Gemcitabine and Oxaliplatin Combinations for Patients with Hepatocellular Carcinoma

Abstract & Commentary

Synopsis: Hepatocellular carcinoma is one of the most common malignancies worldwide, and, for those with advanced disease, treatment responses have been dismal. The current report of a trial of gemcitabine and oxaliplatin offers some hope. Using 2 different schedules of these agents, this study found an approximate 20% objective response rate with stable disease occurring in an additional 50%. The combinations were well tolerated, with Grade 3 hematotoxicity occurring in approximately one-third, but there was no severe hematologic or non-hematologic toxicity, including no cases of Grade 3 or 4 neurotoxicity.

Source: Taieb J, et al. Cancer. 2003;98:2664-2670.

Hepatocellular carcinoma (HCC) is among the most common tumors worldwide, yet effective treatment remains elusive. In the current report from France, 2 different schedules of gemcitabine and oxaliplatin were examined prospectively in a total of 21 patients with HCC. Eleven patients received gemcitabine 1000 mg/m2, as an infusion of 10 mg/m2 per minute (total of 100 minutes/m2) on Day 1, followed by oxaliplatin 100 mg/m2 as a 2-hour infusion on Day 2 (GEMOX-1 regimen). Ten subsequent patients received same-day therapy with gemcitabine 1500 mg/m2 as a 30-minute infusion followed by oxaliplatin 85 mg/m2 as a 2-hour infusion (GEMOX-2). Treatments were repeated every 2 weeks, and doses were adjusted if Grade 3-4 toxicity occurred. If Grade 3 oxaliplatin neurosensitivity developed, the drug was discontinued and patients continued with gemcitabine as a single agent. Patients who responded or had stable disease received the full treatment for at least 4 months. Treatment was discontinued in patients with progressive disease, repeated Grade 3-4 toxicity, or with treatment refusal.

Patients were recruited onto study for a 6-month period, 10 patients were receiving initial chemotherapy, and 11 had previously been treated and progressed on a different chemotherapy regimen. Several of the patients had hepatitis B or C infections, and some had a history of heavy alcohol use. Underlying cirrhosis was present in 18 of the 21 patients. These characteristics were balanced with regard to those treated with the GEMOX1 vs GEMOX2 schedules.

The overall response rate was 19% (95% CI, 13-26%). Ten patients (48%) had stable disease and 7 patients (33%) had progression. Responses lasted from 4 to 8 months, and the median progression-free survival was 5 months and overall survival, 12 months. There were no differences in overall survival or progression-free survival were between the 2 treatment groups. Among the 16 patients with initially elevated AFP levels, the level fell by > 50% during therapy in 9 patients. Among the 15 patients with an initial performance status of > 0, 8 patients (53%) exhibited improvement during treatment. Weight gain (without edema or ascites) was observed in 8 patients and pain, ascites appetite and asthenia improved in 6 of 10 patients who were initially symptomatic. The median time to symptom improvement was 6 weeks.

Grade 3-4 toxicity occurred in 8 patients, with hematological toxicity being most common. There were no treatment-related deaths and no episodes of febrile neutropenia. No Grade 3 neurotoxicity was observed. Comparing GEMOX-1 with GEMOX-2, there was no significant difference in antitumor efficacy, but GEMOX-1 was tolerated better.

Comment by William B. Ershler, MD

The prior experience with chemotherapy for HCC has been discouraging. Accordingly, even the modest findings reported seem like a ray of sunshine. Measurable, sustained improvement in 19% and stable disease in close to 50% compares favorably to any other published experience, especially when considering that more than half of the patients had progressed on prior chemotherapy. Furthermore, the toxicity profile was reasonable, and dose reductions and delays were infrequent. Other chemotherapy regimens have included 5-flurouracil, cisplatin, and doxorubicin with response rates varying 5-25% but with significant toxicity.1-3 In one recently reported trial, there was a 0% objective response rate with either single-agent doxorubicin or nolatrexed.4 Similarly, Phase II studies of other agents, including paclitaxel, irinotecan, and topotecan have yielded discouraging results.

Thus, the combination of gemcitabine and oxaliplatin offers a promising new approach to the management of this difficult tumor. Additional, larger-scale trials are needed to establish the optimal dosing and scheduling of these agents and to determine if there are predictive factors that would indicate likely treatment response.

Dr. Ershler is Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

References

1. Falkson G, et al. Cancer. 1987;60:2141-2145.

2. Lai EC, et al. Cancer. 1990;66:1685-1687.

3. van Eeden H, et al. Ann Oncol. 1992;3: 404-405.

4. Mok TS, et al. Cancer Chemother Pharmacol. 1999;44:307-311.