Long-term Adjuvant Treatment of Primary Intermediate to High-Risk Malignant Melanoma by Matthias Augustin et al. Category: Cancer and Iscador Summary: A long-term Iscador treatment in patients with mean- to high-risk primary malignant melanoma appears to be safe. A tumor enhancement was not observed. In comparison with an untreated parallel control group from the same cohort the results of the mistletoe treatment show a significant survival advantage in the UICC-/AJCC stages II-III. Study Design The study was designed as a multicenter, comparative, retrolective, epidemiological, cohort study with parallel group design, without intervention. The data with the starting point (i.e. the primary tumor surgery) located in the past was collected forward in time, without previous knowledge of the outcome (i.e. “retrolective” cohort approach) [56−60] from anonymously made medical records in standardized case report forms (CRF). The disease course of the FME-treated patients was compared within the same cohort with the course of untreated control patients who were carefully followed (“watchful waiting”) during a comparable time interval. The pre-specified study protocol was designed in accordance with Good Epidemiological Practice (GEP) guidelines [61, 62] and the IFAG standard operating procedures (SOPs) for retrolective cohort studies [57, 60]. Similar optimized comparative observational study approaches were repeatedly validated against randomized controlled (clinical) trials and successfully used for evaluation of clinical therapy [63−67] and for complementary cancer treatment [68-72]. Comparative epidemiological cohort studies can be accepted for the proof of efficacy and safety of “well established” and marketed drugs in the EC [73], and can also meet the Evidence Based Medicine (EBM) requirements (with evidence level II) [74, 75]. (Excerpted from Results) In the comparative survival analysis, no evidence of any form of tumor enhancement in the FME group was found. Particularly, there was no indication for an increased frequency or earlier onset of brain metastases in the FME group. In contrast, despite the longer follow-up duration the FME group showed a lower incidence rate (3.0 % vs. 4.2 %) and significantly reduced the adjusted hazard ratio for brain metastases (HR = 0.33 (0.13−0.86), p = 0.024), when compared with the control group. Similarly, for lung/mediastinal metastases, the incidence was significantly lower in the FME group (5.5 % vs. 10.4 %, p = 0.024). In conclusion, the safety analysis results suggest that the FME treatment was safe and well tolerated. A tumor enhancement was not found, and there is no indication of increasing incidence of brain or any other metastases in the FME treatment group. Assessment of FME efficacy In the course of the study and follow-up, in a total of 212 (30.9 %) patients recurrence or progression was observed, and 107 (15.6 %) died. The total unadjusted tumor-related mortality was 9.9 %. Tumor-related survival (TS) Tumor-related survival was the primary endpoint of efficacy in this study. The unadjusted tumor-related mortality rate was 8.9 % vs. 10.7 % for the whole follow-up duration in the FME vs. control group, respectively. The exploratory Kaplan-Meier analysis of unadjusted data showed a significant survival benefit of the FME group compared with the controls (Log rank test, p = 0.017). The primary endpoint result, the estimated adjusted hazard ratio (95 % confidence limit, CI) for tumor-related mortality, was calculated as HR (TS) = 0.41 (0.238722;0.71), p = 0.002, which confirmed the survival benefit of the FME treatment. A sufficient number of cases was available “at risk” for the survival analysis in both therapy groups (242 vs. 194 at 5 years, 159 vs. 101 at 8 years and 115 vs. 66 at 10 years). Among the prognostic factors a significantly higher adjusted tumor-related mortality hazard ratio was observed in UICC/AJCC stage III vs. stage II (HRTS) = 4.11 (2.118722;8.02), p < 0.001) and in males vs. females (HR(TS) = 2.38 (1.38-4.10), p = 0.002). The adjusted effects of age, melanoma type and localization, as well as the tumor thickness (Breslow) were not statistically significant. In conclusion, the results suggest a significant and clinically relevant reduction of the tumor-related mortality hazard in the FME group in comparison with the control group. [56] Bock, P. R., Friedel, W. E., Hanisch, J. et al., Retrolective, Comparative, Epidemiological Cohort Study with Parallel Groups Design for Evaluation of Efficacy and Safety of Drugs with “Well-Established Use”. Forsch. Komplementärmed. 11 (Suppl. 1), 23 (2004) [57] Schneider, B., Analysis of therapeutic efficacy in observational cohort studies. Cancer Chemother. Pharmacol. 47 (Suppl.), 35 (2001) [58] Schneider, B., Bock, P. R., [Epidemiological Cohort Studies. Analysis of the efficacy of drugs with observational studies]. Epidemiologische Kohortenstudien. Analyse der therapeutischen Wirksamkeit von Arzneimitteln. Schweiz. Zschr. GanzheitsMedizin 14, 400 (2002) [59] Feinstein, A. R., Clinical Epidemiology. The Architecture of Clinical Research. W.B. Saunders Company, Philadelphia (1985) [60] Hanisch, J., Bock, P. R., Karasmann, M., Standard operating procedures and the operational manual for retrolective cohort studies according to the IFAG-standard (RetrospectTM), Manual. IFAG Basel AG (2000) [61] Andrews, E. B., Avorn, J., Bortuichek, E. A. et al., Guidelines for Good Epidemiology Practices for drug, device, and vaccine research in the United States. Internet publication 1996. http://www.harvard.edu/organizations/DDIL/gep−PE.html [62] Bellach, B.-M., Leitlinien und Empfehlungen zur Sicherung von Guter Epidemiologischer Praxis (GEP). Bundesgesundheitsblatt 43, 468 (2000) [63] Benson, K., Hartz, A. J., A comparison of observational studies and randomized clinical trials. N. Engl. J. Med. 342, 1878 (2000) [64] Concato, J., Shah, N., Horwitz, R. I. et al., Randomized, controlled trials, observational studies, and the hierarchy of research design. N. Engl. J. Med. 342, 1887 (2000) [65] Feinstein, A. R., The role of observational studies in the evaluation of therapy. Stat. Med. 3, 341 (1984) [66] Hlatky, M. A., Califf, R. M., Harrell-FE, J. et al., Comparison of predictions based on observational data with the results of randomized controlled clinical trials of coronary artery bypass surgery. J. Am. Coll. Cardiol. 11, 237 (1988) [67] Rosati, R. A., Lee, K. L., Califf, R. M. et al., Problems and Advantages of an Observational Data Base Approach to Evaluating the Effect of Therapy on Outcome. Circulation 65 (Suppl. II), 27 (1982) [68] Beuth, J., Ost, B., Pakdaman, A. et al., Impact of complementary oral enzyme application in the postoperative treatment results of breast cancer patients − results of an epidemiological multicenter retrolective cohort study. Cancer Chemother. Pharmacol. 47 (Suppl.), 45 (2001) [69] Bock, P. R., Friedel, W. E., Hanisch, J. et al., [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland]. Arzneim.-Forsch./Drug Res. 54, 456 (2004) [70] Popiela, T., Kulig, J., Hanisch, J. et al., Influence of a complementary treatment with oral enzymes on patients with colorectal cancers − an epidemiological retrolective cohort study. Cancer Chemother. Pharmacol. 47 (Suppl.), 55 (2001) [71] Sakalova´, A., Bock, P. R., Dedik, L. et al., Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother. Pharmacol. 47 (Suppl.), 38 (2001) [72] Schumacher, K., Schneider, B., Reich, G. et al., [Post surgical complementary therapy of primary breast carcinoma with a lectin-standardized mistletoe extract − an epidemiological, controlled, multicenter, retrolective cohort study]. German J. of Oncol. 34, 106 (2002) [73] EU, European Parliament, Das Europäische Parlament, European Council, Der Rat der Europäischen Union. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to human medicinal products. Official Journal of the European Communities L 311, 67−128 (2001) [74] German Cochrane Center. Evidence hierarchy. 2002; Internet Communication URL: http://www.cochrane.de/deutsch/ccevidenzhierarchie. htm [75] Oxford Centre for Evidence-based Medicine. Levels of Evidence and Grades of Recommendation 2001; Internet Communication. URL: http://www.cebm.net/levels−of−evidence.asp `Arzneim.-Forsch./Drug Research' on 1/1/2005 http://articles.weleda.com/Details.asp?PUBARTICLE_ID=174&RecordsPerPage=1&TextLike=iscador&Archive=0&ArticlesOrder=PUBARTICLE_PublishedOnDate&ArticlesDir=desc Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.