XP For Metastatic HCC

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Successful treatment for patients with metastatic HCC remains elusive. In this Phase II study, a combination of capecitabine and cisplatin was administered safely to a cohort of 32 HCC patients with measurable extrahepatic disease. Objective response was seen in only 6.3 patients, and the median time to progression was just 2 months. Nonetheless, stable disease was observed in 33.4% and overall survival was 12.2 months.

Source: Lee JO, et al. Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncology. 2009;20:1402-1407.

Hepatocellular Carcinoma (HCC) commonly presents at an advanced stage and, often, extrahepatic disease precludes local surgical or ablative approaches. Historically, systemic chemotherapy has been of marginal value in HCC patients1 but, recently, the multikinase inhibitor sorafenib has been shown to extend overall survival in patients who present with advanced disease.2,3 However, a subgroup analysis of the large phase III studies revealed a relatively low benefit for sorafenib over placebo in patients with extrahepatic spread.2 Thus, there persists a need for the development of effective treatment for patients with metastatic HCC.

In this context, Lee et al evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic HCC. This approach was based upon earlier studies indicating some activity of each drug used as single agents.4,5 Over a four-year period, they enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2,000 mg/m2/day) with a schedule of two weeks on and one week off and cisplatin (60 mg/m2) on the first day of each three-week cycle.

The study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was two months (95% confidence interval [CI] 1.5-2.4) and the median overall survival (OS) time was 12.2 months (95% CI 6.5-17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%), and anemia (2.1%). The grade 3/4 nonhematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%), and nausea (3.2%). There was no treatment-related mortality.

Commentary

There are a number of strategies approved, or under development, for the treatment of localized HCC. These include surgical resection, liver transplantation, percutaneous ethanol injection (PEI), and radiofrequency ablation.1 However, the great majority of patients present with more advanced disease, precluding curative intent approach. Transarterial chemoembolization (TACE) is the recommended first-line, non-curative therapy for inoperable cases,6,7 but this procedure is indicated for patients who have good liver function, good performance status, no portal hypertension, and no portal vein thrombosis.8 Sorafenib represents a major advance for the management of this disease, but there remain some for which demonstrable benefit has been only slight. Included are those with extrahepatic metastatic disease.

Based on the observations reported by Lee et al, we remain without a standard systemic approach for patients with metastatic disease. The response rate and TTP in XP-treated patients was only modest. However, the combination showed tolerable toxicity and was associated with a favorable overall survival. Although there remains no standard approach for HCC patients with metastatic disease, XP might be a reasonable approach for some, and might also be explored as an adjunct to primary local approaches in the setting of a clinical trial.

References

1. Mendizabal M, Reddy KR. Current management of hepatocellular carcinoma. Med Clin North Am. 2009; 93:885-900.

2. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.

3. Cheng AL, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34.

4. Okada S, et al. A phase 2 study of cisplatin in patients with hepatocellular carcinoma. Oncology. 1993;50:22-26.

5. Patt YZ, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004;101:578-586.

6. Zhong C, et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for Stage III A hepatocellular carcinoma. J Cancer Res Clin Oncol. 2009;135:1437-1445.

7. Llovet JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet. 2002;359:1734-1739.

8. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.