Abstract
BackgroundBased on promising results from a Phase I study of hepatic arterial infusion chemotherapy using a combination of miriplatin and cisplatin powder (DDP-H) for unresectable hepatocellular carcinoma (UMIN-CTR000003541), a multicenter, open-label, randomized phase II study was conducted to evaluate the efficacy and safety of the combination therapy versus miriplatin monotherapy.MethodsNineteen patients, five and fourteen Barcelona-Clinic Liver Cancer staging classification A and B cases, respectively, were randomly assigned to receive either miriplatin monotherapy (n = 9) or miriplatin/DDP-H combination therapy (n = 10). DDP-H and/or miriplatin were administered through the hepatic arteries supplying the lobes of the liver containing tumors, and progression free survival was analyzed as a primary end point in addition to other secondary endpoints. The corresponding therapy was repeated unless disease progression or severe adverse events were recorded.ResultsThe monotherapy or combination therapy was performed for 15 or 36 sessions in total, respectively. Although there were no significant differences between the two groups for treatment intervals (p = 0.96) or the dose of miriplatin used in each session (p = 0.99), the progression free survival and overall disease control rate were significantly better in the combination therapy group (91 vs 423 days, p = 0.025; 40.0 vs 77.8%, p = 0.0025, respectively). Consistent with these observations, a trend of a significantly slower increase in des-γ-carboxyprothrombin was observed, and the number of treatment sessions was nearly significantly larger in the combination therapy group (p < 0.0001, p = 0.057, respectively). Conversely, the median survival time did not show a significant difference (706 days, monotherapy vs 733 days, combination therapy; p = 0.40). A significant decrease in cholinesterase was observed during the course of treatment only in patients receiving combination therapy (r = −0.86, p < 0.0001). A few cases in both arms showed hematological and/or non-hematological toxicities that were categorized as grade 1 (NCI-CTCAE).ConclusionsThe higher disease control effects with the combination of miriplatin and DDP-H indicate that it is a promising alternative treatment for cases with multiple HCCs, especially for those that can tolerate the treatment without experiencing a reduction in hepatic reserve.Trial registrationThis study was registered on 1 January 2012 with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm, UMIN000004691).
Highlights
Based on promising results from a Phase I study of hepatic arterial infusion chemotherapy using a combination of miriplatin and cisplatin powder (DDP-H) for unresectable hepatocellular carcinoma (UMINCTR000003541), a multicenter, open-label, randomized phase II study was conducted to evaluate the efficacy and safety of the combination therapy versus miriplatin monotherapy
Based on a pretreatment evaluation, 20 eligible patients were enrolled in this study and randomly assigned to one of the 2 study arms, either the transarterial oily chemoembolization (TOCE) monotherapy or TOCE + hepatic arterial infusion chemotherapy (HAIC) combination therapy
Among the 11 patients allocated to the TOCE + HAIC, one case was excluded from further followup because radio frequency ablation therapy was performed on the target before the first efficacy evaluation
Summary
Based on promising results from a Phase I study of hepatic arterial infusion chemotherapy using a combination of miriplatin and cisplatin powder (DDP-H) for unresectable hepatocellular carcinoma (UMINCTR000003541), a multicenter, open-label, randomized phase II study was conducted to evaluate the efficacy and safety of the combination therapy versus miriplatin monotherapy. Because the chemotherapeutic action of platinum agents depends on their concentration, HAIC has been widely applied in Japan by utilizing a CDDP powder (DDP-H, IA-call®; Nippon Kayaku Co., Ltd), as it has been reported to provide the highest concentration of CDDP [8, 10, 11] Given these advances in the development of new chemotherapeutics, we conducted a phase I study on the combination therapy of miriplatin-TOCE and DDP-H-HAIC and demonstrated that miriplatin and DDP-H can be administered in combination up to the maximum tolerated dose of each drug without additional adverse events. We report the safety and efficacy profiles of the combination therapy based on the results of the subsequent phase II clinical trial
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