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A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

SUBMITTER: Dalhoff K

PROVIDER: S-EPMC2394267 | biostudies-other | 2003 Jul

REPOSITORIES: biostudies-other

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Project description:Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of patients with HCC remain very poor. This study was conducted to evaluate the efficacy and safety of viscum fraxini-2 in patients with chemotherapy-naïve, advanced hepatocellular carcinoma. 23 patients with unrespectable HCC who had received no prior systemic chemotherapy with objectively measurable tumors were enrolled on this study. The mistletoe preparation for the study is an aqueous injectable solution. It contains one milliliter of viscum fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe herb from ash tree, diluted in di-natrium-mono-hydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/ml injection ampoules. 2 ampoules of viscum fraxini-2 were administered subcutaneously once weekly. As assessed by conventional imaging criteria, 3 (13.1%) patients have achieved complete response, 2 (8.1%) patients have achieved a partial response. 9 (39.1%) had progressive disease while 9 (39.1%) patients didn't have evaluation of response due to early death. The median overall survival time for all patients was 5 months (range 2-38 months), for those who achieved a CR was 29 months (range 12-38 months) and, for those who achieved a PR was 6.5 months (range 6-7 months). The median progression free survival for all patients was 2 months (range 1-38 months), for those who achieved a CR, it was 29 months (range 8-38 months) and for those who achieved a partial response, it was 5 months (range 4-6 months). No hematologic toxicity has been encountered. The spectrum of non-hematologic toxicity was mild. The WHO toxicity criteria grade 3-4 were 34.8% drug related fever, 13.1% erthyma at injection site and 17.4% pain at the site of injection. No drug related discontinuation or toxic deaths have occurred. Viscum fraxini-2 seems to be particularly promising in patients with advanced HCC, it shows antitumor activity and low toxicity profile. Further studies in combination with other active agents are clearly warranted.

Project description:Lessons learnedDefinitive concurrent chemoradiotherapy based on oxaliplatin and endostatin was effective with the objective response rate exceeding 80%, and the treatment-related toxicities were acceptable.The treatment compliance of the current combination was much higher, without significant reduction in survival outcomes, than historical reports.BackgroundThis phase II trial aimed at assessing the efficiency and safety of definitive concurrent chemoradiotherapy (dCRT) using oxaliplatin (OHP) and endostatin in patients with inoperable esophageal squamous cell carcinoma (ESCC).MethodsRadiotherapy was delivered with a daily fraction of 2.0 Gy to a total dose of 60.0 Gy over 6 weeks. Endostatin and OHP were both intravenously administered at doses of 7.5 mg/m2 daily for 2 weeks and 135 mg/m2 on day 1, respectively, every 3 weeks. The primary endpoint was the objective response rate (ORR).ResultsThe analysis included 37 patients. The median age was 63 years (range: 49-71 years), and all patients were stage III-IVA. Of these patients, 97.3% (36/37) completed the dCRT course with an ORR of 83.8%, including 10 (27.0%) patients with complete response and 21 (56.8%) patients with partial response. The median overall survival (OS) time was 18.5 months (95% confidence interval [CI]: 10.6-26.4) with a 2-year OS rate of 39.6% (95% CI: 0.202-0.590). The median progression-free survival (PFS) time was 11.5 months (95% CI: 7.6-15.4) with a 2-year PFS rate of 20.2% (95% CI: 0.049-0.355). Grade 3 toxicities included esophagitis (five patients) and leukocytopenia (three patients). Grade 4 leukopenia was observed in one patient. Late toxicity was infrequent, and no treatment-related death occurred. Posttreatment dysphagia scores were significantly improved when compared with baseline (p < .001).ConclusiondCRT based on OHP and endostatin resulted in high treatment compliance with manageable toxicities. This combination resulted in encouraging ORR without compromising survival outcomes. It should be validated in future clinical studies.

Project description:Lessons learnedTrebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2.BackgroundAng-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).MethodsPatients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2.ResultsThirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts.ConclusionThere was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

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A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.

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