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Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

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Late Effects of the Digestive System

Dental

Overview

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:
Osteoradionecrosis and second cancers in the oral cavity also occur.

Abnormalities of tooth development

Abnormalities of dental development reported in childhood cancer survivors include the following:[1-11]
  • Absence of tooth development.
  • Hypodontia.
  • Microdontia.
  • Enamel hypoplasia.
  • Root malformation.
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 the following:[3,11]
  • Head and neck radiation therapy.
  • Any chemotherapy.
  • Hematopoietic stem cell transplantation (HSCT).
Children younger than 5 years are at greatest risk for dental anomalies, including 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.[3]
Key findings related to cancer treatment effect on tooth development include the following:
  1. Radiation therapy. 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.[3,5,6,12] However, the most significant degree of tooth aplasia or delayed eruption occurs in younger children (aged <4 years) who are exposed to radiation doses of 20 Gy or higher.[13]
    Developing teeth may be irradiated in the course of treating head and neck sarcomas, Hodgkin lymphoma, neuroblastoma, central nervous system leukemia, nasopharyngeal cancer, brain tumors, 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.[14] 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 higher than 40 Gy.[4,5]
  2. Chemotherapy. Chemotherapy, especially exposure to alkylating agents, can affect tooth development.[3,6,7] Chemotherapy for the treatment of leukemia or neuroblastoma is associated with shortening and thinning of the premolar roots and enamel abnormalities.[15-17] 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.[3]
  3. HSCT. 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.[9] Dental abnormalities have been reported in patients who underwent HSCT without TBI, particularly in patients younger than 2 years at the time of the transplant.[18]

Salivary gland dysfunction

Xerostomia, the sensation of dry mouth, is a potential side effect after head and neck irradiation or HSCT that can severely impact quality of life. Complications of reduced salivary secretion include the following:[19,20]
  • Increased caries.
  • Susceptibility to oral infections.
  • Sleep disturbances.
  • Difficulties with chewing, swallowing, and speaking.
The prevalence of salivary gland dysfunction after cancer treatment varies based on measurement techniques (patient report vs. stimulated or unstimulated salivary secretion rates).[21] In general, the prevalence of self-reported persistent posttherapy xerostomia is low 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.[3]
Key findings related to cancer treatment effect on salivary gland function include the following:
  1. Radiation therapy. 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.[19]
  2. HSCT. 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.[22] In contrast, in another study, the prevalence of reduced salivary secretion did not differ among long-term survivors on the basis of the conditioning regimen (single-dose TBI, 47%; fractionated TBI, 47%; busulfan, 42%).[23]
  3. Chemotherapy. The association of chemotherapy alone with xerostomia remains controversial.[19] 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, an increase in dental caries was not noted and patient-reported xerostomia was not evaluated.[7]
The impact of infectious complications and alterations in the microflora during and after therapy is not known.[6]

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.[5,24,25] 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.
Osteoradionecrosis of the jaw is a rare complication observed in childhood survivors treated with high-dose craniofacial radiation (>40 Gy), particularly after dental extractions in irradiated mandibles.[26,27]
Remediation of cosmetic and functional abnormalities often requires multiple surgical interventions.

Posttherapy management

Some studies suggest that fluoride products or chlorhexidine rinses may be beneficial in patients who have undergone radiation therapy.[28] 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.[20]
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.[29] The Children’s Oncology Group Long-term Follow-Up GuidelinesExit Disclaimer 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.)
Table 4 summarizes oral and dental late effects and the related health screenings.
Table 4. Oral/Dental Late Effectsa
Predisposing TherapyOral/Dental EffectsHealth Screening/Interventions
CT = computed tomography; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
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 x-ray 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 x-ray before dental procedures to evaluate root development
Referral to otolaryngologist for assistive devices for jaw opening
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
Referral for biopsy of suspicious lesions
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

Overview

The gastrointestinal (GI) tract is sensitive to the acute toxicities of chemotherapy, radiation therapy, 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.
Treatment-related late effects include the following:
  • Upper and lower digestive tract late effects associated with dose intensity of chemotherapy and/or abdominal radiation.
  • Adhesions secondary to abdominal surgery predisposing to postoperative bowel obstruction.
Digestive tract–related late effects include the following:
  • Esophageal dysmotility.
  • Esophageal stricture.
  • Gastroesophageal reflux.
  • Gastritis, enteritis, or colitis.
  • GI motility dysfunction (diarrhea, constipation, encopresis, bowel obstruction).
  • Subsequent malignant neoplasms

GI outcomes from selected cohort studies

Evidence (GI outcomes from selected cohort studies):
  1. Among 5-year childhood cancer survivors participating in the CCSS, the cumulative incidence of self-reported GI conditions was 37.6% at 20 years from cancer diagnosis (25.8% for upper GI complications and 15.5% for lower GI complications), 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.[30]
    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 therapy.
    • Abdominal surgery.
  2. A cohort study of children treated for acute myeloid leukemia with chemotherapy alone found that GI disorders were relatively rare and not significantly different from those reported by sibling controls.[31]
  3. 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.[32-34]
    In general, fractionated radiation doses of 20 Gy to 30 Gy can be delivered to the small bowel without significant long-term morbidity. Doses greater than 40 Gy are associated with a higher risk of bowel obstruction or chronic enterocolitis.[35] 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, bowel-injuring chemotherapy, and/or radiation therapy. Thus, these tumors would be expected to be particularly prone to long-term digestive tract issues.
A limited number of reports describe GI complications in pediatric patients with genitourinary solid tumors treated with radiation therapy:[36-40]
  1. 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 therapy and received additional interventions predisposing them to GI tract complications, including abdominal laparotomy in 43 patients (98%) and chemotherapy in 25 patients (57%).[36]
    • 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.
  2. The CCSS evaluated the incidence and risk of late-occurring intestinal obstruction requiring surgery in 12,316 5-year survivors (2,002 with and 10,314 without abdominopelvic tumors) and 4,023 siblings. The most common diagnoses among survivors with abdominopelvic tumors were Wilms tumors and neuroblastomas but also included soft tissue sarcomas, lymphomas, and bone tumors.[41]
    • The cumulative incidence of late intestinal obstruction requiring surgery at 35 years was 5.8% among survivors with abdominopelvic tumors, 1.0% among those without abdominopelvic tumors, and 0.3% among siblings.
    • Elevated risk of intestinal obstruction requiring surgery was associated with presence of an abdominopelvic tumor (adjusted rate ratio [ARR], 3.6; P < .001) and exposure to abdominal or pelvic radiation therapy within 5 years of cancer diagnosis (ARR, 2.4; P < .001).
    • Among survivors of abdominopelvic tumors, the median time from diagnosis to the first late intestinal obstruction requiring surgery was 12 years (range, 8–19 years).
    • Lymphoma resulted in the highest cumulative incidence of late-occurring intestinal obstruction requiring surgery (7.2% at 35 years after diagnosis).
  3. Childhood cancer survivors are at increased risk of late anorectal disease after pelvic radiation exposure. A report from the CCSS demonstrated the following results:[42]
    • Among survivors, pelvic radiation therapy higher than 30 Gy within 5 years of cancer diagnosis was associated with late-onset anorectal disease (ARR for 30–49.9 Gy vs. none, 1.6; ARR for ≥50 Gy vs. none, 5.4).
    • The most frequent anorectal disease reported was fistula-in-ano, followed by stricture and anorectal subsequent malignant neoplasm.
    • Late-onset anorectal disease was associated with psychological impairment in all domains, as characterized by increased emotional distress and impaired quality of life.
  4. Reports from the Intergroup Rhabdomyosarcoma Study evaluating GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma infrequently observed abnormalities of the irradiated bowel.[37,38,40]
    • 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.
Table 5 summarizes digestive tract late effects and the related health screenings.
Table 5. Digestive Tract Late Effectsa
Predisposing TherapyGastrointestinal EffectsHealth Screening/Interventions
GVHD = graft-versus-host disease; KUB = kidneys, ureter, bladder (plain abdominal radiograph).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Radiation impacting esophagus; hematopoietic cell transplantation with any history of chronic GVHDGastroesophageal reflux; esophageal dysmotility; esophageal 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

Overview

Hepatic complications resulting from childhood cancer therapy are observed primarily as acute treatment toxicities.[43] Because many chemotherapy agents and radiation are hepatotoxic, transient liver function anomalies are common during therapy. Severe acute hepatic complications rarely occur. Survivors of childhood cancer can occasionally exhibit long-standing hepatic injury.[44]
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 liver resection, or even transplant, are at higher risk of liver injury.
  • Children receiving radiation therapy to the liver are at higher risk of liver injury.
  • Children undergoing bone marrow transplant are at higher risk of 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 late effects

Asymptomatic elevation of liver enzymes is the most common hepatobiliary complication.
  • Asymptomatic elevation of liver enzymes. Liver injury related to treatment for childhood cancer is often asymptomatic and indolent in course. While elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT) levels can reflect transient acute liver injury during chemotherapy, they are not predictive of late hepatic dysfunction or cirrhosis.
    Dutch investigators observed hepatobiliary dysfunction in 8.7% of 1,362 long-term survivors (median follow-up, 12.4 years 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.[45] 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.[30]
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 therapy, and HSCT.[46,47] Gallbladder disease was the most frequent late-onset liver condition reported among participants in the CCSS, with a twofold excess risk compared with sibling controls (RR, 2.0; 95% CI, 2.0–40.0).[30]
  • Focal nodular hyperplasia. Lesions made up of regenerating liver called focal nodular hyperplasia have been incidentally noted on screening imaging studies after chemotherapy or HSCT.[48,49]
    These lesions are thought to be iatrogenic benign 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,[49] 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.[48]
    The lesions can mimic metastatic or subsequent tumors, but MRI imaging has a characteristic pattern and is generally diagnostic. Biopsy or resection is usually unnecessary unless the lesions grow or patients have worrisome symptoms.
  • Nodular regenerative hyperplasia.[50] 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.[51] Nodular regenerative hyperplasia has rarely been observed in survivors of childhood cancer treated with chemotherapy, with or without liver irradiation.[52,53]
    Biopsy may be necessary to distinguish nodular regenerative hyperplasia from a subsequent malignancy.
  • Microvesicular fatty change.[50] 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.[54] 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 therapy before allogeneic stem cell transplantation who were not overweight or obese.[55] Prospective studies are needed to define whether acute posttherapy fatty liver change contributes to the development of late steatohepatitis or the metabolic syndrome in this population.
  • Transfusion-related iron overload. Red blood cell transfusion 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.[56,57] 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.[56] Receipt of allogeneic transplantation is a significant risk factor.[58] A study of 116 childhood cancer survivors identified three patients (2.6%) with ferritin greater than 500 ng/mL. The total packed red blood cell volume correlated with elevated ferritin (r = 0.74; P < .0001).[59] Additional research is needed to better characterize survivors at risk of clinically significant transfusion-related iron overload who warrant interventions to reduce iron burden and organ dysfunction.

Treatment-related risk factors for hepatobiliary late effects

The type and intensity of previous therapy influences risk for late-occurring hepatobiliary effects. 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.
Key findings related to cancer treatment effect on hepatobiliary complications include the following:
  1. 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 have been reported in a subset of children who developed VOD/SOS after treatment with 6-thioguanine.[60-62] Acute, dose-related, reversible VOD/SOS has been observed in children treated with dactinomycin for pediatric solid tumors.[63,64]
    In the transplant setting, VOD/SOS has also been observed after conditioning regimens that have included cyclophosphamide/TBI, busulfan/cyclophosphamide, and carmustine/cyclophosphamide/etoposide.[65] High-dose cyclophosphamide, common to all of these regimens, is speculated to be a potential causative factor.
  2. Radiation therapy. Acute radiation-induced liver disease also causes endothelial cell injury that is characteristic of VOD/SOS.[66] 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.[66,67]
    Radiation hepatopathy after contemporary treatment appears to be uncommon in long-term survivors without predisposing conditions such as viral hepatitis or iron overload.[68] The dose threshold for irreversible injury is uncertain, but is being examined by the Pediatric Normal Tissue Effects in the Clinic (PENTEC)Exit Disclaimer initiative. 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 such as dactinomycin and doxorubicin.[69-72] 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.[44]
  3. HSCT. Chronic liver dysfunction in patients after HSCT is multifactorial in etiology. The most common etiologies for chronic liver dysfunction include iron overload, chronic GVHD, and viral hepatitis.[73] Patients with chronic GVHD of the GI tract who exhibit an elevated bilirubin have a worse prognosis and quality of life.[74] While chronic liver dysfunction may be seen in more than half of long-term stem cell transplantation survivors, and the course of the disease appears to be indolent, continued follow-up is needed to establish its long-term impact on survivor health.[75]

Infectious risk factors for hepatobiliary late effects

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.[76-82]
Chronic hepatitis predisposes the childhood cancer survivor to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Concurrent infection with hepatitis B and C in combination or in co-occurrence with other hepatotrophic 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 on the basis of date of diagnosis/treatment is recommended unless there is absolute certainty that the patient did not receive any blood or blood products.[83] Therefore, all survivors of childhood cancer who received treatment before 1972 should be screened for hepatitis B, and those who received treatment before 1993 should be screened for hepatitis C and referred for discussion of treatment options if screening results are positive.

Posttherapy management

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 summarizes hepatobiliary late effects and the related health screenings.
Table 6. Hepatobiliary Late Effectsa
Predisposing TherapyHepatic EffectsHealth Screening/Interventions
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
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/cirrhosis; focal nodular hyperplasiaExam: 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 TBI or abdominal irradiation are known to have an increased risk of insulin resistance and diabetes mellitus.[84-86] While corticosteroids and asparaginase are associated with acute toxicity to the pancreas, late sequelae in the form of exocrine or endocrine pancreatic function for those who sustain acute injury have not been reported.
Evidence (risk of diabetes mellitus):
  1. 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.[87]
    • Sixty-five cases of diabetes mellitus were validated; the risk increased with radiation therapy 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 therapy, 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 therapy 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%.
  2. 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.[88]
    • 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 therapy.
    • The risk of diabetes mellitus increased with higher doses to the pancreatic tail.
  3. CCSS investigators evaluated the risk of diabetes mellitus among 20,762 5-year childhood cancer survivors and 4,853 siblings.[89]
    • Survivors exposed to abdominal radiation (n = 4,568) were almost three times more likely to develop diabetes than were siblings and 1.6 times more likely than survivors who were not exposed to abdominal radiation.
    • Among survivors treated with abdominal radiation therapy, multivariable modeling identified independent risk factors for developing diabetes, which included older attained age, higher BMI, and increasing dose to the pancreatic tail.
    • A significant interaction was also identified between younger age (<10 years) at cancer diagnosis and higher mean pancreatic tail dose.
  4. St. Jude Lifetime Cohort investigators evaluated the prevalence of and risk factors for diabetes mellitus among 1,044 adult survivors of childhood acute lymphoblastic leukemia (mean age, 34 years) who were clinically assessed more than 10 years after treatment and 368 community controls (mean age, 35 years).[90]
    • Type 2 diabetes mellitus was prevalent in 7.5% of survivors and 3.8% of controls.
    • Independent risk factors for developing diabetes among survivors included older age (odds ratio [OR], 1.05 for each additional year), body mass index of 30 kg/m2 or higher (OR, 7.4), and history of drug-induced hyperglycemia during therapy (OR, 4.67).
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer for digestive system late effects information including risk factors, evaluation, and health counseling.
References
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