Efficacy and safety of viscum fraxini-2 in advanced hepatocellular

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10 454 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8 www. springerlink. com/content/1613-9089 457 ing Table into 1 Patient account characteristics the viability of hepatic tumors rather than tumor shrinkage. The subsets of patients in the cur- n % rent study presenting with similar criteria (early stage of the Sex disease with minimal or no symptoms) gained the best Male 83 69.2 benefit from palliative treatment with viscum fraxini-2. Female 37 30.8 The overall objective response rate was significantly bet- Performance Status (ECOG) ter in cases with: good PS (32% in patients with PS 0–1), 0 3 2.5 and earlier tumor stage (47% in Okuda Stage I). 1 59 49.2 2The treatment in the current study 58 was well tolerated; 48.3 the Ascites most common drug-related adverse events were pain and Absent erythema at the injection site and 56 drug related 46.7 fever. The Present adverse events were generally mild, 64 manageable 53.3 and gradually Hepatitis abate with subsequent injections. There were no HCV drug (+) related discontinuation or toxic 72 deaths. 60.0 HbsAg The median (+) overall survival was 8 months; 26 this 21.7 cannot be Both compared (+) to other studies due to differences 10 in 8.3 study design, Virology selection (–) criteria and etiology 12 of cirrhosis. 10.0 However Child-pugh in our classstudy a remarkable median overall survival of A16 months was recorded in patients 37 who achieved 30.8 a disease B control on treatment. 83 69.2 Number On the of lesions basis of the study results, it can be concluded Single 48 40.0 that, Viscum Fraxini-2 is an effective treatment for pa- Multifocal 72 60.0 tients with advanced HCC. It can achieve a disease control Okuda stage rate of 53% including a 20% overall response, with some I 30 25.0 occasional complete responses. The response is higher in II 90 75.0 patients Metastasis/macro-vascular with good performance invasion status and earlier stage of the Absent disease (Okuda Stage I). Cases who 53achieve a 44.2 disease control Presentare expected to obtain a significantly 67 higher 55.8 overall Agesurvival. Given the high safety of viscum fraxini-2 and the Mean previous (SD) reports on its ability to reduce 56.0 (9.0) the side effects Range of chemotherapy, further phase II trials 38.0–81.0 in combination Bilirubin with (mg/dL) other active agents in HCC are highly indicated. Analysis Mean (SD) with a larger number of patients 2.4 in (2.1) a controlled phase Range III clinical trial is clearly warranted. 0.3–12.0 Albumin (gm/dL) Mean (SD) 3.2 (0.5) References Range 2.2–4.7 INR 1. Varela M, Sala M, Llovet JM, Bruix J. Treatment of hepatocellular Mean (SD) 1.5 (0.3) carcinoma: is there an optimal strategy? Cancer Treat Rev, 2003, 29: Range 99–104. 1.0–2.3 2. AFP Llovet (ng/mL) JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, Mean staging, (SD) and treatment of hepatocellular carcinoma. 1508 (3329) Liver Transpl, Range 2004, 10: S115–120. 4–22040 3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet, 2003, 362: 1907–1917. tendency and dispersion. Association between categori- 4. Thomas MB. Systemic therapy for hepatocellular carcinoma. Cancer cal J, variables 2008, 14: was 123–127. tested by the Chi Square Test. Survival 5. and Simonetti time to RG, progression Liberati A, Angiolini analyses C, et were al. Treatment calculated of hepatocel- by the Kaplan-Meier lular carcinoma: Product-Limit a systematic review Estimator. of randomized Progression controlled trials. free survival Ann Oncol, was 1997, calculated 8: 117–136. from the date of entry to the date 6. of objective Mathurin P, disease Rixe O, progression Carbonell N, et or al. death. Overview Overall of medical survival treat- was ments measured in unresectable from the hepatocellular date of entry carcinoma to the – an date impossible of last follow meta-analysis? up or death. Aliment The Pharmacol study outcomes Ther, 1998, were 12: 111–126. assessed ac- 7. cording Martin to RC the 2nd, intention-to-treat Jarnagin WR. Randomized principle. clinical trials All in statistical hepatocellular carcinoma and biliary cancer. Surg Oncol Clin N Am, 2002, 11: tests were two-sided. 193–205. 8. Table Llovet 2 JM, Tumor Ricci response* S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008, 359: 378–390. 95% CI 9. Becker H. Botany of European n mistletoe % (Viscum Lower album L). Oncology, Upper 1986, 43 Suppl 1: 2–7. Complete response 2 1.7 0.0 4.2 10. Kienle GS, Berrino F, Bussing A, et al. Mistletoe in cancer – a sys- Partial tematic response review on controlled 22 clinical 18.3 trials. Eur J 11.7 Med Res, 25.0 2003, 8: Stable 109–119. disease 40 33.3 25.0 42.5 11. Progressive Bussing disease A, Schietzel M. Apoptosis-inducing 50 41.7 properties 32.5 of Viscum 50.8 al- Not Assessed bum L. extracts from different 6 host trees, 5.0 correlate 1.7 with their 9.2 content • Intention-to-treat of toxic mistletoe analysis lectins. Anticancer Res, 1999, 19: 23–28. 12. Park WB, Lyu SY, Kim JH, et al. Inhibition of tumor growth and metastasis by Korean mistletoe lectin is associated with apoptosis and Results antiangiogenesis. Cancer Biother Radiopharm, 2001, 16: 439–447. 13. Kienle GS, Glockmann A, Schink M, et al. Extracts in breast and gyn- Patient aecological characteristics cancers: a systematic review of clinical and preclinical A research. total of J Exp 120 Clin patients Cancer Res, were 2009, enrolled 28: 79. between June 2007 14. Therasse and January P, Arbuck 2009. SG, Baseline Eisenhauer characteristics EA, et al. New guidelines are shown to in (Table evaluate 1); the the response mean to age treatment of studied in solid cases tumors. was European 56 years Or- with ganization a male for to Research female ratio and Treatment of 2.2/1. of Chronic Cancer, National hepatitis Cancer C virus Institute infection of the United was the States, predominant National Cancer cause Institute of of liver Canada. dis- J Natl Cancer Inst, 2000, 92: 205–216. ease (60%), followed by hepatitis B (22%). The diagnosis 15. Simon R. Optimal two-stage designs for phase II clinical trials. Con- of HCC trol Clin was Trials, based 1989, on 10: fine 1–10. needle cytology in 55 patients (46%). 16. Mohmad The NH, remaining El-Zawahry 65 HM, patients Mokbtar NM, (54%) et al. were Review diagnosed of epidemi- by marked ologic and elevation clinicopathologic of α-fetoprotein features of 403 hepatocellular level and carcinoma imaging studies patients. indicating J Egyptian HCC. Nat Cancer Distant Inst, 2000, metastasis 12: 87–93. were present in 17. 37 Abdel-Wahab cases (31%), M, El-Ghawalby 18 cases (15%) N, Mostafa lymph M, et node al. Epidemiology metastasis, of 11 cases hepatocellular (9%) bone carcinoma metastasis, in lower Egypt, and 8 Mansoura cases (7%) Gastroenterology lung metastasis. Center. Thrombosis Hepatogastroenterology, of the main 2007, portal 54: 157–162. vein or one of its two 18. Elluru major SR, branches VAN Huyen was JP, Delignat present S, in et al. 51 Antiangiogenic cases (43%). properties of viscum album extracts are associated with endothelial cytotoxicity. All patients were chemotherapy naive. The median Anticancer Res, 2009, 29: 2945–2950. duration 19. Harmsma of M, treatment Gromme M, on Ummelen viscum M, et fraxini-2 al. Ramaekers, is 17 Differential weeks (range effects 2–121 of Viscum weeks). album extract IscadorQu on cell cycle progression and apoptosis in cancer cells. Int J Oncol, 2004, 25: 1521–1529. Response 20. Sagar SM, Yance D, Wong RK. Natural health products that inhibit According angiogenesis: to a the potential RECIST source 24 for patients investigational (20%) new achieved agents to objective treat cancer-Part response, 2. Curr 2 patients Oncol, 2006, (1.7%) 13: 99–107. achieved complete response 21. Lyu SY, Choi and SH, 22 Park patients WB. Korean (18.3%) mistletoe achieved lectin-induced partial apoptosis response. in hepatocarcinoma Forty patients cells is (33.3%) associated achieved with inhibition stable of telomerase disease. via mitochondrial controlled pathway independent of p53. Arch Pharm Progressive disease has been shown in 50 patients (41%). Res, 2002, 25: 93–101. 6 22. patients Kim WH, (5%) Park did WB, not Gao have B, et evaluation al. Critical role of response of reactive due oxygen to early species death and (Table mitochondrial 2). membrane potential in Korean mistletoe The lectin-induced overall apoptosis objective in human response hepatocarcinoma rate was significantly cells. Mol Phar- higher macol, in 2004, cases 66: with: 1383–1396. good PS (32% in patients with PS 0–1 23. Harmsma vs. only M, 7% Ummelen in patients M, Dignef with W, PS et 2), al. well Ramaekers, compensated Effects of cirrhosis mistletoe (32% (Viscum in album Child-Pugh L.) extracts class Iscador A vs. on cell 15% cycle in and Child- sur- Pugh vival class of tumor B), cells. and Arzneimittelforschung, earlier tumor stage 2006, (47% 56: 474–482. in Okuda Stage 24. Horneber I vs. 11% MA, Bueschel in Okuda G, Huber stage R, II) et (Table al. Mistletoe 3). On therapy multivari- in oncology. Cochrane Database Syst Rev, 2008, 2: CD003297. ate regression analysis only PS 0-1 and Okuda Stage I was 25. Chao Y, Chan WK, Birkhofer MJ, et al. Phase II and pharmacokinetic associated study of paclitaxel with better therapy response for unresectable to treatment hepatocellular (Table carcinoma 4). patients. Br J Cancer, 1998, 78: 34–39. Survival 26. Rougier P, Ducreux M, Kerr D, et al. A phase II study of raltitrexed By ('Tomudex') the end in of patients follow with up hepatocellular 20 patients carcinoma. (20%) remained Ann Oncol, progression 1997, 8: 500–502. free, the median progression free survival for all 27. patients Stuart K, Tessitore was 4 J, months Rudy J, (range et al. A Phase 1–28 II months; trial of nolatrexed 95% CI di- 3.3:4.7 hydrochloride months) in (Fig. patients 1). with The advanced median hepatocellular overall survival carcinoma. for all patients Cancer, 1999, was 86: 8 410–414. months (range 1–28 months; 95% CI
458 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8 www. springerlink. com/content/1613-9089 453 11 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] 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 . These positive results and the need for effec- scan (CT) of the abdomen, and a nuclear bone scan when tive safe systemic agents for patients with advanced HCC needed. prompted this phase II study to determine the response Patients were seen on a weekly basis during treatment rate to viscum fraxini-2 in advanced HCC. The second- for history taking and physical examination. A complete ary objectives were to evaluate the safety of the drug, the blood count serum creatinine and liver functions were predictive factors of tumor response, and to estimate the performed every 4 weeks. The tumor was assessed by CT progression free and overall survival in studies patients. scan of the abdomen every 8 weeks. Responses were evaluated by independent staff radiologists and confirmed by Patients and methods CT after 4 weeks. Tumor response was classified on the basis of the response evaluation criteria in solid tumors This was a prospective uncontrolled phase II trial in guidelines (RECIST) patients with advanced HCC. The protocol was approved by the institutional review board. Informed consent was obtained from each patient. Patient characteristics The study population consisted of patients with advanced-stage HCC. The diagnosis of HCC was confirmed by pathological analysis or α-fetoprotein > 400 ng/mL with a hepatic tumor highly suggestive of HCC by imaging studies. Patients were classified as having advanced disease if they were not eligible for surgical or locoregional therapies. Patients were required to have at least one target lesion that could be measured in one dimension. Exclusion Criteria included: (1) Eastern Cooperative Oncology Group (ECOG) performance status > 2; (2) Advanced hepatic decompensation (Child-Pugh class C); (3) Advanced medical co-morbidity; (4) Previous systemic therapy; (5) Other malignancy or concomitant anti-tumor therapy including tamoxifen and interferon. [14] . 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 © 28. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of 29. Mabed M, El-Helw L, Shamaa S. Phase II study of viscum fraxini-2 in doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst, 2005, 97: 1532–1538. patients with advanced hepatocellular carcinoma. Br J Cancer, 2004, 90: 65–69. 《中德临床肿瘤学杂志》2011年征稿启事《中德临床肿瘤学杂志》是由中华人民共和国教育部主管,华中科技大学主办的医学肿瘤学学术期刊(全英文月刊),是中国科技论文统计源期刊、中国科技核心期刊,被德国SpringerLink、中国知网、万方数据等国内外多家数据库收录。国际、国内刊号为:ISSN 1610-1979 (纸版),1613-9089 (网络版);CN 42-1654/R,邮政代号: 38-121。本刊主要刊登世界各国作者,特别是中国作者在肿瘤学领域的优秀科研成果和临床诊疗经验,包括与临床肿瘤学密切相关的基础理论研究等成果,并全文以英语发表,在国内外公开发行。辟有述评、专家笔谈、论著、临床研究、实验研究、综述、病例报道、人物专栏等栏目。本刊具有编审效率高、出版周期短、学术价值高、临床实用性强、印刷精美等特点。承诺将一如既往地以广大作者为依托,积极为作者和读者服务,严格做到对所有来稿处理及时、审稿认真、退修详细、发稿迅速。对具有国际领先水平的创新科研成果及国家重点项目开辟“绿色通道”,审稿迅速,刊登及时。欢迎全国各级肿瘤学医务工作者踊跃投稿、组稿! 《中德临床肿瘤学杂志》2011年重点专栏报道计划如下: 1,肺癌;2,肝癌;3,胰腺肿瘤;4,胃肠肿瘤;5,乳腺肿瘤;6,甲状腺癌;7,骨肿瘤;8,泌尿生殖系肿瘤;9,脑肿瘤;10,血液系统疾病;11,妇科肿瘤;12,耳鼻喉科肿瘤;13,皮肤肿瘤;14,肿瘤诊断学(特别是肿瘤影像诊断学);15,肿瘤化疗;16,肿瘤放疗;17,肿瘤心理学;18,其他。敬请您关注,欢迎您踊跃投稿、组稿!具体投稿和联系方式请参见杂志版权页。 for windows (Statistical Package for Social Scientists) Release 15. All tests ——中德临床肿瘤学杂志编辑部 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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