Progressive familial intrahepatic cholestasis type 1 (PFIC1), also known as Byler disease, is a rare, autosomal recessive liver disease caused by a mutation in the ATPase phospholipid transporting 8B1 (ATP8B1) gene that leads to cholestasis and progressive liver dysfunction (Fig. 1C).1ATP8B1 encodes the FIC1 protein on the canicular membrane of the hepatocytes. FIC1 is a transporting transmembrane adenosine triphosphatase that is involved in biliary acid secretion across the canicular membrane.1 There is not a known association with PFIC1 or ATP8B1 mutations and the risk of developing Ewing sarcoma, or any other pediatric malignancy. Patients with PFIC1 can have a waxing and waning cholestasis, with periods of hyperbilirubinemia alternating with periods of more normal liver function. Here, we present a successful approach to treating Ewing sarcoma in a patient with a rare cholestatic liver disease.
An 11-year-old female with a known diagnosis of PFIC1 (Fig. 1A–C) presented with prolonged epistaxis, right-sided chest pain, and increased jaundice from baseline. A positron emission tomography/computed tomography scan was performed, and she was found to have a large right-sided posterior mediastinal mass with right-sided loculated hemothorax (Fig. 2A). Biopsy of the mass demonstrated sheets of small, round blue cells (Fig. 2B) with diffuse staining for CD99 (Fig. 2C). EWSR1 FISH testing was positive, rendering a final diagnosis of Ewing sarcoma. Additional staging workup demonstrated no sites of distant metastatic disease. The patient’s direct bilirubin at presentation was 19 g/dL, presenting a unique treatment challenge, as standard-of-care therapy for localized Ewing sarcoma consists of multiple chemotherapic agents that undergo hepatic metabolism.
In North America, Ewing sarcoma is treated with alternating, compressed cycles of vincristine, doxorubicin, cyclophosphamide (VDC), and ifosfamide and etoposide (IE).2 Anthracyclines (doxorubicin) and vinca alkaloids (vincristine) are primarily metabolized and excreted in the liver.3–5 Doxorubicin has been studied in patients with poor liver function and the main toxicity noted is myelosuppression. In small studies where full dose doxorubicin was administered to patients with hepatic impairment, severe toxicity occurred.6 Vincristine is mainly metabolized through biliary excretion and when administered to patients with hepatic dysfunction, increased neurotoxicity is reported (Fig. 3A).5 Because of these associated toxicities, recent phase III trials for the treatment of Ewing sarcoma have recommended delaying and/or withholding administration of doxorubicin and vincristine in setting of direct bilirubin >×3 the upper limit of normal (~1.5 mg/dL). Other experts have recommended dose adjustment/elimination of doxorubicin and vincristine when total bilirubin is >3 mg/dL.7 The metabolism of etoposide, another important chemotherapeutic in the treatment of Ewing sarcoma, also relies upon adequate liver function. Etoposide mainly circulates bound to albumin and the free fraction of etoposide increases in setting of hypoalbuminemia.8 Although etoposide undergoes clearance through the biliary tract, poor hepatic clearance can be compensated for by increased renal clearance. For this reason, patients with hepatic dysfunction may tolerate full doses of etoposide if renal function is adequate.
Given this patient’s hepatic dysfunction, cancer-directed therapy required significant modifications. It was decided that in the setting of extreme hyperbilirubinemia, administration of doxorubicin and vincristine was unlikely to be safe at any point in therapy and these agents were eliminated from the treatment plan. In addition, etoposide would be 50% dose reduced. To alter the chemotherapy regimen to avoid hepatoxicity, other regimens with activity in Ewing sarcoma were considered. Specifically, cyclophosphamide and topotecan have been used in the setting of relapsed Ewing sarcoma with clinical efficacy.9 More recently, the phase III Children’s Oncology Group clinical trial AEWS1031 studied the addition of cyclophosphamide and topotecan (regimen B) to the standard-of-care VDC/IE backbone for the treatment of upfront localized Ewing sarcoma. The results of this trial demonstrated equivalent outcomes to VDC/IE alone.10 Thus, it was decided to incorporate cycles of topotecan and cyclophosphamide to this patient’s treatment plan (Fig. 3B). Total cumulative doses of each chemotherapeutic agent that this patient received included: 12.25 g/m2 of cyclophosphamide, 18.75 mg/m2 topotecan, 63 g/m2 ifosfamide, and 1.75 g/m2 etoposide. In comparison, cumulative doses on regimen B of AEWS1031 are 30 mg/m2 vincristine (max 40 mg), 18.75 mg/m2 of topotecan, 12.25 g/m2 cyclophosphamide, 375 mg/m2 of doxorubicin, 63 g/m2 of ifosfamide, and 3.5 g/m2 of etoposide. This patient’s liver function and direct bilirubin were monitored very closely (Fig. 4). Although this patient’s direct bilirubin remained elevated, no evidence of worsening liver dysfunction was noted throughout therapy. Just before local control, repeat imaging revealed a partial response per RECIST criteria, with a 70% reduction in tumor volume. After induction therapy, local control with en bloc surgical excision of the primary tumor was performed. Surgical resection was complicated by neuroforaminal involvement. Pathology review of the resected specimen noted the presence of microscopic positive margins and some areas of viable tumor. Because of these findings, the patient subsequently underwent adjuvant radiation with 50.4 Gy in 28 fractions. From a chemotherapy standpoint, she was able to complete interval compressed therapy for 9 out of the 17 planned chemotherapy cycles. The remaining 8 cycles were delayed by 1 to 2 weeks because of myelosuppression (thrombocytopenia and neutropenia). During therapy, she had 1 admission for sepsis secondary to bacterial pneumonia.
Three months after the completion of therapy, this patient notably presented with a 3-week history of headaches, several days of a left sided facial nerve palsy, and an magnetic resonance imaging obtained demonstrated hydrocephalus and papilledema. This patient was subsequently diagnosed with and treated for Cryptococcal meningitis. As part of the evaluation for developing this rare meningitis, a review of her laboratory results was conducted and revealed a persistent, severe lymphopenia >4 months after the completion of chemotherapy. This patient’s absolute lymphocyte count remained <1000×106/L until ~1 year after completion of chemotherapy. Before this patient’s diagnosis of Ewing sarcoma and treatment with chemotherapy, she had no history of lymphopenia or significant infections. As part of her evaluation for this rare and severe infection, she underwent a comprehensive immunologic evaluation, which demonstrated low CD3, CD4, CD8, and natural killer cell counts. The B cell count and quantitative immunoglobulin levels were normal. The patient consented to a genetic sequencing panel for the evaluation of primary immunodeficiencies; however, no abnormal variants were present. The family declined further genetic testing. This patient is currently 18 months off therapy with no evidence of disease.
Here, we report a patient with PFIC1 and localized Ewing sarcoma who was able to achieve complete remission using a modified treatment protocol that eliminated or dose-reduced agents that require intact hepatic metabolism. We were able to utilize chemotherapy (Tc) from AEWS1031 regimen B to accomplish this. Although AEWS1031 enrolled patients with only localized disease, cyclophosphamide/topotecan has been tested in patients with relapsed/refractory disease with clinical activity. This may provide evidence that a similar adapted regimen with cyclophosphamide/topotecan would be reasonable in a similar patient with impaired hepatic metabolism and metastatic disease at diagnosis. There have been specific reports of the use of some chemotherapeutic agents in patients with liver dysfunction11–14; however, we believe this represents the first report of this specific combination being used for anticancer therapy in a patient with Ewing sarcoma and inherited liver dysfunction.
Administration of chemotherapeutic agents requiring hepatic metabolism in a patient with PFIC1 poses a significant risk for increased myelosuppression and more severe infectious complications. We suspect that this patient’s severe, persistent lymphopenia, bacterial pneumonia during therapy, and off-therapy fungal meningitis was likely related to increased lymphotoxicity secondary to the use of chemotherapy in the setting of underlying liver dysfunction. In patients with cirrhosis and/or advanced liver dysfunction, lymphopenia is observed and is an early sign of immune dysfunction.15 It is possible that this patient was predisposed to specific lymphocyte depletion/dysfunction due to her hepatic dysfunction and chemotherapy exacerbated this existing immune dysfunction. This case highlights the fact that patients with hepatic dysfunction receiving chemotherapy may be at significant risk of infectious complications due to delayed immune recovery, and such patients may benefit from additional long-term prophylaxis (fungal, etc.) long after treatment completion.
Dr Bailey thanks the Brian Morden Foundation for their continued support and dedication to helping pediatric patients with cancer.
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