Fatal liver failure after the administration of raltitrexed for cancer chemotherapy

Abstract

BACKGROUND Acute fatal liver failure is a relatively rare event after the administration of antineoplastic drugs. To the authors' knowledge, there have been no published reports of this phenomenon after the administration of the widely applied cytotoxic agent raltitrexed. METHODS The authors present two cases of fulminant fatal liver failure that occurred after the administration of raltitrexed as anticancer chemotherapy. RESULTS A female patient age 76 years and a male patient age 56 years were given raltitrexed as adjuvant treatment of colorectal carcinoma and as palliative therapy for advanced biliary carcinoma, respectively. Although the initial cycles of chemotherapy were uneventful, both patients developed fulminant liver failure with rapid deterioration of their condition after the second and sixth cycles of chemotherapy, respectively, and both died within 24 hours despite immediate hospitalization. Histologic evaluation of liver samples taken during autopsy showed signs of acute necrosis involving roughly 50% of the liver without signs of subacute liver toxicity. CONCLUSIONS To the authors' knowledge the current study is the first to demonstrate fatal liver toxicity after chemotherapy with the thymidylate synthase inhibitor raltitrexed. Clinicians should be aware of the potential acute fatal side effect of this otherwise well tolerated and widely used cytotoxic agent. Cancer 2000;89:890–2. © 2000 American Cancer Society.

Phase I Trial and Pharmacokinetic Study of Raltitrexed in Children with Recurrent or Refractory Leukemia: A Pediatric Oncology Group Study

“…Nevertheless, grade 3 or 4 hepatotoxicity has been observed in 3% to 24% of adults with solid tumors after raltitrexed administration (3,24,22). Fulminant hepatic necrosis, an apparently rare and idiosyncratic adverse event, has also been reported in two adults after raltitrexed administration (25). Other grade 3 adverse events after raltitrexed included fatigue, diarrhea, and myelosuppression (3).…”

“…He noted that these elevations were reversible, returning to baseline in subsequent courses without dose reduction and were not associated with significant liver pathology. However, raltitrexed was associated with significant liver toxicity in other studies, including death from fulminant hepatic necrosis (25,26). Liver toxicity correlated with elevated baseline transaminases and high cumulative raltitrexed dose in these studies (26).…”

Comparing effectiveness and safety of paclitaxel plus raltitrexed vs. paclitaxel alone in second-line palliative chemotherapy for metastatic gastric adenocarcinoma: A randomized phase II clinical trial

“…The mechanism underlying 5FU resistance has been investigated with a focus on the level of the thymidylate synthase (TS) ternary complex formed with fluorodeoxyuridine monophosphate (FdUMP) [11][12][13] . Raltitrexed is a specific TS inhibitor that does not require modulation effects on RNA [14][15][16] . A meta-analysis that included 11 studies with 4622 colorectal cancer (CRC) patients reported equivalent OS and overall response rates (ORRs) with acceptable toxicities between traditional 5FU-and raltitrexed-based regimens [16][17][18][19] .…”

Comparison of efficacy and safety of second-line palliative chemotherapy with paclitaxel plus raltitrexed and paclitaxel alone in patients with metastatic gastric adenocarcinoma: a randomized phase 2 clinical trial

“…Raltitrexed is a speci c TS inhibitor which doesn't requires modulation effects on RNA [13,14,15]. A meta-analysis included 11 studies with 4622 CRC patients leads to an equivalent overall survival and response rates with acceptable toxicities comparing with traditional 5-uorouracil-based regimen and raltitrexed-based regimen [16,17,18,19,20].…”