Efficacy and safety of viscum fraxini-2 in advanced hepatocellular

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Reprint from: Chinese-German Journal of Clinical Oncology Vol. 9, No. 8/2010 pp 452 – 458 © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2010 ABNOBA 2010/2011
Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8 Wirksamkeit und Sicherheit von Viscum Fraxini-2* bei fortgeschrittenem hepatozellulärem Karzinom: cotoxins cause membranolysis. Polysaccharides activate natural killer cells. Vesicles enhance T-cell proliferation especially helper cells [11, 12] . In a systematic review on controlled clinical trials, 23 studies were identified: 16 randomized, 2 quasi-randomized and 5 non-randomized. Cancer sites included breast, lung, stomach, colon, rectum, head and neck, kidney, bladder, melanoma, and genital. Among these studies, statistically significant positive outcomes were reported for survival (n = 8), tumor remission (n = 1), overall quality of life (n = 3), and quality of life in relation to side effects during cytoreductive therapy (n = 3) [10] . A more recent review evaluated the therapeutic effectiveness of viscum album extract on gynecological and breast cancer. The review included 19 randomized, 16 non-randomized controlled studies, and 11 single-arm cohort studies. Nine randomized controlled trials and 13 non-randomized controlled studies assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. Single-arm cohort studies investigated tumor behavior, and safety. Tumor remission was observed after high dosage and local application. The treatment was well tolerated [13] Eine Phase II Studie Ziel Um die Prognose von Patienten mit hepatozellulärem Karzinom im fortgeschrittenen Stadium zu verbessern, werden neue systemische Therapien benötigt. Diese Studie wurde durchgeführt, um die Wirksamkeit und Sicherheit von Viscum Fraxini-2 (abnobaVISCUM Fraxini 20 mg*) bei fortgeschrittenem hepatozellulärem Karzinom (HCC) zu ermitteln. Methoden Es handelt sich um eine Phase II Studie mit einem 2-Phasen-Design, . These in positive welche results 120 Chemo-naive and the need Patienten for effec- mit tive fortgeschrittenem safe systemic agents HCC for patients eingeschlossen with advanced wurden. HCC Das in prompted der Studie this verwendete phase II study Mistelpräparat to determine ist eine the response wässrige Injektionslösung, rate to viscum fraxini-2 welche in ein advanced Milliliter HCC. abnobaVISCUM The second- Fraxini ary objectives 20 mg were enthält. to evaluate Es wurden the zwei safety Ampullen of the drug, einmal the wöchentlich predictive factors subkutan of tumor verabreicht. response, and to estimate the progression free and overall survival in studies patients. Patients Ergebnisseand methods Die chronische Infektion mit dem Hepatitis-C Virus war This der überwiegende was a prospective Grund uncontrolled (60 %) der Lebererkrankun- phase II trial in patients gen in der with Patientenpopulation. advanced HCC. The Gemessen protocol an was den approved Respon- by se-Kriterien the institutional für solide review Tumoren board. erreichten Informed 24 consent Patien was ten (20 obtained %) eine from „Objective each patient. Response“ (davon 2 mit „Complete Response“) und 40 Patienten (33,3 %) erreichten „Stable Disease“. Patient characteristics Das mediane progressionsfreie Überleben aller Patienten The study betrug population 4 Monate consisted (1–28 Monate; of patients 95 % with Konfiaddenz-Intervall:vanced-stage HCC. 3,3–4,7 The diagnosis Monate). of Das HCC mediane was confirmed Gesamtüberleben by pathological für alle analysis Patienten or α-fetoprotein betrug 8 Monate > 400 (1–28 ng/mL Monate; with a 95 hepatic % Konfidenz-Intervall: tumor highly suggestive 6,3–9,7 of HCC Mo nate). by imag- Für Patienten, ing studies. welche Patients eine were „Stable classified Disease“ as having oder ein advanced Tumoransprechen disease if they erreichten, were not betrug eligible die for mediane surgical Überlebens- or locorezeitgional 16 therapies. Monate. Patients were required to have at least one Die target Nebenwirkungen, lesion that could hauptsächlich be measured in one Form dimen- einer sion. Lokalreaktion (an der Injektionsstelle)* und Fieber, waren im Exclusion Allgemeinen Criteria schwach included: und die (1) Eastern Verträglichkeit Cooperative war Oncology gut. Es gab Group keinen (ECOG) arzneimittelbedingten performance status Studienabbruch > 2; (2) Advanced und keine hepatic Nebenwirkungen decompensation mit (Child-Pugh tödlichem Ausgang. class C); (3) Advanced medical co-morbidity; (4) Previous systemic therapy; (5) Other malignancy or concomitant anti-tumor therapy including tamoxifen and interferon. 4533 Treatment schedule and toxicity assessment 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-monohydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/mL injection ampoules. Two ampoules of viscum fraxini-2 were administered subcutaneously once weekly. The treatment was administered till unacceptable toxicity or documented progression or if the patient chose to discontinue treatment. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria, version 3.0. Pretreatment, follow-up, and response evaluation Prior to treatment all patients provided a complete history and underwent thorough physical examination. Laboratory studies included a complete blood count, biochemical liver function tests, serum creatinine, electrolyes and AFP. Radiological evaluation included chest X-ray, ultrasonography (US) and triphasic computerized scan (CT) of the abdomen, and a nuclear bone scan when needed. Patients were seen on a weekly basis during treatment for history taking and physical examination. A complete blood count serum creatinine and liver functions were performed every 4 weeks. The tumor was assessed by CT scan of the abdomen every 8 weeks. Responses were evaluated by independent staff radiologists and confirmed by CT after 4 weeks. Tumor response was classified on the basis of the response evaluation criteria in solid tumors guidelines (RECIST) [14] Zusammenfassung Die Therapie mit abnobaVISCUM Fraxini 20 mg stellt eine wirksame und sichere Behandlung für Patienten mit fortgeschrittenem HCC dar. Es wird empfohlen, weitere randomisierte und kontrollierte Studien durchzuführen. *) Die mit „*” gekennzeichneten Ergänzungen dienen dem besseren Verständnis. Das hier mit „Viscum Fraxini-2” bezeichnete Arzneimittel entspricht abnobaVISCUM Fraxini 20 mg und wird in Ägypten unter der o. g. Bezeichnung vertrieben. . Statistical analysis A phase II study designed with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥ 20%. The study progressed using the Simon’s two-stage design [15] , recruiting a total of 42 patients in the first stage; the trial will be terminated if 4 or fewer patients respond. If the trial goes on to the second stage, a total of 120 patients will be studied. If the total number responding is less than or equal to 17, the drug is rejected. The first interim analysis suggested potential activity (10 patients responded); therefore, patient enrollment was permitted to continue. Data were analyzed on a personal computer running SPSS © for windows (Statistical Package for Social Scientists) Release 15. All tests are considered significant if (P < 0.05). For descriptive statistics of qualitative variables the Frequency distribution procedure was run with calculation of the number of cases and percentages. For descriptive statistics of quantitative variables the Mean, Range and Standard Deviation were used to describe central
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Efficacy and safety of viscum fraxini-2 in advanced hepatocellular

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