Late hepatotoxicity after treatment for childhood cancer

Abstract

Contemporary treatment approaches have resulted in excellent cure rates for childhood cancer; however, these therapeutic advances are accompanied by adverse, long-term health outcomes, commonly referred to as late effects. Among these, late hepatic toxicity remains an underrecognized yet potentially serious consequence. Unlike acute liver injury, long-term hepatotoxicity often develops insidiously, with potential progression to severe morbidity or even life-threatening conditions. This review focuses on late hepatic adverse effects in childhood cancer survivors, highlighting the role of specific therapeutic exposures that compromise liver health. Early identification, monitoring, and timely intervention are essential to mitigate risk. Furthermore, long-term, multidisciplinary follow-up remains critical to improve quality of life in this growing population of survivors. Greater awareness and dedicated research are needed to address the burden of late therapy-related liver complications and to optimize survivorship care.

Key Words: Childhood cancer; Survivors; Late effects; Liver disease; Hepatotoxicity

Core Tip: Modern treatment regimens have markedly improved survival rates in children with cancer. However, these advances are accompanied by the risk of long-term health complications, collectively termed late effects. Among these, late hepatic toxicity remains under-investigated despite its potential to cause subtle, progressive, and even life-threatening liver damage. Given the silent nature of liver involvement, ongoing multidisciplinary follow-up of childhood cancer survivors is crucial for early detection, prevention, and timely intervention.

INTRODUCTION

Survival outcomes for pediatric cancer have improved dramatically in recent decades, with cure rates now exceeding 80% among children who receive contemporary therapies[1]. These therapeutic advances, however, are accompanied by the risk of long-term adverse physical and psychological outcomes, known as late effects, which may emerge months to years after treatment completion. Studies demonstrate that 60% to 90% of childhood cancer survivors (CCS) develop at least one chronic health problem, and 20%-80% of CCS encounter serious or life-threatening complications later in life[2].

Although many late effects of childhood cancer therapy are well documented, late hepatic complications remain understudied, with limited data on their prevalence and long-term outcomes. A recent Cochrane systematic review reported that the prevalence of late hepatic adverse effects, assessed by elevations in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), varies considerably, ranging from 1%-53%. This wide variation can be explained in part by differences in the definitions applied: Broader criteria, such as any ALT elevations, resulted in higher prevalence, whereas stricter thresholds, such as ALT greater than twice the upper limit of normal, resulted in lower rates. In addition, the included studies varied in their follow-up duration, with median times ranging from 3 to 23 years after cancer diagnosis, allowing more cumulative or late-onset hepatic complications to be detected in studies with longer surveillance. Further variability came from differences in the type of primary malignancy, treatment, patient-related risk factors, and underlying population characteristics across the studies, such as age at diagnosis and gender[3]. This editorial provides insights into late hepatotoxicity following childhood cancer treatment and underscores the importance of systematic evaluation and long-term monitoring of liver health in CCS, with the ultimate goal of improving their overall health outcomes and quality of life.

CLASSIFICATION AND GRADING OF LATE HEPATIC TOXICITY

Hepatic toxicity may be categorized, based on the timing of onset, as acute, subacute, chronic, and late. Acute hepatotoxicity typically occurs during or immediately after therapy and may manifest as aminotransferase elevations, sinusoidal obstruction syndrome (SOS), or cholestasis. Subacute hepatic toxicity is defined by injury arising 3 months to 6 months after treatment cessation, whereas chronic toxicity refers to injury persisting beyond 6 months. Late or delayed hepatotoxicity occurs months to years after the completion of therapy and is often asymptomatic, typically detected through routine long-term surveillance programs[3,4].

Late hepatic toxicity may be further classified according to patterns of liver injury, which reflect the underlying pathophysiologic mechanisms. These include hepatocellular injury, cholestatic injury, SOS, steatosis and nonalcoholic fatty liver disease, fibrosis and cirrhosis, and focal hepatic lesions[5,6].

Late hepatotoxicity may also be classified etiologically, based on the type of therapy received. This includes chemotherapy (e.g., thioguanine, methotrexate); hematopoietic stem cell transplantation (HSCT), which may be complicated by SOS, iron overload, or graft-versus-host disease (GVHD)-related cholestasis; radiotherapy, potentially resulting in radiation-induced liver disease; blood transfusions which can cause iron overload and secondary cirrhosis; and targeted therapies and immunotherapies, whose long-term hepatic adverse effects remain incompletely understood and warrant further investigation[6,7].

The Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, is the most widely used system for grading hepatic injury in cancer therapy, integrating both laboratory parameters and clinical findings[8]. Grading is primarily based on changes in AST, ALT, alkaline phosphatase (ALP), and bilirubin levels relative to baseline values and the upper limit of normal (Table 1). While CTCAE is primarily designed for use during active treatment, several studies have retrospectively applied it to classify the severity of late hepatotoxicity[9,10].

Table 1 Grading of hepatotoxicity by the common terminology criteria of adverse events v5.

Parameter/CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Alanine aminotransferase increased	> ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 3.0-5.0 × ULN ALT and/or AST > ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Alkaline phosphatase increased	> ULN - 2.5 × ULN if baseline was normal; 2.0-2.5 × baseline if baseline was abnormal	> 2.5-5.0 × ULN if baseline was normal; > 2.5-5.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Aspartate aminotransferase increased	> ULN - 3.0 × ULN if baseline was normal; 1.5-3.0 × baseline if baseline was abnormal	> 3.0-5.0 × ULN if baseline was normal; > 3.0-5.0 × baseline if baseline was abnormal	> 5.0-20.0 × ULN if baseline was normal; > 5.0-20.0 × baseline if baseline was abnormal	> 20.0 × ULN if baseline was normal; > 20.0 × baseline if baseline was abnormal
Blood bilirubin increased	> ULN - 1.5 × ULN if baseline was normal; > 1.0-1.5 × baseline if baseline was abnormal	> 1.5-3.0 × ULN if baseline was normal; > 1.5-3.0 × baseline if baseline was abnormal	> 3.0-10.0 × ULN if baseline was normal; > 3.0-10.0 × baseline if baseline was abnormal	> 10.0 × ULN if baseline was normal; > 10.0 × baseline if baseline was abnormal
Hepatic failure	–	–	Asterixis; mild encephalopathy; drug-induced liver injury; limiting self care ADL	Life-threatening consequences; moderate to severe encephalopathy; coma	Death
Hepatic necrosis				Life-threatening consequences; urgent invasive intervention indicated	Death

ADL: Activities of daily living; CTCAE: Common terminology criteria of adverse events; ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

The Children’s Oncology Group (COG) has developed long-term follow-up guidelines that provide a risk-based framework for evaluating late hepatic toxicity. These guidelines incorporate laboratory findings (e.g., persistent transaminase elevations), imaging results (e.g., FNH, fibrosis), and clinical outcomes (e.g., portal hypertension, liver failure). While the COG system does not assign numerical grades like CTCAE, it emphasizes clinical relevance, distinguishing between subclinical abnormalities and symptomatic disease[5].

In cases where liver biopsy is performed, histological grading systems such as METAVIR or Ishak scores may be applied to evaluate the degree of inflammation and fibrosis. While not routinely used in surveillance due to their invasive nature, these tools are valuable in research settings and in the evaluation of patients undergoing liver transplantation[11].

CHEMOTHERAPY-RELATED HEPATIC INJURY: MECHANISMS AND CLINICAL MANIFESTATION

The liver plays a central role in the metabolism of xenobiotics, including cytotoxic agents, rendering it particularly vulnerable to chemotherapy-induced injury. Hepatic damage may involve hepatocytes, but can also affect sinusoids, hepatic vasculature, and bile ducts[12].

A broad spectrum of cytotoxic agents has been associated with hepatotoxicity, with heterogeneous clinical and biochemical presentations. 6-mercaptopurine produces methyl-thioinosine nucleotides which are linked to dose-dependent hepatocyte and endothelial damage, while cytarabine can be directly toxic to hepatocytes via toxic metabolites[8]. Methotrexate depletes glutathione (GSH) and impairs mitochondrial respiration, along with the GSH-independent block of cellular respiration, leading to hepatocyte damage[13]. Doxorubicin undergoes redox cycling in hepatocytes, which results in generating large amounts of reactive oxygen species (ROS) and in activating apoptotic pathways. Consequently, doxorubicin produces hepatocellular necrosis and can contribute to fibrosis over time[14]. Dactinomycin is known to cause injury to sinusoidal endothelium which leads to swelling, obliteration of hepatic venules, and portal hypertension with centrilobular necrosis. In addition, it generates ROS in hepatocytes, thus damaging DNA and triggering pro-apoptotic signaling[15]. Cisplatin depletes GSH and generates ROS, activating NF-κB signaling and pro-inflammatory cytokines, while also simultaneously binding mitochondrial DNA, causing irreversible mtDNA damage and the release of proapoptotic factors[16,17]. Carboplatin hepatotoxicity is rare and idiosyncratic. The precise mechanism remains unclear. Busulfan forms reactive metabolites by being metabolized in the liver by GSH conjugation. This produces oxidative stress, whereas high-dose busulfan directly injures sinusoidal endothelium. Moreover, animal models show that busulfan, combined with cyclophosphamide, damages liver cells through NLRP3-inflammasome activation[18,19]. The active metabolite of irinotecan called SN-38 impairs mitochondrial function and autophagy, disrupting lipid metabolism. Furthermore, it causes mitochondrial ROS release in hepatocytes which promotes fatty change and inflammation in the liver[20]. Oxaliplatin-induced ROS cause oxidative injury to hepatocyte mitochondria and damage sinusoidal endothelial cells[21]. Paclitaxel damages the liver mainly through hypersensitivity reactions, yet it can additionally have a direct impact on microtubules[8]. Cyclophosphamide produces a toxic metabolite acrolein and depletes GSH, resulting in oxidative damage and interference with cytochrome enzymes[22]. Preclinical studies show that the liver activates the inflammatory pathway and changes gene expression after ifosfamide, which might be the key mechanism of its toxicity[23]. Melphalan is directly toxic to sinusoidal endothelial cells, causing them to slough into the sinusoidal lumen[8].

Elevations in liver function tests (LFTs) are frequently observed with dactinomycin, busulfan, oxaliplatin, methotrexate, thioguanine, paclitaxel, and irinotecan[6,24-26]. SOS has been most commonly associated with doxorubicin, melphalan, busulfan, and carboplatin[26,27]. Hepatitis or steatohepatitis has been linked to cisplatin, 6-mercaptopurine, docetaxel, and etoposide. Cholestatic injury is typically associated with azathioprine, while hepatic fibrosis has been reported with cytarabine[6,24,26,28]. Beyond conventional cytotoxic agents, hepatotoxicity has been increasingly recognized with targeted therapies; for example, lapatinib has been associated with SOS, whereas imatinib frequently induces elevation in serum transaminases[29,30].

As far as clinical presentation is concerned, late hepatotoxicity can be present in several forms and can occur without any prior episode of acute liver injury. Unlike acute hepatotoxicity, which often manifests asymptomatically through elevated ALT and AST, late toxicity frequently presents with painless hepatomegaly, esophageal or gastric varices, or splenomegaly with thrombocytopenia[31,32].

Thiopurines (6-thioguanine and 6-mercaptopurine) are known to cause delayed hepatic dysfunction, commonly manifesting as persistent hepatomegaly, splenomegaly, and thrombocytopenia. CCS exposed to treatment regimens containing these agents remain at increased risk of developing chronic hepatic fibrosis. Additional risk factors include chronic viral hepatitis, transfusion-related hemosiderosis, and thiopurine methyltransferase homozygosity[5].

Methotrexate is more frequently associated with acute or subacute liver injury, characterized by transient elevations in LFTs or ALP[33]. Histopathological evaluations in the pediatric population suggest that methotrexate-related injury generally results in only mild hepatic architectural changes, with a low incidence of portal fibrosis. Notably, methotrexate-induced fibrosis that develops during therapy often stabilizes or regresses after discontinuation, and only rarely progresses to end-stage liver disease[33,34]. However, it has been shown that daily oral methotrexate is over twice as likely to be associated with fibrosis or cirrhosis compared to intermittent parenteral administration. In support of this, a small cohort study from Iran involving 30 children treated with high-dose methotrexate reported that, at 10 years post-therapy, 13% of patients had elevated ALT and/or total bilirubin, 10% had elevated direct bilirubin, 17% demonstrated mild hepatomegaly or steatosis on ultrasound, while no cases of cirrhosis or portal hypertension were observed. These findings collectively suggest that clinically significant long-term hepatotoxicity from methotrexate is uncommon in CCS[35].

Dactinomycin is well documented as a cause of acute hepatotoxicity, but its role in late-onset hepatic injury remains uncertain and requires further investigation[36].

Cyclophosphamide and ifosfamide more commonly cause acute hepatic toxicity, but can also contribute to late liver injury in children, particularly when administered at high doses or as part of HSCT conditioning regimens, which may lead to SOS[8,22,37].

In a large cohort study by Mulder et al[38], busulfan was not identified as a significant risk factor for late LFTs abnormalities among CCS. In contrast, other studies have suggested that busulfan may induce oxidative stress and inflammation through glutathione depletion, potentially leading to persistent liver enzyme elevation, cholestasis, or hepatic fibrosis[3,39].

As for the anthracyclines, Goldsby et al[40] reported that doxorubicin and daunorubicin were significantly associated with long-term elevations in LFTs, indicative of mild, ongoing hepatocellular injury that may persist more than a decade following treatment. These effects are often subclinical, though their full clinical relevance remains to be fully elucidated. Conversely, Mulder et al[38] found no significant correlation between anthracyclines and late hepatic toxicity in their cohort.

RADIOTHERAPY-RELATED HEPATIC INJURY

Radiation therapy, particularly when directed to the upper abdomen or liver, can also contribute to hepatotoxicity. It can be associated with fibrosis, cirrhosis, cholelithiasis, and SOS. When radiation is combined with chemotherapy, the risk and severity of liver injury are significantly increased. Agents that have demonstrated synergistic hepatotoxic effects with radiation include vincristine, doxorubicin, and dactinomycin[41]. In this case, liver injury typically manifests within several months after treatment completion[42]. Radiation is incorporated into the management of multiple pediatric malignancies, including neuroblastoma, Wilms tumor, and rhabdomyosarcoma[43]. In a cohort study, Mulder et al[38] observed that 17.9% of CCS who received liver-involving radiation exhibited abnormal LFTs at a median follow-up of 12 years following initial cancer diagnosis. Hall et al[7] reported that the incidence of SOS in children receiving whole-liver irradiation was 6.1% at a dose of 10 Gy and increased to 14.5% at 20 Gy. Conversely, the incidence of late hepatotoxicity in CCS undergoing radiotherapy for malignancies not directly involving the liver remains low, as modern radiation field planning allows precise targeting, thus sparing normal liver tissue. However, in patients with viral hepatitis and/or iron overload or other predisposing conditions, late hepatic effects are more likely to manifest[44].

Cholelithiasis represents a potential late complication of hepatic irradiation. The risk of radiation-induced liver injury is modulated by multiple factors, including total radiation dose, the hepatic volume irradiated, younger age at exposure, prior partial hepatectomy, and the concurrent administration of radiomimetic chemotherapy agents[5].

HSCT-RELATED HEPATIC INJURY

HSCT is a well-established cause of hepatic injury, typically through immune-mediated mechanisms in which donor-derived T-lymphocytes target the recipient hepatocytes and bile ducts. Long-term CCS may develop chronic hepatitis, progressive fibrosis, and cirrhosis as a consequence of pre-transplant conditioning regimens, SOS, GVHD and subsequent cholestatic injury, or secondary complications such as transfusion-related iron overload[3]. In HSCT survivors, GVHD remains a leading cause of non-relapse mortality beyond two years post-transplant. Hepatic involvement is observed in approximately 80% of patients with chronic GVHD, most commonly presenting as cholestasis with elevated bilirubin and ALP. A severe late complication of chronic GVHD is cirrhosis, often arising secondary to chronic viral hepatitis. Iron overload, frequently resulting from multiple transfusions, may cause hepatic siderosis, which has been detected in nearly 90% of long-term HSCT survivors. The incidence of SOS in patients undergoing HSCT varies widely due to variations in diagnostic criteria, conditioning regimen intensity, population characteristics, and transplant settings. Fatal cases of SOS are most frequently linked to conditioning regimens incorporating cyclophosphamide, busulfan, and total body irradiation. Given the substantial mortality associated with SOS, there is a paucity of studies investigating long-term hepatic sequelae among HSCT survivors who develop this complication[3]. A summary of common late-onset hepatic toxicities associated with childhood cancer therapy and recommended evaluations is presented in Table 2.

Table 2 Potential late hepatic adverse effects of childhood cancer therapy.

Type of cancer treatment	Potential hepatic late effects	Recommended evaluation
Thiopurines	Hepatosplenomegaly, fibrosis	ALT, AST, GGT, ALP, bilirubin, platelets
Methotrexate	Uncommon, possible fibrosis and cirrhosis	ALT, AST, GGT, ALP, bilirubin
Dactinomycin	Uncommon, possible elevations in LFTs	ALT, AST, GGT, ALP, bilirubin
Busulfan	Persistent LFTs elevation, cholestasis, hepatic fibrosis, SOS	ALT, AST, GGT, ALP, bilirubin
Oxaliplatin and cisplatin	LFTs elevation, SOS	ALT, AST, GGT, ALP, bilirubin
Docetaxel	Hepatitis/steatohepatitis, transient LFTs elevation	ALT, AST, GGT, ALP, bilirubin
Etoposide	Uncommon, possible hepatitis/steatohepatitis	ALT, AST, GGT, ALP, bilirubin
	Cholestatic injury
Azathioprine	Hepatic fibrosis	ALT, AST, GGT, ALP, bilirubin
Cytarabine	SOS	ALT, AST, GGT, ALP, bilirubin
Cyclophosphamide and ifosfamide	Persistent LFTs elevation	ALT, AST, GGT, ALP, bilirubin
Anthracyclines	Uncommon	ALT, AST, GGT, ALP, bilirubin
Radiation exposing liver/biliary tract	Hepatic fibrosis/cirrhosis; focal nodular hyperplasia; cholelithiasis	ALT, AST, GGT, ALP, bilirubin, prothrombin time, screen for viral hepatitis; ultrasonography
Hematopoietic stem cell transplantation	Hepatic dysfunction; hepatic fibrosis/cirrhosis; iron overload	ALT, AST, GGT, ALP, bilirubin, prothrombin time, screen for viral hepatitis; ferritin

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; SOS: Sinusoidal obstruction syndrome; LFTs: Liver function tests.

UNRAVELLING THE IMPLICATIONS OF LATE HEPATIC INJURY

Several risk factors have been associated with the development of hepatic late adverse effects in CCS. Elevated ALT and/or gamma-glutamyl transferase (GGT) levels have been significantly linked to higher body mass index Z-scores, alcohol consumption exceeding 14 units per week, older age at diagnosis, and the male sex[38].

CCS with obesity or metabolic syndrome, often related to high-fat diet and inactivity, exhibit higher rates of fatty liver and other hepatic injuries. Conversely, CCS in low-income countries may experience malnutrition and elevated infectious risk, particularly from hepatitis C, which greatly increases the risk of cirrhosis[3,5]. It is important to note that most survivorship research originates from high-income countries, even though low- and middle-income countries carry the largest childhood cancer burden. This disparity extends to follow-up care, where populations with limited access to healthcare — even in wealthy nations — receive less surveillance and lack regular screening[45,46]. Genetic predisposition is another key factor; thiopurine methyltransferase -deficient patients are susceptible to severe thiopurine-induced veno-occlusive liver disease, while other significant factors have yet to be identified[5]. Additional contributors to late hepatotoxicity include pregnancy, a family history of cholelithiasis, the presence of an ileal conduit, use of total parenteral nutrition, and a history of abdominal surgery[5]. Primary cancer and its treatment are also important determinants of hepatotoxicity. Exposure to agents such as busulfan, thioguanine or abdominal radiation in leukemias and solid-tumor protocols significantly increases the risk of liver injury[3,5]. For example, acute lymphoblastic leukemia (ALL) treatment typically includes vincristine and anthracyclines during induction, followed by methotrexate, cytarabine, cyclophosphamide, and mercaptopurine during consolidation and/or maintenance, all of which may contribute to late hepatic toxicity. Neuroblastoma protocols, in contrast, often involve carboplatin, cyclophosphamide, and doxorubicin, which are also hepatotoxic; however, the variety and intensity of agents differ from ALL regimens, leading to distinct patterns and degrees of liver toxicity[47].

CONCLUSION

CCS who have been exposed to therapies associated with late hepatic dysfunction should undergo regular follow-up and monitoring within a structured survivorship care program, even though the overall incidence of such complications is relatively low[5]. Routine laboratory assessments – including ALT, AST, ALP, GGT, bilirubin, ferritin, platelet count, and prothrombin time – are widely available and useful for early detection of hepatic injury, and should be performed at least annually in all CCS. For CCS exposed to high-risk cytotoxic regimens, which include busulfan, thioguanine, thiopurines, abdominal or liver irradiation, or HSCT with conditioning regimens incorporating cyclophosphamide, laboratory evaluations are recommended every 6 months for the first 5 years post-therapy, followed by annual testing thereafter.

Comprehensive assessment should also include a detailed medical history (e.g., colicky abdominal pain associated with fatty meals, excessive flatulence) and a thorough physical examination at each visit. Clinical signs such as jaundice, scleral icterus, ascites, hepatomegaly, splenomegaly, spider angiomas, palmar erythema, xanthomata, and right upper quadrant tenderness may suggest liver dysfunction. The aforementioned individual risk factors must guide surveillance, and semiannual physical examinations are recommended for CCS at risk. When indicated, further investigations and consultation with a hepatologist should be pursued[2,5].

Given the limited research on late hepatic toxicity in CCS, additional longitudinal studies are needed to better define risk factors, establish evidence-based screening protocols, and guide long-term management strategies in this vulnerable population.