Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Background and objective: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib.

Methods: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9–3.3) compared to 5.0 months (95% CI 2.5–8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9–14.4) compared to 15.1 months (95% CI 11.7–17.8) for those who were not given metformin (p = 0.014).

Conclusions: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.     

根皮苷可增强索拉非尼抑制肝癌细胞能量代谢及活力

目的：探讨根皮苷联合索拉非尼对肝癌细胞能量代谢与凋亡的影响。方法：将根皮苷5 μmol/L和（或）索拉非尼5 μmol/L作用于HepG2细胞48 h后,检测肝癌细胞活力、肝癌细胞葡萄糖摄取与细胞内ATP含量、caspase-3活力与凋亡细胞计数。结果：索拉非尼组肝癌细胞活力降低,与对照组差异有统计学意义（P<0.05）;索拉非尼与根皮苷联合组肝癌细胞活力进一步降低,与其他各组（对照组、索拉非尼组及根皮苷组）差异均有统计学意义（P<0.05）。根皮苷组葡萄糖摄取及ATP生成减少,与对照组差异有统计学意义（P<0.05）;索拉非尼与根皮苷联合组葡萄糖摄取及ATP生成进一步减少,与其他组差异均有统计学意义（P<0.05）。索拉非尼组与根皮苷组caspase-3活力与细胞凋亡较对照组增强（P<0.05）;索拉非尼与根皮苷联合组caspase-3活力与细胞凋亡进一步增强,与其他组差异均有统计学意义（P<0.05）。结论：根皮苷可以通过抑制肿瘤细胞ATP生成和促进肿瘤细胞凋亡来提高索拉非尼疗效。     

Adjuvant treatments for resectable hepatocellular carcinoma

Hepatocellular carcinoma often recurs even after curative resection. Although some encouraging data showing improvements in recurrence-free times have been reported with the use of intraarterial 131I-lipiodol infusion, retinoids, interferon, or immunotherapy after hepatectomy, there is no consensus regarding standard adjuvant therapy for resectable hepatocellular carcinoma. A novel target agent, sorafenib, which has recently become a standard of care for advanced disease, may also be promising in an adjuvant setting to prevent early recurrence after curative surgery. In future trials, it will be important to identify appropriate target populations for each type of adjuvant approach; that is, an agent with definitive antitumor activity for high-risk patients, and one that shows chemoprevention for low-risk patients.     

Feasibility of Sorafenib Combined with Local Radiotherapy in Advanced Hepatocellular Carcinoma

Purpose

Sorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy.

Materials and Methods

From July 2007 to July 2011, 31 patients were treated with a daily dose of 800 mg of sorafenib and radiotherapy. Among them, 13 patients who received radiotherapy on the bone metastasis were excluded. Thirteen patients received 30-54 Gy of radiotherapy on the primary tumor (primary group) and 5 patients received 30-58.4 Gy on the measurable metastatic lesions (measurable metastasis group). Tumor responses at 1 month after the completion of radiotherapy and overall survival were evaluated.

Results

The in-field response rate was 100% in the primary group and 60% in the measurable metastasis group. A decrease of more than 80% in the tumor marker α-fetoprotein was observed in 7 patients in the primary group (54%). Toxicities of grades 3-4 were hand-foot syndrome in 3 (17%) patients, duodenal bleeding in 1 (6%) patient, thrombocytopenia in 3 (17%) patients and elevation of aspartate transaminase in 1 (6%) patient. The median overall survival was 7.8 months (95% confidence interval, 3.0-12.6).

Conclusion

The combined treatment of sorafenib and radiotherapy was feasible and induced substantial tumor responses in the target lesions. The results of this study emphasize the importance of individualized approach in the management of advanced hepatocellular carcinoma and encourage the initiation of a controlled clinical trial.