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Late Effects of Treatment for Childhood Cancer (PDQ®)

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Late Effects of the Digestive System

Dental
Digestive Tract
Hepatobiliary
Pancreas



Dental

Both chemotherapy and radiation therapy can cause multiple cosmetic and functional abnormalities of dentition, most predominantly in children treated before age 5 years who have not yet developed deciduous dentition.[1-9] However, even older prepubertal children are at risk. Developing teeth are 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 20 Gy to 40 Gy can cause root shortening or abnormal curvature, dwarfism, and hypocalcification.[10] More than 85% of survivors of head and neck rhabdomyosarcoma who receive radiation doses greater than 40 Gy may have significant dental abnormalities, including mandibular or maxillary hypoplasia, increased caries, hypodontia, microdontia, root stunting, and xerostomia.[6,7]

Chemotherapy for the treatment of leukemia can cause shortening and thinning of the premolar roots and enamel abnormalities.[1,11,12] Childhood Cancer Survivor Study 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.[4] TBI has been linked to the development of short, V-shaped roots, microdontia, enamel hypoplasia, and premature apical closure.[2,3,13] The younger a patient is when treated with hematopoietic stem cell transplantation (HSCT), the more severely disturbed dental development will be and the more deficient vertical growth of the lower face will be. In children who have undergone HSCT, busulfan has been as deleterious to dental development and craniofacial growth as single-dose TBI.[14] Children who undergo bone marrow transplantation with TBI for neuroblastoma are at substantial risk for a spectrum of abnormalities and require close surveillance and appropriate interventions.[15]

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.[16] Dental caries are the most problematic consequence. The use of topical fluoride can dramatically reduce the frequency of caries, and saliva substitutes and sialagogues can ameliorate sequelae such as xerostomia.[17]

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.[18] These findings give health care providers further impetus to encourage routine dental 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 and cancer patients.)

Table 4. Oral/Dental Late Effects
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 cavityDental developmental abnormalities; tooth/root agenesis; microdontia; root thinning/shortening; enamel dysplasiaDental 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 cavityMalocclusion; temporomandibular joint dysfunctionDental 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 GVHDXerostomia/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)OsteoradionecrosisHistory: 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

Digestive Tract

Radiation and specific chemotherapeutic agents may produce gastrointestinal (GI) or hepatic toxicity that is acute and transient in the majority of patients, but rarely may be delayed and persistent. 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.[19-21] 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.[22] Sensitizing chemotherapeutic agents such as dactinomycin or anthracyclines can increase this risk.

A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation.[23-27] One study comprehensively evaluated intestinal symptoms in 44 children with cancer who underwent whole-abdominal (10 Gy to 40 Gy) and involved-field (25 Gy to 40 Gy) radiation and received additional interventions predisposing them to GI tract complications including abdominal laparotomy in 43 (98%) and chemotherapy in 25 (57%) patients.[23] Late small bowel obstruction was observed in 36% of patients surviving 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.[24,25,27] 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.[24,27] 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.[26,28] Among 5-year childhood cancer survivors participating in the Childhood Cancer Survivor Study (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 (relative risk [RR], 1.8; 95% confidence interval [CI], 1.6–2.0) and lower GI (RR, 1.9; 95% CI, 1.7–2.2) complications compared with sibling controls. Factors predicting higher risk of specific GI complications include older age at diagnosis, intensified therapy (anthracyclines for upper GI complications and alkylating agents for lower GI complications), abdominal radiation, and abdominal surgery.[29]

Table 5. Digestive Tract Late Effects
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 GVHDEsophageal strictureHistory: dysphagia, heart burn
Esophageal dilation, antireflux surgery
Radiation impacting bowelChronic enterocolitis; fistula; stricturesHistory: 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; laparotomyBowel obstructionHistory: 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; cystectomyFecal incontinenceHistory: chronic constipation, fecal soiling
Rectal exam

Hepatobiliary

Hepatic complications resulting from childhood cancer therapy are uncommon and observed primarily as acute treatment toxicities.[30] Dutch investigators observed hepatobiliary dysfunction in 8.7% of 1,362 long-term survivors (12.4 years median follow-up since diagnosis) evaluated by alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (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, higher alcohol intake, and longer follow-up time; older age at diagnosis was only significantly associated with elevated GGT levels.[31]

Recipients of HSCT are the exception to this rule because these individuals frequently experience chronic liver dysfunction related to microvascular, immunologic, infectious, metabolic, and toxic etiologies. 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.[32-34] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[35,36] In the transplant setting, VOD/SOS has also been observed after conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide and carmustine/cyclophosphamide/etoposide.[37] 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.

Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS.[38] 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.[38,39] 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.[40] The risk of injury in children increases with radiation dose, hepatic volume, younger age at treatment, prior partial hepatectomy, and concomitant use of radiomimetic chemotherapy like dactinomycin and doxorubicin.[41-44] 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.[45]

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.[46-52] Chronic hepatitis predisposes cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with both viruses accelerates the progression of liver disease. Since the majority of 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.[53] Therefore, all children who received blood transfusions before 1972 should be screened for hepatitis B and before 1993 should be screened for hepatitis C virus and referred for discussion of treatment options.

Less commonly reported hepatobiliary complications include cholelithiasis, focal nodular hyperplasia, nodular regenerative hyperplasia, and microvesicular fatty change. In limited studies, an increased risk of cholelithiasis has been linked to ileal conduit, parenteral nutrition, abdominal surgery, abdominal radiation, and HSCT.[54,55] 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).[29] Lesions made up of regenerating liver called focal nodular hyperplasia have been incidentally noted after chemotherapy or HSCT.[56,57] These lesions are thought to be iatrogenic manifestations of vascular damage and have been associated with VOD, high-dose alkylating agents (e.g., busulfan and melphalan), and liver radiation therapy. The prevalence of this finding is unknown, noted at less than 1% in some papers;[57] however, 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.[56] 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 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.[58] Nodular regenerative hyperplasia has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver radiation therapy.[59,60] Biopsy may be necessary to distinguish nodular regenerative hyperplasia from a subsequent malignancy.

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.[61] 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 radiation before allogeneic stem cell transplantation who were not overweight or obese.[62] 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. Likewise, information about the long-term outcomes of transfusion-related iron overload is lacking, especially among survivor cohorts who did not undergo hematopoietic cell transplantation.

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.

Table 6. Hepatobiliary Late Effects
Predisposing Therapy Hepatic Effects Health Screening/Interventions 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.
Methotrexate; mercaptopurine/thioguanine; HSCTHepatic dysfunctionLab: ALT, AST, bilirubin levels
Ferritin in those treated with HSCT
Mercaptopurine/thioguanine; HSCTVeno-occlusive disease/sinusoidal obstructive syndromeExam: scleral icterus, jaundice, ascites, hepatomegaly, splenomegaly
Lab: ALT, AST, bilirubin, platelet levels
Ferritin in those treated with HSCT
Radiation impacting liver/biliary tract; HSCTHepatic fibrosis/cirrhosisExam: 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 tractCholelithiasisHistory: 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

Pancreas

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 total-body or abdominal radiation are known to have an increased risk of insulin resistance and diabetes mellitus.

A retrospective cohort study, based on self-reports of 2,520 five-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 diagnosis. Sixty-five cases of diabetes 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 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 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 was 16%.[63]

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.

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