Cetuximab-Gemcitabine for Cholangiocarcinoma: The Belgian Experience
ABSTRACT & COMMENTARY
By William B. Ershler, MD
Synopsis: In a multicenter Phase 2 trial, cetuximab combined with gemcitabine resulted in a progression-free survival rate of 47% at 6 months and median overall survival of 13.5 months. KRAS mutation status did not predict enhanced progression-free survival but the occurrence of grade 3/4 skin toxicity did.
Source: Borbath I, et al, on behalf of the Belgian Group of Digestive Oncology. Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology. Ann Oncol 2013;24:2824-2829.
Cholangiocarcinomas occur uncommonly and remain without effective treatment. The tumors arise from the neoplastic transformation of biliary epithelial cells either within the liver or extrahepatic biliary ducts, most commonly at the hilum.1,2 In part because of their relatively uncommon occurrence, advances in treatment have been slow in development. Thus, surgery remains the only chance for long-term survival, and radical approaches, such as hepatic transplantation, have been undertaken under selected circumstances.3,4 For patients with unresectable disease, some improvement in progression-free and overall survival has been achieved with gemcitabine and cisplatin systemic therapy.5 The demonstration of overexpression of the epidermal growth factor receptor (EGFR) in some cases of cholangiocarcinoma6 or mutated forms in others7 has led to the speculation that EGFR might be an effective target for treatment of cholangiocarcinoma.
Accordingly, the Belgian Group of Digestive Oncology reports a multicenter Phase 2 trial in chemotherapy-naive patients with unresectable cholangiocarcinoma using the monoclonal EGFR-blocking antibody cetuximab (400 mg/m2 at week 1, then 250 mg/m2/week) and gemcitabine (1 g/m2 on days 1, 8, and 15) every 4 weeks. The primary endpoint was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Secondary outcomes included overall survival (OS) and safety profile. Further, the PFS and OS results were examined in the context of skin toxicity and KRAS mutational status.
Enrolled patients either had locally advanced disease (41%) or demonstrable metastatic disease (59%). Median age was 61.5 years and performance status (ECOG) was 0 (68%) or 1 (32%). Six-month PFS reached 47%. Median OS was 13.5 months (95% confidence interval [CI], 9.831.8 months). Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were hematological (52.2%), skin rash (13.6%), and fatigue (11.4%). KRAS mutations were found in 7
of 27 patients and had no influence on PFS. Skin toxic effect ≥ grade 2 was associated with increased PFS (P = 0.05).
The authors conclude that gemcitabine and cetuximab is an active combination for patients with cholangiocarcinoma, as PFS exceeded what would be expected for gemcitabine alone.8 In the small sample size, KRAS mutation status offered no predictive value in contrast to treatment-related skin toxicity, which was a statistically significant indicator of improved PFS.
An alternative to the cetuximab-gemcitabine combination would be cisplatin-gemcitabine. In 2010, the Upper Gastrointestinal Cancer Clinical Studies Group of the United Kingdom published results from the ABC-02 trial in which 410 patients (including those with cholangiocarcinoma as well as gall bladder and ampullary cancers) received either cisplatin (25 mg/m2) followed by gemcitabine (1000 mg/m2), each administered on days 1 and 8, every 3 weeks for eight cycles, or gemcitabine alone (1000 mg/m2 on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks.5 Median survival was 11.7 months for those receiving both drugs compared to 8.1 months for those receiving gemcitabine alone. PFS also favored the combination (8.0 months vs 5.0 months, respectively). Thus, the combination (cisplatin/gemcitabine) would seem comparable to cetuximab/gemcitabine as currently reported. However, the Belgian and U.K. studies were different in many important ways, particularly with regard to inclusion criteria warranting caution with regard to such a comparison.
What is fair to conclude is that cetuximab combined with gemcitabine is an active regimen to be considered for patients with unresectable or metastatic cholangiocarcinoma. A direct comparison with the cisplatin/gemcitabine regimen in a randomized trial might establish one combination as superior in terms of both efficacy and tolerability. Short of that, clinicians may rely on these published reports and their own experience to select first-line systemic therapy in this setting. n
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