Paclitaxel-Induced Hepatotoxicity in Ovarian Cancer Patients: A Case Report

Abstract

Paclitaxel plus carboplatin is the most common regimen for the treatment of ovarian cancer. While generally effective, these chemotherapy agents can cause adverse events such as myelotoxicity, nausea, vomiting, and rarely, hepatotoxicity. Paclitaxel is associated with mild elevations in serum aminotransferase levels, but significant hepatotoxicity is uncommon, particularly in patients without prior liver disease. We present a patient with ovarian cancer who developed significant elevation of serum aminotransferases up to 12 times the upper limit of normal after the first cycle of paclitaxel plus carboplatin chemotherapy. Extensive evaluations excluded other potential causes of liver injury and the diagnosis of paclitaxel-induced liver injury was confirmed. The patient was treated with liver protective medications and a reduced dose of paclitaxel (135 mg/m²) for subsequent cycles. Her liver function tests stabilized within 2 to 3 times the upper limit of normal, allowing continuation of chemotherapy and achieving a favorable outcome.

Background

Paclitaxel plus carboplatin is the most common regimen for the treatment of ovarian cancer (OC). Like many other chemotherapy medications, the administration of paclitaxel and carboplatin is associated with many adverse events, such as myelotoxicity, nausea, and vomiting. Most adverse reactions can be managed by pre- or post-administration pharmacologic treatments or dose reduction of the following cycles. ¹

Hepatotoxicity is generally uncommon in patients with OC receiving paclitaxel plus carboplatin without previous liver disease or injury history. Paclitaxel has been associated with the elevation of serum aminotransferase in 7% to 26% of patients, but the value is rarely greater than 5 times the upper limit of normal (ULN). ² For carboplatin, it is minimally hepatic metabolized and associated with only mild and transient elevation in serum aminotransferase levels. ³ In this case, we reported a 53-year-old woman with high-grade serous carcinoma (HGSC) who received a standard dose regimen of paclitaxel plus carboplatin and developed a significant elevation of serum aminotransferases up to 12 times the ULN after the first cycle of chemotherapy. We did a full check-up of the patient’s medical history and laboratory tests to exclude other causes and closely monitored the patient’s liver function. The diagnosis of paclitaxel-induced liver injury was confirmed and successfully managed by dose reduction of paclitaxel for the following cycles, use of liver protective medications, and frequent monitoring of liver function tests (LFTs). Our treatment experience in this case will help better manage this uncommon drug adverse reaction in patients with OC.

Case Summary

The patient is a 53-year-old postmenopausal woman. She had no other significant medical or surgical history besides mild menopause symptoms. There was no family history of malignancy. In July 2022, the patient came to a local hospital with claims of a “touchable” abdominal mass, mild constipation, and urgency of urination. The ultrasound showed 10 cm × 8 cm × 8 cm and 6 cm × 8 cm × 4 cm masses in the left and right side of the pelvic cavity, respectively. For values of related cancer biomarkers, the cancer antigen 125 (CA125) was 499.4 U/mL (the normal value is <35 U/mL). The decision was made by the gynecologist to perform a primary debulking surgery after the prior operation evaluations, which were generally normal. The surgery was successful. From the post-surgery note, total hysterectomy, double adnexectomy, omentectomy, appendectomy, and pelvic lymph node dissection were performed. No abnormalities were found in the intestinal tube, liver, stomach, spleen, abdominal wall, appendix, and diaphragm surface. The pathology note stated HGSC of the left and right ovary with mass size 10 × 9 × 5 cm and 9 × 8 × 4 cm, respectively, left tubal epithelial hyperplasia with mesangial cyst, serous carcinoma growth in the right fallopian tube, no cancer in the uterine endometrium, cervix, bilateral ovarian arteriovenous, omentum, and appendix, and no cancer metastasis was found in the left and right pelvic lymph node samples. The genetic testing report showed somatic breast cancer antigen (BRCA) 1/2 mutations negative. In August 2022, the patient came to our hospital to set up an adjuvant chemotherapy treatment plan and for further evaluations.

Based on the patient’s medical records, we classified the patient as stage IIb HGSC. The chemotherapy regimen was decided to be paclitaxel 240 mg and carboplatin 474 mg (175 mg/m²) on day 1 with a 3-week cycle length for a total of 6 cycles. The patient’s complete blood count (CBC) results are normal. For LFTs, the alanine transaminase (ALT) was 31 U/L (the ULN is 40 U/L), aspartate transaminase (AST) was 20 U/L (the ULN is 35 U/L), alkaline phosphatase (ALP) was 83 U/L (the ULN is 135 U/L), and total bilirubin was 8.2 μmol/L (the normal range is 3.4-20.4 μmol/L). The CA125 was down to the normal range of 22.5 U/mL. The appropriate pre-medications for preventing the chemotherapy-induced nausea and vomiting and hypersensitive reactions were given. The patient did not come back for the first post-chemotherapy check-up, and in her scheduled second check-up, which was 15 days after day 1, the CBC was normal, and CA125 was down to 10.05 U/mL. However, her LFTs were significantly elevated as the ALT was 493 U/L, AST was 198 U/L, which were approximately 12 and 6 times ULN, and the ALP was barely within the normal range of 134 U/L. The R ratio defined as (ALT/ULN)/(ALP/ULN) was calculated to be 12.4, which suggested hepatocellular injury. ⁴ Strangely, her total bilirubin was in the normal range of 10.6 μmol/L. We then confirmed with the patient that she did not have any liver or autoimmune disease history or previously elevated ALT and AST, did not use excess non-steroid anti-inflammatory drugs or herbal medications, and did not drink any alcohol recently. The repeat HBV and HCV tests were negative. The patient denied abdominal discomfort, extremities edema, skin color change, or altered mental status. As there were no signs or symptoms of acute liver injury or failure, a liver biopsy was not indicated at that time.

After a multidisciplinary consultation and a Naranjo score of 13 indicating a definite reaction (Table 1), we made a diagnosis of sub-acute liver injury from paclitaxel-induced hepatotoxicity and recommended the patient receive glutathione 1.2 g and magnesium isoglycyrrhizinate 0.2 g IV for 14 days and recheck LFTs. After the treatment, the AST and ALT were down to 197 and 50 U/L. On day 38 after day 1 of the first cycle, the ALT and AST were down to 70 and 33 U/L and we decided the patient could restart the second cycle with a reduced paclitaxel dose of 180 mg (135 mg/m²). The patient tolerated the following cycles and her LFTs were stable and generally within 2 to 3 times the ULN (Figure 1). After 6 cycles of chemotherapy, the decision was made by the care team and patient to stay on routine surveillance.

Table 1.

Naranjo Adverse Drug Reaction Probability Scale for Case.

Questions	Case
Are there previous conclusive reports on this reaction?	Yes (2)
Did the adverse event appear after the suspected drug was administered?	Yes (2)
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	Yes (2)
Did the adverse event reappear when the drug was readministered?	Yes (2)
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	No (2)
Did the reaction reappear when a placebo was given?	Do not know (0)
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	Do not know (0)
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	Yes (2)
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	Do not know (0)
Was the adverse event confirmed by any objective evidence?	Yes (1)
Total score	13

Naranjo scoring: definite, score 9 or higher; probable, score 5-8; possible, score 1-4; doubtful, 0 or less.

Figure 1.

Liver Function Test Results.

Discussion

Paclitaxel-induced hepatotoxicity is a relatively rare drug adverse reaction in patients with OC. In this case, we presented a patient who had elevated serum aminotransferases up to 12 times ULN with normal total bilirubin and ALP 14 days after the administration of IV paclitaxel plus carboplatin. Following the American Association for the Study of Liver Diseases Practice (AASLD) guideline,4 we have done complete check-ups of the patient’s liver function, potential infection causes, medication usage, and medical histories. After excluding the alternative causes, it led us to attribute the liver injury to the use of paclitaxel. According to the LiverTox,2 the likelihood score that estimates whether a medication is a cause of liver injury for paclitaxel is D (possible cause of acute hepatic necrosis associated with a hypersensitivity reaction to the initial infusions). In this case, we excluded the hypersensitivity reaction due to no signs or symptoms such as chest tightness or facial flushing during the infusion and the following first week.

Because the total bilirubin and ALP were normal initially and there were no signs or symptoms of acute liver injury or failure, our primary plan is to closely monitor the patient’s LFTs weekly and administer liver protective medications. In China, unlike in many other countries, a wide range of medications is frequently used to treat elevated liver enzymes arising from various causes. The use of liver protective medication remains controversial due to the lack of robust evidence supporting its efficacy. While some clinical studies suggest benefits,^5,6 more high-quality, randomized controlled trials are needed to confirm their efficacy in the context of chemotherapy-induced liver injury. According to the Chinese Medical Association’s guideline, for patients with mild to moderate hepatocellular and mixed drug-induced liver injury without jaundice, oral or intravenous drugs such as glycyrrhetinic acids and glutathione may be used due to their favorable safety profile. ⁷ In this case, the patient was treated with magnesium isoglycyrrhizinate and glutathione to potentially support adherence to the timeline for chemotherapy cycles, which is crucial for maintaining chemotherapy efficacy. Considering the available evidence and the patient’s situation, we believe the benefits of using liver protective medications outweigh the risks for this patient.

The decision to rechallenge with paclitaxel was based on several considerations. The patient showed a favorable response to chemotherapy, indicated by the normalization of CA125 levels, suggesting the regimen was effective in managing her OC. In addition, after the initial elevation of LFTs, the patient’s liver enzymes significantly improved after using liver protective medications and a 3-week recovery period. This indicated that the liver injury was manageable and not progressing to acute liver failure. As we excluded a hypersensitivity reaction to paclitaxel and this regimen is preferred according to National Comprehensive Cancer Network (NCCN) guidelines,1 we decided to rechallenge the patient with paclitaxel at a reduced dose (135 mg/m² instead of 175 mg/m²) based on package-insert recommendations. ⁸ This was expected to mitigate the risk of further hepatotoxicity while maintaining therapeutic efficacy. The patient’s LFTs were closely monitored throughout subsequent cycles, allowing for early detection and management of further liver function abnormalities. As shown in Figure 1, the patient’s LFTs were continuously elevated around 2 to 3 times the ULN after each cycle of IV chemotherapy. However, following a 3-week recovery, the patient’s LFTs were stable enough to continue chemotherapy, as our threshold to restart the chemotherapy cycle was around 2 times the ULN. Using a lower dose of paclitaxel may reduce the efficacy of decreasing the risk of recurrent OC. However, considering the patient’s disease stage and the trend in CA125 levels, we deemed it appropriate to continue with the lower paclitaxel dose instead of switching to alternatives. Overall, we believe the 3-week delay in the first cycle and the dose reduction of paclitaxel for subsequent cycles did not jeopardize the patient’s prognosis. If the disease progresses or recurs, we may consider using albumin-bound paclitaxel, as some studies have shown a lower risk of adverse reactions.^9,10

To summarize this case, we presented a patient with OC developed sub-acute liver injury due to the use of paclitaxel and successfully managed by frequent LFTs monitoring, using liver protective medications, and dose reduction of paclitaxel for the following chemotherapy cycles. It will provide a reference for caring for this type of patient and optimizing the prognosis by balancing the prevention of further liver injury and ensuring the efficacy of chemotherapy. Further study is needed to clarify the mechanism of paclitaxel-induced hepatotoxicity and identify the high-risk group of patients to develop liver injury corresponding to the use of paclitaxel.