Liver
Chemotherapy Toxicity
There is little information about chronic persistent or latent hepatic dysfunction after chemotherapy treatment for childhood cancer.
The latency period before liver dysfunction becomes apparent is unknown. It is difficult to establish links between hepato-biliary disease in adulthood and prior cancer history.
Chemotherapy agents known to cause liver damage are:
- Antimetabolite agents:
- 6-mercaptopurine
- 6-thioguanine
- Methotrexate
- Dactinomycin (rare)
Thiopurines:
The antimetabolites, 6-thioguanine and 6-mercaptopurine are associated with subacute hepatocellular and cholestatic disease.
Some patients have an underlying genetic risk for acute toxicity with thiopurine S-methyltransferase (TPMT) deficiency.
The rare, but severe acute toxicity of these antimetabolites, and 6-thiguanine specifically is the occurrence of venoocclusive disease (VOD). VOD is also called sinusoidal obstruction syndrome (SOS).
Most children with the complication of thiopurine associated VOD recover, but a subset of patients have progressive fibrosis leading to:
- Portal hypertension
- Persistent hepatomegaly
- Splenomegaly
- Thrombocytopenia
Chronic viral hepatitis, TPMT homozygosity, and hemosiderosis contribute towards chronic fibrosis in these survivors.
Information from National Cancer Institute: Late Effects of Treatment for Childhood Cancer:
"New data suggests an association between thioguanine exposure and hepatotoxicity. In a phase III trial (CCG-1952) for ALL, 1,011 patients were randomized to treatment with thioguanine compared with mercaptopurine. There were 200 reports of hepatic veno-occlusive disease, but no fatalities were directly attributed to the syndrome. An additional 32 patients did not have full clinical features of veno-occlusive disease, but did have episodes of thrombocytopenia out of proportion to neutropenia and were felt to have a subclinical form of veno-occlusive disease. An additional 51 patients have developed persistent splenomegaly identified during the end of maintenance or during the first year off therapy, and 25% have documented portal hypertension. Similar results were reported by the United Kingdom Children’s Cooperative Group for their ALL study employing the use of thioguanine".
Methotrexate:
Acute and subacute methotrexate-induced hepatic injury is characterized by transient elevations of serum transaminases or alkaline phosphatase.
Biochemical changes do not consistently correlate with the severity of hepatic injury and the risk of this complication varies:
- Risk of fibrosis or cirrhosis is increased after daily oral methotrexate (over twice the risk) vs intermittent parenteral administration in some childhood leukemia treatment protocols.
- No reports of delayed hepatotoxicity in osteosarcoma survivors who receive shorter duration, high-dose methotrexate despite elevated transaminase levels during therapy.
- Leukemia survivors with viral hepatitis who received high-dose, parenteral or oral methotrexate regimens have an increased risk for progressive hepatic dysfunction which may persist into adulthood.
- Hepatic RT may contribute added risk for progression of late methotrexate hepatic sequelae.
In general hepatic histology in children after methotrexate therapy shows mild structural changes and low incidence of portal fibrosis.
Methotrexate-induced fibrosis regresses or stabilizes after stopping the drug and rarely produces end-stage liver disease in the absence of other antimetabolite therapy, or co-morbidities.
Dactinomycin:
Dactinomycin is associated with acute, dose related, reversible VOD/SOS in children treated for Wilms tumor and rhabdomyosarcoma.
Despite the acute hepatic dysfunction in the patients who did not receive RT, overall survival exceeded 80% in the National Wilms Tumor Study.
The prevalence of chronic liver disease with follow-up is unknown.
