Staged approach to overcome hyperbilirubinemia: tailored chemotherapy in liver metastases-a case report

Introduction

Hyperbilirubinemia presents a significant challenge in the treatment of patients with liver dysfunction, especially those with metastatic liver disease, particularly when chemotherapy is required. Many chemotherapeutic agents are metabolized and eliminated via the liver, making their administration in the setting of hepatic dysfunction complex due to altered drug metabolism, increased toxicity risk, and the lack of robust clinical guidelines for dose adjustments (1). Historically, patients with severe hepatic impairment have been excluded from clinical trials, limiting available data on the safety and efficacy of chemotherapy in this population (2).

In hepatically impaired patients, a tailored therapeutic approach is crucial to balance the risks of under-treatment with disease progression against the potential toxicity of systemic therapy (1). Alternative strategies, such as the use of radiation therapy and corticosteroids, have been explored to mitigate hyperbilirubinemia and create a window for safe chemotherapy initiation (2). Some studies suggest that steroids may reduce bilirubin levels by decreasing hepatic inflammation and improving bile flow, potentially enhancing the patient’s ability to tolerate chemotherapy (3). Similarly, the use of non-hepatically metabolized agents, such as platinum-based chemotherapy, has been proposed as a viable option for patients with severe hepatic dysfunction (4). However, these approaches remain largely supported by small case series, show variable and often temporary benefit, and there is no established sequencing or standardized treatment algorithm, highlighting a clear knowledge gap.

Despite these evolving strategies, clinical evidence remains sparse, and oncologists must rely on case-based experiences and expert recommendations to guide treatment decisions. Cases of poorly differentiated neuroendocrine carcinoma presenting with severe hyperbilirubinemia are uncommon, and reports describing structured, staged approaches to safely enable systemic therapy are limited. This report describes a case of severe hyperbilirubinemia in a 73-year-old woman diagnosed with a poorly differentiated neuroendocrine tumor of unknown origin, with liver metastases and significant hepatic dysfunction at initial presentation. Due to her elevated bilirubin levels, standard-of-care chemotherapy was contraindicated, necessitating an alternative treatment strategy that provides a potentially useful framework for similar rare and clinically challenging scenarios. Herein, we report our approach regarding the treatment of this patient, in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-113/rc).

Case presentation

History and diagnosis

A 73-year-old female who had been in her usual state of health, started experiencing persistent epigastric and periumbilical abdominal pain, which worsened with bowel movements and coughing. While the pain resolved, she subsequently developed diarrhea lasting for two weeks, characterized by liquid stools every 1–2 hours, occurring even at night. There was no associated blood or melena, and fasting did not improve the symptoms.

A subsequent computed tomography (CT) scan of the abdomen and pelvis revealed hepatomegaly with morphological changes suggestive of cirrhosis and multiple diffuse small hepatic nodules. Given the concerning radiologic findings, an magnetic resonance imaging (MRI) of the abdomen was performed, confirming extensive hepatic involvement with innumerable liver nodules demonstrating restricted diffusion and minimal enhancement.

A liver biopsy revealed metastatic poorly differentiated neuroendocrine carcinoma with extensive liver involvement. Immunohistochemical analysis suggested a high-grade malignancy with a Ki-67 proliferation index exceeding 80%, indicating an aggressive tumor biology. The site of origin remained unclear, with possible primary sites including the lung or pancreatobiliary system.

Presentation and admission

By the time of admission, the patient reported worsening fatigue, weight loss of 20 pounds over two weeks, loss of appetite, and persistent diarrhea. She also described nausea without vomiting and some cognitive fogginess. A physical examination noted an Eastern Cooperative Oncology Group (ECOG) performance status of 3–4, indicative of poor baseline functional status requiring inpatient management.

Laboratory findings at admission included significantly elevated total bilirubin levels at 11.3 mg/dL, consistent with severe hyperbilirubinemia. Liver function tests were also deranged, with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and hypoalbuminemia. Additional imaging, including a follow-up CT scan, revealed progression of the malignancy with increased size of hepatic lesions, splenic metastases, and newly detected retroperitoneal soft tissue metastases.

Treatment

Given the patient’s severe hyperbilirubinemia and extensive liver involvement, standard-of-care chemotherapy was initially contraindicated. Instead, we pursued a staged therapeutic approach, starting with palliative radiation therapy to the liver, with seven planned sessions.

Simultaneously, the patient was initiated on corticosteroids (dexamethasone 2 mg twice daily, later transitioned to prednisone 10 mg thrice daily, and tapered gradually) to reduce hepatic inflammation and edema. Over the next few weeks, her bilirubin levels declined to 6.9 mg/dL, permitting the initiation of weekly cisplatin therapy at week 4. The patient received six weekly doses of cisplatin, leading to a notable reduction in bilirubin to 2.6 mg/dL.

By week 10, with bilirubin levels stabilized, gemcitabine was introduced in combination with cisplatin, allowing for a more aggressive systemic regimen. However, during the fourth cycle, the patient developed thrombocytopenia, necessitating a 50% dose reduction in gemcitabine at week 12. Gemcitabine dose reduction was performed in accordance with prescribing guidance and tailored to the patient’s hematologic parameters and hepatic dysfunction. Despite dose adjustments, treatment was continued with cisplatin plus gemcitabine at week 14, demonstrating further bilirubin reduction and improved clinical stability.

The trend in total bilirubin over time in relation to each therapeutic intervention is shown in Figure 1.

Figure 1 Total bilirubin levels over time during sequential therapeutic interventions. The patient presented with severe hyperbilirubinemia and extensive liver metastases from a poorly differentiated neuroendocrine carcinoma. Corticosteroids (prednisone) and liver-directed radiation were administered first, followed by weekly cisplatin, then addition of gemcitabine once bilirubin improved, with later dose reduction for thrombocytopenia.

Follow-up

While the initial treatment approach successfully lowered bilirubin levels and enabled systemic chemotherapy, a follow-up CT scan a few weeks later, showed progression of disease, with increased size of hepatic and splenic metastases, as well as new retroperitoneal lesions. Additionally, an MRI brain revealed innumerable intracranial metastases with associated microhemorrhages, indicating worsening metastatic spread.

Given the poor prognosis and declining functional status, treatment goals were reevaluated, and palliative care discussions were initiated. Supportive measures were prioritized, focusing on symptom control, quality of life, and comfort care. The patient was transitioned to hospice care following shared decision-making with her oncology team and family. No delayed treatment-related toxicities were observed during the short window between treatment cessation and hospice transition. The patient’s prognosis remained poor given rapid disease progression and neurologic involvement. The overall clinical course, including diagnosis, interventions, bilirubin response, and subsequent progression, is summarized in Figure 2.

Figure 2 Timeline of diagnosis, treatment, and clinical course. The patient initially presented with abdominal pain and was found to have diffuse liver metastases from a poorly differentiated neuroendocrine carcinoma. Total bilirubin at presentation was 11.3 mg/dL. Sequential interventions included corticosteroids and liver-directed radiation to improve hepatic function, followed by weekly cisplatin, subsequent addition of gemcitabine once bilirubin decreased, and later gemcitabine dose reduction for thrombocytopenia. Follow-up imaging showed disease progression with new hepatic, splenic, retroperitoneal, and intracranial metastases, leading to hospice transition. CT, computed tomography; MRI, magnetic resonance imaging; NEC, neuroendocrine carcinoma.

Ethical statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. The requirement for written informed consent for publication was waived because the patient was deceased and could not be contacted, and no identifiable information is presented. A copy of the waiver documentation is available for review by the editorial office upon request.

Discussion

We adopted a staged therapeutic approach combining radiation therapy to the liver and corticosteroids, which successfully lowered bilirubin levels and created a window of opportunity for chemotherapy initiation. This case highlights the potential of individualized treatment approaches in managing patients with liver dysfunction, demonstrating how targeted interventions can expand oncologic treatment options while maintaining patient safety.

The management of hyperbilirubinemia in patients with liver dysfunction poses significant challenges, particularly when systemic chemotherapy is needed. The liver plays a crucial role in drug metabolism and excretion, and hepatic dysfunction can alter pharmacokinetics, leading to increased toxicity risks and reduced therapeutic efficacy (1). Many cytotoxic agents, including gemcitabine and irinotecan, are extensively metabolized in the liver and are often contraindicated or require dose adjustments in patients with severe hepatic impairment (4). However, the lack of robust clinical data on dosing modifications often forces oncologists to rely on empirical judgment (5).

Hyperbilirubinemia in patients with liver metastases is frequently a result of extensive tumor burden obstructing bile ducts, hepatic parenchymal destruction, or secondary inflammation (3). This leads to a clinical dilemma—on one hand, these patients require urgent systemic therapy to control disease progression, yet on the other, chemotherapy-induced hepatotoxicity may further compromise liver function. Recent strategies have explored using non-hepatically metabolized agents, such as cisplatin, which is primarily eliminated renally and therefore offers a safer alternative in this setting (4). Additionally, radiation therapy to the liver has been reported as a method to decrease tumor burden and reduce biliary obstruction, thereby lowering bilirubin levels and making chemotherapy safe to administer (6).

Corticosteroids have also been utilized in the management of hyperbilirubinemia due to their potent anti-inflammatory effects. Studies suggest that steroids may decrease hepatocellular inflammation and bile duct edema, thereby improving bile flow and reducing bilirubin levels (3). Yasumasa et al. described two cases where systemic steroid therapy successfully lowered bilirubin levels in patients with liver metastases, allowing subsequent chemotherapy initiation (2). While steroids alone may not be a definitive treatment for tumor-related biliary obstruction, they can serve as a valuable adjunct bridging approach.

In the presented case, we adopted a staged approach by first targeting hyperbilirubinemia with corticosteroids and liver-directed radiation therapy before initiating systemic chemotherapy. This strategy aligns with previous reports that emphasize the importance of improving liver function before starting hepatically metabolized chemotherapy (7). Our initial choice of cisplatin, a non-liver metabolized drug, was based on its ability to avoid exacerbating hepatic dysfunction while still exerting anti-tumor activity (1). Once bilirubin levels declined, gemcitabine, which typically requires hepatic metabolism, was cautiously introduced at a reduced dose. This highlights how a dynamic treatment strategy can expand therapeutic options for patients who might otherwise be deemed ineligible for systemic therapy (4).

The patient’s tumor demonstrated a Ki-67 proliferation index >80%, consistent with a highly aggressive phenotype. Studies have shown that high Ki-67 levels, particularly ≥55%, are associated with poor prognosis and reduced overall survival in patients with poorly differentiated neuroendocrine carcinomas (8). In a Nordic NEC cohort study, patients with Ki-67 ≥55% had a median overall survival of only 14 months compared to 22 months in those with lower proliferation rates, underscoring the impact of tumor biology on outcomes (9). These findings support the inclusion of Ki-67 as a key prognostic and potentially predictive biomarker in guiding therapeutic intensity and expectations in high-grade neuroendocrine carcinomas.

Recent advances in the treatment of neuroendocrine neoplasms have explored immunotherapy and molecularly targeted strategies. For high-grade extrapulmonary neuroendocrine carcinomas, a multicenter retrospective study reported that atezolizumab in combination with platinum-etoposide chemotherapy resulted in a higher response rate compared to chemotherapy alone, although progression-free and overall survival remained similar between groups (10). The phase 3 CABINET trial demonstrated improved progression-free survival with cabozantinib in patients with progressive neuroendocrine carcinomas, further supporting the role of tyrosine kinase inhibition (11). Ongoing studies are also evaluating the utility of mTOR inhibitors and other novel agents in both low- and high-grade neuroendocrine carcinomas, potentially reshaping treatment paradigms beyond conventional cytotoxic therapy (12,13).

Our staged therapeutic approach aligns with previous reports that have explored strategies to manage hyperbilirubinemia in patients with hepatic dysfunction, yet key differences in sequencing and intervention choices may explain variations in outcomes. Yasumasa et al. described cases where corticosteroids were used to lower bilirubin levels in patients with liver metastases, ultimately allowing chemotherapy initiation. However, their approach focused solely on steroids without concurrent liver-directed therapy, which may have limited efficacy in cases with high tumor burden (2). In contrast, Quidde et al. highlighted the role of non-hepatically metabolized agents like cisplatin in treating patients with severe hyperbilirubinemia secondary to liver metastases, showing temporary stabilization but limited long-term disease control (4). Our approach combined these strategies—incorporating both corticosteroids to reduce inflammation and radiation therapy to alleviate biliary obstruction before chemotherapy initiation—potentially accounting for the more sustained bilirubin reduction observed in our case. Additionally, Gabrovska et al. reported that weekly cisplatin alone could reverse hepatic dysfunction in patients with extensive liver metastases, but their report lacked adjunctive supportive measures, which may have contributed to more limited efficacy in cases with aggressive tumor biology (5). Our case further emphasizes the importance of timing and sequencing, as the progressive bilirubin decline enabled the introduction of gemcitabine at a later stage, allowing for more intensified systemic therapy. These comparisons highlight that while similar approaches have been attempted, the combination of multimodal interventions—radiation therapy, corticosteroids, and non-hepatically metabolized chemotherapy—may provide the most effective strategy in cases of severe hepatic dysfunction.

The safety of chemotherapy in liver dysfunction remains debated, yet some agents have shown relative tolerability. Saif et al. reported that capecitabine, despite hepatic metabolism, was safe in select patients with liver impairment when appropriately dose-adjusted. While capecitabine was not used in our case, this supports our stepwise chemotherapy introduction, reinforcing that personalized treatment strategies can expand systemic therapy options for patients otherwise deemed ineligible (14). The current guidelines on chemotherapy dosing in hepatic dysfunction are insufficient, with most recommendations based on retrospective analyses or expert consensus rather than prospective clinical trials (7,15). Many oncologists hesitate to treat patients with severe hyperbilirubinemia due to the fear of worsening liver failure, yet our case, alongside previous reports, suggests that careful pre-treatment interventions can create safe opportunities for chemotherapy administration (6). This underscores the necessity for further prospective studies to establish standardized protocols for managing hyperbilirubinemia in oncology settings.

In conclusion, this case reinforces the need for a personalized and staged approach in patients with hepatic dysfunction and hyperbilirubinemia. A combination of corticosteroids and radiation therapy can be effective in temporarily improving liver function, enabling the subsequent introduction of systemic chemotherapy. Oncologists should consider pharmacokinetic properties, hepatic metabolism, and patient-specific factors when selecting chemotherapy regimens for these high-risk patients. Further research is needed to refine treatment algorithms, ensuring that patients with hepatic dysfunction are not unnecessarily excluded from potentially life-prolonging therapies (5,6).

Strengths and limitations

This case report highlights several key strengths in the management of hyperbilirubinemia in the setting of metastatic liver disease. First, it demonstrates a staged therapeutic approach, combining corticosteroids and radiation therapy to initially lower bilirubin levels before initiating systemic chemotherapy. This method provides a practical and adaptable strategy for patients who would otherwise be ineligible for treatment due to hepatic dysfunction. Second, the case illustrates the importance of individualized chemotherapy selection, as the choice of cisplatin—a non-hepatically metabolized agent—allowed treatment initiation without exacerbating liver dysfunction. Third, this report not only presents a novel case but also strengthens its findings by comparing our approach to prior reports, highlighting key differences in sequencing, intervention choices, and outcomes. This comparative analysis underscores how multimodal interventions may provide a more effective strategy in managing severe hepatic dysfunction. This case also adds to the growing body of literature on chemotherapy in hepatic impairment, contributing valuable clinical insights to an area with limited prospective data. Lastly, this report underscores the feasibility of managing severe hyperbilirubinemia in oncology, reinforcing the idea that a careful, patient-centered approach can expand treatment options for high-risk patients.

Despite these strengths, there are several limitations to consider. First, as a single-patient case report, the findings may not be generalizable to broader patient populations with hepatic dysfunction, as clinical responses to steroids, radiation, and chemotherapy can vary significantly. Second, long-term outcomes were not explored in detail, limiting the ability to assess the durability of the treatment strategy beyond the initial response. Third, while the case highlights a successful approach, it does not provide a systematic protocol that can be easily replicated in other settings, as decisions were made based on individual patient factors rather than a standardized guideline. Additionally, potential confounders such as undetected liver function fluctuations, concurrent supportive therapies, or underlying variations in tumor biology may have influenced the patient’s response.

Conclusions

This case report underscores the complexity of managing hyperbilirubinemia in metastatic liver disease, particularly when chemotherapy is necessary but contraindicated due to hepatic dysfunction. The staged therapeutic approach employed—incorporating corticosteroids, radiation therapy, and non-hepatically metabolized chemotherapy—enabled a progressive reduction in bilirubin levels, creating an opportunity for systemic therapy initiation. The patient’s initial response to treatment demonstrates that hyperbilirubinemia does not have to be an absolute barrier to chemotherapy, provided that strategic interventions are used to optimize liver function before initiating cytotoxic agents.

Despite initial improvements, disease progression ultimately limited therapeutic options, leading to a transition to palliative care. This highlights the aggressive nature of poorly differentiated neuroendocrine tumors and the need for continued research to refine treatment protocols for patients with hepatic dysfunction. The case also emphasizes the importance of individualized treatment strategies, particularly in patients who may otherwise be deemed ineligible for systemic therapy.

Moving forward, prospective clinical studies are needed to establish evidence-based guidelines for chemotherapy dosing in hepatic impairment, as well as to further explore supportive interventions such as steroids, radiation therapy, and novel treatment modalities. By expanding oncologic treatment options for patients with hepatic dysfunction, clinicians can enhance therapeutic outcomes and improve quality of life, ensuring that patients receive the best possible care despite significant clinical challenges.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-113/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-113/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-113/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. The requirement for written informed consent for publication was waived because the patient was deceased and could not be contacted, and no identifiable information is presented. A copy of the waiver documentation is available for review by the editorial office upon request.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Eklund JW, Trifilio S, Mulcahy MF. Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park) 2005;19:1057-63; discussion 1063-4, 1069.
2. Yasumasa K, Morimoto Y, Hatanaka N, et al. Two Cases of Systemic Steroid Therapy for Hyperbilirubinemia after Right Hepatic Lobectomy of Liver Metastasis from Colorectal Cancer. Gan To Kagaku Ryoho 2016;43:1739-41. [PubMed]
3. Criel M, Geurs F, Ponette S, et al. Reversal of jaundice in two patients with inoperable cholangiocarcinoma treated with Cisplatin and gemcitabine combination. Case Reports Hepatol 2012;2012:138381. [PubMed]
4. Quidde J, Azémar M, Bokemeyer C, et al. Treatment approach in patients with hyperbilirubinemia secondary to liver metastases in gastrointestinal malignancies: a case series and review of literature. Ther Adv Med Oncol 2016;8:144-52. [PubMed]
5. Gabrovska M, Geurs F, Ponette S, et al. Weekly cisplatin may reverse liver dysfunction and jaundice caused by diffuse liver metastases of solid tumors. Hepat Med 2009;1:9-12. [PubMed]
6. Shibata T, Ebata T, Fujita K, et al. Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction. Cancer Sci 2016;107:168-72. [PubMed]
7. Gong J, Cho M, Fakih M. Chemotherapy in patients with hepatobiliary cancers and abnormal hepatic function. J Gastrointest Oncol 2017;8:314-23. [PubMed]
8. La Rosa S. Diagnostic, Prognostic, and Predictive Role of Ki67 Proliferative Index in Neuroendocrine and Endocrine Neoplasms: Past, Present, and Future. Endocr Pathol 2023;34:79-97. [PubMed]
9. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013;24:152-60. [PubMed]
10. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist 2025;30:oyae372. [PubMed]
11. Chan JA, Geyer S, Zemla T, et al. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med 2025;392:653-65. [PubMed]
12. Medici B, Caffari E, Maculan Y, et al. Everolimus in the Treatment of Neuroendocrine Tumors: Lights and Shadows. Biomedicines 2025;13:455. [PubMed]
13. Zhu L, Ye X, She Y, et al. Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis. J Gastrointest Oncol 2024;15:689-709. [PubMed]
14. Saif MW, Tejani MA. Safety of capecitabine use in patients with liver dysfunction. Clin Adv Hematol Oncol 2007;5:730-2; discussion 736. [PubMed]
15. Saadati H, Saif MW. Capecitabine as salvage therapy for a pancreatic cancer patient with extensive liver metastases and associated impairment of liver function. JOP 2008;9:354-6. [PubMed]