excessive caries related to disruption of ameloblast (enamel producing) and odontoblast (dentin producing) activity early in life.
Key findings related to cancer treatment effect on tooth development include the following:
- Radiation directed at oral cavity or surrounding structures increases the risk of dental anomalies because ameloblasts can be permanently damaged by doses as low as 10 Gy.[3,5,6] Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, and as a component of total-body irradiation (TBI). Doses of 10 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification. Significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia have been reported in more than 85% of survivors of head and neck rhabdomyosarcoma treated with radiation doses greater than 40 Gy.[4,5]
- Chemotherapy, especially exposure to alkylating agents, can affect tooth development.[3,6,7] Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots and enamel abnormalities.[11-13] Childhood Cancer Survivor Study (CCSS) investigators identified age younger than 5 years and increased exposure to cyclophosphamide as significant risk factors for developmental dental abnormalities in long-term survivors of childhood cancer.
- HSCT conditioning, especially regimens containing TBI, may result in tooth agenesis and root malformation. Younger children who have not developed secondary teeth are most vulnerable.[1,2,6] Children who undergo HSCT with TBI may develop short V-shaped roots, microdontia, enamel hypoplasia, and/or premature apical closure.[1,2,8] The younger a patient is when treated with HSCT, the more severely disturbed dental development will be and the more deficient vertical growth of the lower face will be. These high-risk patients require close surveillance and appropriate interventions.
Salivary gland dysfunction
Xerostomia, the sensation of dry mouth, is a potential side effect following head and neck irradiation or HSCT that can severely impact quality of life. Complications of reduced salivary secretion include increased caries, susceptibility to oral infections, sleep disturbances, and difficulties with chewing, swallowing, and speaking.[14,15] The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques (patient report vs. stimulated or unstimulated salivary secretion rates). In general, the prevalence of self-reported persistent posttherapy xerostomia is infrequent among childhood cancer survivors. In the CCSS, the prevalence of self-reported xerostomia in survivors was 2.8 % compared with 0.3% in siblings, with an increased risk in survivors older than 30 years.
- Salivary gland irradiation incidental to treatment of head and neck malignancies or Hodgkin lymphoma causes a qualitative and quantitative change in salivary flow, which can be reversible after doses of less than 40 Gy but may be irreversible after higher doses, depending on whether sensitizing chemotherapy is also administered.
- The association of chemotherapy alone with xerostomia remains controversial. Only one study of pediatric patients demonstrated an excess risk (odds ratio, 12.32 [2.1–74.4]) of decreased stimulated saliva flow rates among patients treated with cyclophosphamide; however, no increased dental caries were noted and patient-reported xerostomia was not evaluated.
- HSCT recipients are at increased risk of salivary gland dysfunction related to transplant conditioning or graft-versus-host disease (GVHD). GVHD can cause hyposalivation and xerostomia with resultant dental disease. In a study of pediatric HSCT survivors, 60% of those exposed to a conditioning regimen with cyclophosphamide and 10 Gy single-dose TBI had decreased salivary secretion rates, compared with 26% in those who received cyclophosphamide and busulfan. In contrast, in another study, the prevalence of reduced salivary secretion did not differ among long-term survivors based on conditioning regimen (single-dose TBI, 47%; fractionated TBI, 47%; busulfan, 42%).
- The impact of infectious complications and alterations in the microflora during and after therapy is not known.
Abnormalities of craniofacial development
Craniofacial maldevelopment is a common adverse outcome among children treated with high-dose radiation therapy to the head and neck that frequently occurs in association with other oral cavity sequelae such as dental anomalies, xerostomia, and trismus.[5,19,20] The extent and severity of musculoskeletal disfigurement is related to age at treatment and radiation therapy volume and dose, with higher risk observed among younger patients and those who received 30 Gy or more. Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions.
Some studies suggest there may be a benefit of fluoride products or chlorhexidine rinses in patients who have undergone radiation. Dental caries are a problematic consequence of reduced salivary quality and flow. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.
It has been reported that the incidence of dental visits for childhood cancer survivors falls below the American Dental Association's recommendation that all adults visit the dentist annually. The Children’s Oncology Group Long-term Follow-Up Guidelines recommend biannual dental cleaning and exams for all survivors of childhood cancer. These findings give health care providers further impetus to encourage routine dental care and dental hygiene evaluations for survivors of childhood treatment. (Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information about oral complications in cancer patients.)
|Predisposing Therapy||Oral/Dental Effects||Health Screening/Interventions|
|CT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.|
|Any chemotherapy; radiation impacting oral cavity||Dental developmental abnormalities; tooth/root agenesis; microdontia; root thinning/shortening; enamel dysplasia||Dental evaluation and cleaning every 6 months|
|Regular dental care including fluoride applications|
|Consultation with orthodontist experienced in management of irradiated childhood cancer survivors|
|Baseline panorex before dental procedures to evaluate root development|
|Radiation impacting oral cavity||Malocclusion; temporomandibular joint dysfunction||Dental evaluation and cleaning every 6 months|
|Regular dental care including fluoride applications|
|Consultation with orthodontist experienced in management of irradiated childhood cancer survivors|
|Baseline panorex before dental procedures to evaluate root development|
|Radiation impacting oral cavity; hematopoietic cell transplantation with history of chronic GVHD||Xerostomia/salivary gland dysfunction; periodontal disease; dental caries; oral cancer (squamous cell carcinoma)||Dental evaluation and cleaning every 6 months|
|Supportive care with saliva substitutes, moistening agents, and sialogogues (pilocarpine)|
|Regular dental care including fluoride applications|
|Radiation impacting oral cavity (≥40 Gy)||Osteoradionecrosis||History: impaired or delayed healing after dental work|
|Exam: persistent jaw pain, swelling or trismus|
|Imaging studies (x-ray, CT scan and/or MRI) may assist in making diagnosis|
|Surgical biopsy may be needed to confirm diagnosis|
|Consider hyperbaric oxygen treatments|
The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation, and surgery. However, these important treatment modalities can also result in some long-term issues in a treatment- and dose-dependent manner. Reports published about long-term GI tract outcomes are limited by retrospective data collection, small sample size, cohort selection and participation bias, heterogeneity in treatment approach, time since treatment, and method of ascertainment.
Key concepts about GI complications observed in childhood cancer survivors include the following:
- Treatment-related late effects include the following:
- Cancer and its therapy can increase the risk of upper and lower digestive tract late effects.
- Dose intensity of chemotherapy and use of abdominal irradiation influences the risk of digestive tract late effects.
- Abdominal surgery increases risk of adhesions and predisposes patients to postoperative bowel obstruction.
- Digestive tract–related late effects include the following:
- Esophageal dysmotility.
- Gastroesophageal reflux.
- Gastritis, enteritis, or colitis.
- GI motility dysfunction (diarrhea, constipation, bowel obstruction).
- Subsequent malignant neoplasms
GI outcomes from selected cohort studies
GI outcomes from selected cohort studies include the following:
- Among 5-year childhood cancer survivors participating in the CCSS, the cumulative incidence of self-reported GI conditions was 37.6% at 20 years (25.8% for upper GI complications and 15.5% for lower GI complications) from cancer diagnosis, representing an almost twofold excess risk of upper GI complications (relative risk [RR], 1.8; 95% confidence interval [CI], 1.6–2.0) and lower GI complications (RR, 1.9; 95% CI, 1.7–2.2), compared with sibling controls. Factors predicting higher risk of specific GI complications include the following:
- Older age at diagnosis.
- Intensified therapy (anthracyclines for upper GI complications and alkylating agents for lower GI complications).
- Abdominal radiation.
- Abdominal surgery.
- Another cohort study of children treated for acute myeloid leukemia with chemotherapy alone found that reported GI disorders were relatively rare and not significantly different from those reported by sibling controls.
- Late radiation injury to the digestive tract is attributable to vascular injury. Necrosis, ulceration, stenosis, or perforation can occur and are characterized by malabsorption, pain, and recurrent episodes of bowel obstruction, as well as perforation and infection.[25-27] In general, fractionated doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy cause bowel obstruction or chronic enterocolitis. Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.
Impact of cancer histology on GI outcomes
Intra-abdominal tumors represent a relatively common location for several pediatric malignancies, including rhabdomyosarcoma, Wilms tumor, lymphoma, germ cell tumors, and neuroblastoma. Intra-abdominal tumors often require multimodal therapy, occasionally necessitating resection of bowel and bowel-injuring chemotherapy and/or radiation. Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues.
- One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10–40 Gy) and involved-field (25–40 Gy) radiation and received additional interventions predisposing them to GI tract complications including abdominal laparotomy in 43 patients (98%) and chemotherapy in 25 patients (57%). Late small-bowel obstruction was observed in 36% of patients surviving for 19 months to 7 years, which was uniformly preceded by small bowel toxicity during therapy.
- Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel.[30,31,33] Radiation-related complications occurred in approximately 10% of long-term survivors of paratesticular and bladder/prostate rhabdomyosarcoma and included intraperitoneal adhesions with bowel obstruction, chronic diarrhea, and stricture or enteric fistula formation.[30,33]
- Children irradiated at lower doses for Wilms tumor also uncommonly develop chronic GI toxicity. Several studies have reported cases of small bowel obstruction after abdominal surgery, but the role of radiation appears to be less important as operative findings of enteritis have not consistently been observed.[32,34]
- Another study evaluated the risk of small bowel obstruction in patients diagnosed with intra-abdominal malignancies at a single institution. Eleven of 291 patients (3.8%) developed small bowel obstruction with a mean follow-up of 3.6 years. Wilms tumor, rhabdomyosarcoma, and Burkitt lymphoma appeared to be associated with a higher risk.
|Predisposing Therapy||Gastrointestinal Effects||Health Screening/Interventions|
|GVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph).|
|Radiation impacting esophagus; hematopoietic cell transplantation with any history of chronic GVHD||Esophageal stricture||History: dysphagia, heart burn|
|Esophageal dilation, antireflux surgery|
|Radiation impacting bowel||Chronic enterocolitis; fistula; strictures||History: nausea, vomiting, abdominal pain, diarrhea|
|Serum protein and albumin levels yearly in patients with chronic diarrhea or fistula|
|Surgical and/or gastroenterology consultation for symptomatic patients|
|Radiation impacting bowel; laparotomy||Bowel obstruction||History: abdominal pain, distention, vomiting, constipation|
|Exam: tenderness, abdominal guarding, distension (acute episode)|
|Obtain KUB in patients with clinical symptoms of obstruction|
|Surgical consultation in patients unresponsive to medical management|
|Pelvic surgery; cystectomy||Fecal incontinence||History: chronic constipation, fecal soiling|
Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities. Because many chemotherapy agents and radiation are hepatotoxic, transient liver function anomalies are common during therapy. Severe acute hepatic complications occur rarely. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury. Some general concepts regarding hepatotoxicity related to childhood cancer include the following:
- The risk of long-term hepatotoxicity is not well defined.
- Children with primary liver tumors requiring significant lever resection, or even transplant, are at higher risk for liver injury.
- Children receiving irradiation to the liver are at higher risk for liver injury.
- Children undergoing bone marrow transplant are at higher risk for liver injury.
- Certain factors, including the type of chemotherapy, the dose and extent of radiation exposure, the influence of surgical interventions, and the evolving impact of viral hepatitis and/or other infectious complication, need additional attention in future studies.
Types of hepatobiliary complications
- Asymptomatic elevations of blood biomarkers. Blood biomarkers include the following: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT). Liver injury related to treatment for childhood cancer is often asymptomatic and indolent in course. Dutch investigators observed hepatobiliary dysfunction in 8.7% of 1,362 long-term survivors (12.4 years of median follow-up since diagnosis) evaluated by ALT for hepatocellular injury and GGT for biliary tract injury. Cases with a history of viral hepatitis and a history of veno-occlusive disease were excluded. Predictors for elevated ALT and GGT by multivariable analysis included treatment with radiation therapy involving the liver, higher body mass index (BMI), higher alcohol intake, and longer follow-up time; older age at diagnosis was only signiﬁcantly associated with elevated GGT levels. In a CCSS report, survivors of childhood cancer were more than two times more likely to report a hepatic-related health issue and were nearly nine times more likely to report cirrhosis, compared with sibling controls.
Less commonly reported hepatobiliary complications include the following:
- Cholelithiasis. In limited studies, an increased risk of cholelithiasis has been linked to ileal conduit, parenteral nutrition, abdominal surgery, abdominal radiation, and HSCT.[38,39] Gallbladder disease was the most frequent late-onset liver condition reported among participants in the CCSS, and they had a twofold excess risk compared with sibling controls (RR, 2.0; 95% CI, 2.0–40.0).
- Focal nodular hyperplasia. Lesions made up of regenerating liver called focal nodular hyperplasia have been incidentally noted after chemotherapy or HSCT.[40,41] These lesions are thought to be iatrogenic manifestations of vascular damage and have been associated with veno-occlusive disease, high-dose alkylating agents (e.g., busulfan and melphalan), and liver irradiation. The prevalence of this finding is unknown; while noted at less than 1% in some papers, this is likely an underestimate. In one study of patients who were followed by magnetic resonance imaging (MRI) after transplant to assess liver iron stores, the cumulative incidence was 35% at 150 months posttransplant. The lesions can mimic metastatic or subsequent tumors, but MRI imaging is generally diagnostic, and unless the lesions grow or patients have worrisome symptoms, biopsy or resection is generally not necessary.
- Nodular regenerative hyperplasia. Nodular regenerative hyperplasia is a rare condition characterized by the development of multiple monoacinar regenerative hepatic nodules and mild fibrosis. The pathogenesis is not well established but may represent a nonspecific tissue adaptation to heterogeneous hepatic blood flow. Nodular regenerative hyperplasia has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver irradiation.[43,44] Biopsy may be necessary to distinguish nodular regenerative hyperplasia from a subsequent malignancy.
- Microvesicular fatty change. In a cohort who recently completed intensified therapy for acute lymphoblastic leukemia, histologic evidence of fatty infiltration was noted in 93% and siderosis in up to 70% of patients. Fibrosis developed in 11% and was associated with higher serum low-density lipoprotein (LDL) cholesterol. Fatty liver with insulin resistance has also been reported to develop more frequently in long-term childhood cancer survivors treated with cranial irradiation before allogeneic stem cell transplantation who were not overweight or obese. Prospective studies are needed to define whether acute posttherapy fatty liver change contributes to the development of steatohepatitis or the metabolic syndrome in this population.
- Transfusion-related iron overload. Red blood cell transfusions can result in an accumulation of excess iron due to disruption of the homeostasis of iron storage and distribution when exogenous iron is loaded into organs. Transfusional iron overload has been reported in pediatric oncology patients, but its prevalence, organ distribution, and severity remain incompletely characterized. MRI has emerged as an accurate, noninvasive means for measuring iron in multiple organ systems.[47,48] In a cross-sectional study of 75 patients (4.4 years of median follow-up time; 4.9 years since last transfusion), MRI iron concentrations were elevated in the liver (49.3%) and pancreas (26.4%), but not in the heart. In a multivariable analysis, cumulative packed red blood cell volume and older age at diagnosis predicted elevated liver iron concentration. Further research is needed to better characterize survivors at risk of clinically significant transfusion-related iron overload who may benefit from interventions to reduce iron loading and organ dysfunction.
Treatment-related risk factors for hepatobiliary complications
The type and intensity of previous therapy influences risk for late-occurring hepatobiliary complications. In addition to the risk of treatment-related toxicity, recipients of HSCT frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and other toxic etiologies.
- Chemotherapy. Chemotherapeutic agents with established hepatotoxic potential include antimetabolite agents like 6-mercaptopurine, 6-thioguanine, methotrexate, and rarely, dactinomycin. Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) and cholestatic disease have been observed after thiopurine administration, especially 6-thioguanine. Progressive fibrosis and portal hypertension has been reported in a subset of children who developed VOD/SOS after treatment with 6-thioguanine.[49-51] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[52,53]
In the transplant setting, VOD/SOS has also been observed after conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide and carmustine/cyclophosphamide/etoposide. Because high-dose cyclophosphamide is common to all of these regimens, toxic cyclophosphamide metabolites resulting from the agent’s variable metabolism have been speculated as a causative factor.
- Radiation therapy. Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS. In adults, the whole liver has tolerance up to 30 Gy to 35 Gy with conventional fractionation, the prevalence of radiation-induced liver disease varies from 6% to 66% based on the volume of liver involved and on hepatic reserve.[55,56]
Based on limited data from pediatric cohorts treated in the 1970s and 1980s, persistent radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload. The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, previous partial hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin.[58-61] Survivors who received radiation doses of 40 Gy to at least one-third of liver volume, doses of 30 Gy or more to whole abdomen, or an upper abdominal field involving the entire liver are at highest risk for hepatic dysfunction.
- Hematopoietic stem cell transplantation. Chronic liver dysfunction in patients undergoing HSCT is multifactorial in etiology. The most common etiologies for chronic liver dysfunction include iron overload, chronic GVHD, and viral hepatitis. Patients with chronic GVHD of the GI tract who exhibit an elevated bilirubin have a worse prognosis and quality of life. While chronic liver dysfunction may be seen in more than half of long-term stem cell transplantation survivors, the course of the disease is mild and indolent in most patients.
Infectious risk factors for hepatobiliary complications
Viral hepatitis B and C may complicate the treatment course of childhood cancer and result in chronic hepatic dysfunction. Hepatitis B tends to have a more aggressive acute clinical course and a lower rate of chronic infection. Hepatitis C is characterized by a mild acute infection and a high rate of chronic infection. The incidence of transfusion-related hepatitis C in childhood cancer survivors has ranged from 5% to 50% depending on the geographic location of the reporting center.[66-72]
Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Because most patients received some type of blood product during childhood cancer treatment and many are unaware of their transfusion history, screening based on date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products. Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B, and all children who received blood transfusions before 1993 should be screened for hepatitis C and referred for discussion of treatment options.
Survivors with liver dysfunction should be counseled regarding risk-reduction methods to prevent hepatic injury. Standard recommendations include maintenance of a healthy body weight, abstinence from alcohol use, and immunization against hepatitis A and B viruses. In patients with chronic hepatitis, precautions to reduce viral transmission to household and sexual contacts should also be reviewed.
|Predisposing Therapy||Hepatic Effects||Health Screening/Interventions|
|ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.|
|Methotrexate; mercaptopurine/thioguanine; HSCT||Hepatic dysfunction||Lab: ALT, AST, bilirubin levels|
|Ferritin in those treated with HSCT|
|Mercaptopurine/thioguanine; HSCT||Veno-occlusive disease/sinusoidal obstructive syndrome||Exam: scleral icterus, jaundice, ascites, hepatomegaly, splenomegaly|
|Lab: ALT, AST, bilirubin, platelet levels|
|Ferritin in those treated with HSCT|
|Radiation impacting liver/biliary tract; HSCT||Hepatic fibrosis/cirrhosis||Exam: jaundice, spider angiomas, palmar erythema, xanthomata hepatomegaly, splenomegaly|
|Lab: ALT, AST, bilirubin levels|
|Ferritin in those treated with HSCT|
|Prothrombin time for evaluation of hepatic synthetic function in patients with abnormal liver screening tests|
|Screen for viral hepatitis in patients with persistently abnormal liver function or any patient transfused before 1993|
|Gastroenterology/hepatology consultation in patients with persistent liver dysfunction|
|Hepatitis A and B immunizations in patients lacking immunity|
|Consider phlebotomy and chelation therapy for iron overload|
|Radiation impacting liver/biliary tract||Cholelithiasis||History: colicky abdominal pain related to fatty food intake, excessive flatulence|
|Exam: right upper quadrant or epigastric tenderness (acute episode)|
|Consider gallbladder ultrasound in patients with chronic abdominal pain|
The pancreas has been thought to be relatively radioresistant because of a paucity of information about late pancreatic-related effects. However, children and young adults treated with TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus.[74-76]
A summary of the results of selected cancer cohort studies supporting this association include the following:
- A retrospective cohort study, based on self-reports of 2,520 5-year survivors of childhood cancer treated in France and the United Kingdom, investigated the relationship between radiation dose to the pancreas and risk of a subsequent diabetes mellitus diagnosis. Sixty-five cases of diabetes mellitus were validated; the risk increased with radiation to the tail of the pancreas, where the islets of Langerhans are concentrated. Risk increased up to 20 to 29 Gy and then plateaued. The estimated RR at 1 Gy was 1.61. Radiation dose to other parts of the pancreas did not have a significant effect. Compared with patients who did not receive radiation, the RR of diabetes mellitus was 11.5 in patients who received more than 10 Gy to the pancreas. Children younger than 2 years at the time of radiation were more sensitive than were older patients (RR at 1 Gy was 2.1 for the young age group vs. 1.4 for older patients). For the 511 patients who received more than 10 Gy, the cumulative incidence of diabetes mellitus was 16%.
- Another study evaluated the risk of diabetes mellitus in 2,264 5-year survivors of Hodgkin lymphoma (42% younger than 25 years at diagnosis) After a median follow-up of 21.5 years, the cumulative incidence of diabetes mellitus was 8.3% (95% CI, 6.9%–9.8%) for the overall cohort and 14.2% (95% CI, 10.7%–18.3%) for those treated with more than 36 Gy para-aortic radiation. Survivors treated with more than 36 Gy of radiation to the para-aortic lymph nodes and spleen had a 2.3-fold increased risk of diabetes mellitus compared with those who did not receive radiation. The risk of diabetes mellitus increased with higher doses to the pancreatic tail.
- In a report from the CCSS that compared 8,599 childhood cancer survivors to 2,936 randomly selected sibling controls, and after adjustment for age, BMI, and several demographic factors, the risk of diabetes mellitus was 1.8 times higher in survivors (95% CI, 1.3–2.5; P < .001). Significant associations were found between diabetes mellitus and young age at diagnosis (0–4 years), the use of alkylating agents, and TBI or abdominal radiation. Also, survivors were significantly more likely to be receiving medication for hypertension, dyslipidemia, and/or diabetes mellitus than were sibling controls.
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for digestive system late effects information including risk factors, evaluation, and health counseling.
- Hölttä P, Alaluusua S, Saarinen-Pihkala UM, et al.: Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children. Cancer 103 (1): 181-90, 2005. [PUBMED Abstract]
- Hölttä P, Hovi L, Saarinen-Pihkala UM, et al.: Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer 103 (7): 1484-93, 2005. [PUBMED Abstract]
- Kaste SC, Goodman P, Leisenring W, et al.: Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study. Cancer 115 (24): 5817-27, 2009. [PUBMED Abstract]
- Paulino AC: Role of radiation therapy in parameningeal rhabdomyosarcoma. Cancer Invest 17 (3): 223-30, 1999. [PUBMED Abstract]
- Paulino AC, Simon JH, Zhen W, et al.: Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48 (5): 1489-95, 2000. [PUBMED Abstract]
- Maciel JC, de Castro CG Jr, Brunetto AL, et al.: Oral health and dental anomalies in patients treated for leukemia in childhood and adolescence. Pediatr Blood Cancer 53 (3): 361-5, 2009. [PUBMED Abstract]
- Hsieh SG, Hibbert S, Shaw P, et al.: Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy. Cancer 117 (10): 2219-27, 2011. [PUBMED Abstract]
- Dahllöf G: Oral and dental late effects after pediatric stem cell transplantation. Biol Blood Marrow Transplant 14 (1 Suppl 1): 81-3, 2008. [PUBMED Abstract]
- Hölttä P, Alaluusua S, Saarinen-Pihkala UM, et al.: Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation. Bone Marrow Transplant 29 (2): 121-7, 2002. [PUBMED Abstract]
- Maguire A, Craft AW, Evans RG, et al.: The long-term effects of treatment on the dental condition of children surviving malignant disease. Cancer 60 (10): 2570-5, 1987. [PUBMED Abstract]
- Alpaslan G, Alpaslan C, Gögen H, et al.: Disturbances in oral and dental structures in patients with pediatric lymphoma after chemotherapy: a preliminary report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87 (3): 317-21, 1999. [PUBMED Abstract]
- Kaste SC, Hopkins KP, Jones D, et al.: Dental abnormalities in children treated for acute lymphoblastic leukemia. Leukemia 11 (6): 792-6, 1997. [PUBMED Abstract]
- O'Sullivan EA, Duggal MS, Bailey CC: Changes in the oral health of children during treatment for acute lymphoblastic leukaemia. Int J Paediatr Dent 4 (1): 31-4, 1994. [PUBMED Abstract]
- Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010. [PUBMED Abstract]
- Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 18 (8): 1061-79, 2010. [PUBMED Abstract]
- Garming Legert K, Remberger M, Ringdèn O, et al.: Salivary secretion in children after fractionated or single-dose TBI. Bone Marrow Transplant 47 (3): 404-10, 2012. [PUBMED Abstract]
- Dahllöf G, Wondimu B, Barr-Agholme M, et al.: Xerostomia in children and adolescents after stem cell transplantation conditioned with total body irradiation or busulfan. Oral Oncol 47 (9): 915-9, 2011. [PUBMED Abstract]
- Garming-Legert K, Remberger M, Ringdén O, et al.: Long-term salivary function after conditioning with busulfan, fractionated or single-dose TBI. Oral Dis 17 (7): 670-6, 2011. [PUBMED Abstract]
- Raney RB, Asmar L, Vassilopoulou-Sellin R, et al.: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 33 (4): 362-71, 1999. [PUBMED Abstract]
- Gevorgyan A, La Scala GC, Neligan PC, et al.: Radiation-induced craniofacial bone growth disturbances. J Craniofac Surg 18 (5): 1001-7, 2007. [PUBMED Abstract]
- Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010. [PUBMED Abstract]
- Yeazel MW, Gurney JG, Oeffinger KC, et al.: An examination of the dental utilization practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Public Health Dent 64 (1): 50-4, 2004. [PUBMED Abstract]
- Goldsby R, Chen Y, Raber S, et al.: Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. Gastroenterology 140 (5): 1464-71.e1, 2011. [PUBMED Abstract]
- Skou AS, Glosli H, Jahnukainen K, et al.: Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. Pediatr Blood Cancer 61 (9): 1638-43, 2014. [PUBMED Abstract]
- Bölling T, Willich N, Ernst I: Late effects of abdominal irradiation in children: a review of the literature. Anticancer Res 30 (1): 227-31, 2010. [PUBMED Abstract]
- Churnratanakul S, Wirzba B, Lam T, et al.: Radiation and the small intestine. Future perspectives for preventive therapy. Dig Dis 8 (1): 45-60, 1990. [PUBMED Abstract]
- Sher ME, Bauer J: Radiation-induced enteropathy. Am J Gastroenterol 85 (2): 121-8, 1990. [PUBMED Abstract]
- Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21 (1): 109-22, 1991. [PUBMED Abstract]
- Donaldson SS, Jundt S, Ricour C, et al.: Radiation enteritis in children. A retrospective review, clinicopathologic correlation, and dietary management. Cancer 35 (4): 1167-78, 1975. [PUBMED Abstract]
- Heyn R, Raney RB Jr, Hays DM, et al.: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10 (4): 614-23, 1992. [PUBMED Abstract]
- Hughes LL, Baruzzi MJ, Ribeiro RC, et al.: Paratesticular rhabdomyosarcoma: delayed effects of multimodality therapy and implications for current management. Cancer 73 (2): 476-82, 1994. [PUBMED Abstract]
- Paulino AC, Wen BC, Brown CK, et al.: Late effects in children treated with radiation therapy for Wilms' tumor. Int J Radiat Oncol Biol Phys 46 (5): 1239-46, 2000. [PUBMED Abstract]
- Raney B Jr, Heyn R, Hays DM, et al.: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the Intergroup Rhabdomyosarcoma Study Committee. Cancer 71 (7): 2387-94, 1993. [PUBMED Abstract]
- Ritchey ML, Kelalis PP, Etzioni R, et al.: Small bowel obstruction after nephrectomy for Wilms' tumor. A report of the National Wilms' Tumor Study-3. Ann Surg 218 (5): 654-9, 1993. [PUBMED Abstract]
- Aguayo P, Ho B, Fraser JD, et al.: Bowel obstruction after treatment of intra-abdominal tumors. Eur J Pediatr Surg 20 (4): 234-6, 2010. [PUBMED Abstract]
- Mulder RL, van Dalen EC, Van den Hof M, et al.: Hepatic late adverse effects after antineoplastic treatment for childhood cancer. Cochrane Database Syst Rev (7): CD008205, 2011. [PUBMED Abstract]
- Mulder RL, Kremer LC, Koot BG, et al.: Surveillance of hepatic late adverse effects in a large cohort of long-term survivors of childhood cancer: prevalence and risk factors. Eur J Cancer 49 (1): 185-93, 2013. [PUBMED Abstract]
- Mahmoud H, Schell M, Pui CH: Cholelithiasis after treatment for childhood cancer. Cancer 67 (5): 1439-42, 1991. [PUBMED Abstract]
- Safford SD, Safford KM, Martin P, et al.: Management of cholelithiasis in pediatric patients who undergo bone marrow transplantation. J Pediatr Surg 36 (1): 86-90, 2001. [PUBMED Abstract]
- Sudour H, Mainard L, Baumann C, et al.: Focal nodular hyperplasia of the liver following hematopoietic SCT. Bone Marrow Transplant 43 (2): 127-32, 2009. [PUBMED Abstract]
- Lee MH, Yoo SY, Kim JH, et al.: Hypervascular hepatic nodules in childhood cancer survivors: clinical and imaging features. Clin Imaging 36 (4): 301-7, 2012 Jul-Aug. [PUBMED Abstract]
- Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 11 (5): 787-97, 1990. [PUBMED Abstract]
- Brisse H, Servois V, Bouche B, et al.: Hepatic regenerating nodules: a mimic of recurrent cancer in children. Pediatr Radiol 30 (6): 386-93, 2000. [PUBMED Abstract]
- Chu WC, Roebuck DJ: Nodular regenerative hyperplasia of the liver simulating metastases following treatment for bilateral Wilms tumor. Med Pediatr Oncol 41 (1): 85-7, 2003. [PUBMED Abstract]
- Halonen P, Mattila J, Ruuska T, et al.: Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings. Med Pediatr Oncol 40 (3): 148-54, 2003. [PUBMED Abstract]
- Tomita Y, Ishiguro H, Yasuda Y, et al.: High incidence of fatty liver and insulin resistance in long-term adult survivors of childhood SCT. Bone Marrow Transplant 46 (3): 416-25, 2011. [PUBMED Abstract]
- Ruccione KS, Wood JC, Sposto R, et al.: Characterization of transfusion-derived iron deposition in childhood cancer survivors. Cancer Epidemiol Biomarkers Prev 23 (9): 1913-9, 2014. [PUBMED Abstract]
- Vag T, Kentouche K, Krumbein I, et al.: Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results. Pediatr Radiol 41 (8): 980-4, 2011. [PUBMED Abstract]
- Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005. [PUBMED Abstract]
- De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006. [PUBMED Abstract]
- Rawat D, Gillett PM, Devadason D, et al.: Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia. J Pediatr Gastroenterol Nutr 53 (5): 478-9, 2011. [PUBMED Abstract]
- Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. J Clin Oncol 8 (9): 1525-30, 1990. [PUBMED Abstract]
- Sulis ML, Bessmertny O, Granowetter L, et al.: Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma. J Pediatr Hematol Oncol 26 (12): 843-6, 2004. [PUBMED Abstract]
- McDonald GB: Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 51 (4): 1450-60, 2010. [PUBMED Abstract]
- Dawson LA, Ten Haken RK: Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 15 (4): 279-83, 2005. [PUBMED Abstract]
- Milano MT, Constine LS, Okunieff P: Normal tissue tolerance dose metrics for radiation therapy of major organs. Semin Radiat Oncol 17 (2): 131-40, 2007. [PUBMED Abstract]
- Pan CC, Kavanagh BD, Dawson LA, et al.: Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S94-100, 2010. [PUBMED Abstract]
- Bhanot P, Cushing B, Philippart A, et al.: Hepatic irradiation and adriamycin cardiotoxicity. J Pediatr 95 (4): 561-3, 1979. [PUBMED Abstract]
- Flentje M, Weirich A, Pötter R, et al.: Hepatotoxicity in irradiated nephroblastoma patients during postoperative treatment according to SIOP9/GPOH. Radiother Oncol 31 (3): 222-8, 1994. [PUBMED Abstract]
- Kun LE, Camitta BM: Hepatopathy following irradiation and adriamycin. Cancer 42 (1): 81-4, 1978. [PUBMED Abstract]
- Tefft M: Radiation related toxicities in National Wilms' Tumor Study Number 1. Int J Radiat Oncol Biol Phys 2 (5-6): 455-63, 1977 May-Jun. [PUBMED Abstract]
- Castellino S, Muir A, Shah A, et al.: Hepato-biliary late effects in survivors of childhood and adolescent cancer: a report from the Children's Oncology Group. Pediatr Blood Cancer 54 (5): 663-9, 2010. [PUBMED Abstract]
- Levitsky J, Sorrell MF: Hepatic complications of hematopoietic cell transplantation. Curr Gastroenterol Rep 9 (1): 60-5, 2007. [PUBMED Abstract]
- Pidala J, Chai X, Kurland BF, et al.: Analysis of gastrointestinal and hepatic chronic graft-versus-host [corrected] disease manifestations on major outcomes: a chronic graft-versus-host [corrected] disease consortium study. Biol Blood Marrow Transplant 19 (5): 784-91, 2013. [PUBMED Abstract]
- Tomás JF, Pinilla I, García-Buey ML, et al.: Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 26 (6): 649-55, 2000. [PUBMED Abstract]
- Aricò M, Maggiore G, Silini E, et al.: Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 84 (9): 2919-22, 1994. [PUBMED Abstract]
- Castellino S, Lensing S, Riely C, et al.: The epidemiology of chronic hepatitis C infection in survivors of childhood cancer: an update of the St Jude Children's Research Hospital hepatitis C seropositive cohort. Blood 103 (7): 2460-6, 2004. [PUBMED Abstract]
- Cesaro S, Petris MG, Rossetti F, et al.: Chronic hepatitis C virus infection after treatment for pediatric malignancy. Blood 90 (3): 1315-20, 1997. [PUBMED Abstract]
- Fink FM, Höcker-Schulz S, Mor W, et al.: Association of hepatitis C virus infection with chronic liver disease in paediatric cancer patients. Eur J Pediatr 152 (6): 490-2, 1993. [PUBMED Abstract]
- Locasciulli A, Testa M, Pontisso P, et al.: Hepatitis C virus genotypes and liver disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 19 (3): 237-40, 1997. [PUBMED Abstract]
- Locasciulli A, Testa M, Pontisso P, et al.: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90 (11): 4628-33, 1997. [PUBMED Abstract]
- Paul IM, Sanders J, Ruggiero F, et al.: Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease. Blood 93 (11): 3672-7, 1999. [PUBMED Abstract]
- Lansdale M, Castellino S, Marina N, et al.: Knowledge of hepatitis C virus screening in long-term pediatric cancer survivors: a report from the Childhood Cancer Survivor Study. Cancer 116 (4): 974-82, 2010. [PUBMED Abstract]
- van Waas M, Neggers SJ, Raat H, et al.: Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7 (12): e52237, 2012. [PUBMED Abstract]
- Neville KA, Cohn RJ, Steinbeck KS, et al.: Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 91 (11): 4401-7, 2006. [PUBMED Abstract]
- Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
- de Vathaire F, El-Fayech C, Ben Ayed FF, et al.: Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol 13 (10): 1002-10, 2012. [PUBMED Abstract]
- van Nimwegen FA, Schaapveld M, Janus CP, et al.: Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J Clin Oncol 32 (29): 3257-63, 2014. [PUBMED Abstract]
- Meacham LR, Chow EJ, Ness KK, et al.: Cardiovascular risk factors in adult survivors of pediatric cancer--a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 19 (1): 170-81, 2010. [PUBMED Abstract]