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The effectiveness of additional treatment with ViscumAlbum

The effectiveness of additional treatment with ViscumAlbum

ABNOBA scientific article

The effectiveness and safety of additional long-term treatment with a standard extract of European mistletoe ( Viscum album L .) along with conventional cancer treatment methods for diseases of the primary non-metastatic breast cancer

Results of multicentric, comparative and epidemiological cohort study in Germany and Switzerland

Paul R. Bock, Walter E. Friedel, Jürgen Hanisch, Marita Karasman and Berthold Schneider *

The Institute of Applied Medicine, IFAG Basel AG, Basel (Switzerland), a hospital Bad Bocklet, therapy and oncology department and Institute of Medical Statistics, Medical School of Hannover (Germany)

Overview

Goal setting: The aim of this study is to investigate the effectiveness and safety of long-term adjunctive therapy with a standard extract of European mistletoe ( Viscum album L ., Iscador ®, "an extract of mistletoe") along with the conventional use of additional cancer treatments (chemotherapy, radiotherapy, hormonal therapy, "traditional therapy" ) in patients with primary, non-metastatic breast cancer.

Methods: The project is a multicenter, controlled farmoepidemiologicheskoe cohort study conducted in parallel by experts in the medical centers in Germany and Switzerland, according to the directives of “ Benign Epidemiological Practice ” (GEP). The research group of mistletoe extract subcutaneous injections administered at least 3 months, along with conventional therapy, while only conventional therapy was the control group. The observation time is not less than 3 years, sometimes to the death. The first endpoint was the frequency of occurrences of adverse reactions following the use of traditional medicines therapies. The second criterion was the symptoms caused by the disease and treatment, as well as life expectancy. Safety of treatment was determined by frequency of occurrence and severity of adverse reactions to mistletoe extract therapy, as well as a possible increase in tumors. The results were calculated based on the assumptions, conditions of treatment and other factors, the impact of using logistic regression or „ Cox pro ­ portional hazard regression ". Evaluation took place in accordance with the protocol " per protocol .

Results: The study involved 1442 patients from 16 centers, of which 732 were investigated in the control group, in which, after the first operation was used exclusively traditional therapy, and 710 – in the research group, which additionally received mistletoe extract was administered subcutaneously 2-3 times a week for at least 3 months. Initially, the research group receiving mistletoe extract were patients with more advanced disease and poor prognosis. After the observation over 67 or 61 months of treatment with the mistletoe extract for 52 months significantly fewer patients experienced side effects from traditional therapy (16.3%) than patients in the control group (54.1%) (95% reliability index): OR = 0,47 (0,32-0,67), p < 0,0001). In the group receiving the mistletoe extract, many of the symptoms caused by the disease and therapy significantly decreased than the control group. Karnofsky index indicators improve, body weight increased and the mortality rate was significantly lower (adjusted hazard ratio, HR) (Cox regression (95% confidence index): HR = 0,46 (0,23-0,96), p = 0,038) . After the treatment with the mistletoe extract systemic side-effects appeared in 0.8% of cases, and local - in 17.3%. All side effects were mild or moderate severe (WHO/CTC Grad 1-2). Severe side effects during treatment with mistletoe extract or tumor growth were observed.

Conclusion: The results of this cohort study show that an additional long-term treatment with a standard extract of mistletoe in patients with primary non-metastatic breast cancer in general is well tolerated and can be reasonably assigned. In comparison, studies conducted in parallel with in the group with conventional therapy, mistletoe extract group had significantly fewer side effects of conventional therapy, caused fewer symptoms and treatment of disease and longer life.

Description of the study

  1. Introduction

Breast cancer has the highest identification rate (frequency of occurrence of new cases) (25.9%) and mortality rate (17.1%) of all types of cancer occurring in females in Germany. In the United States recorded a year about 175 thousand new cases of breast cancer die about 43 thousand women..; and around the world - about 1 million women.. Treatment of breast cancer require multimodal therapy, with an initial operation and radiotherapy, chemotherapy and/or hormonal therapy according to the individual characteristics of the tumor status, lymph nodes, menopausal status, and hormonal levels. Because of the frequent occurrence of side effects of conventional treatment and risk of substantial deterioration in the quality of life is becoming increasingly important complementary therapies that can reduce or prevent the occurrence associated with the disease or symptoms of treatment, even if you have not shown convincing evidence with regards to the therapy, leading to the progression of reduction disease and increase life expectancy.

As an adjunctive therapy for the treatment of cancer patients in Europe, in Germany, in most cases used an extract of European mistletoe ( Viscum alburn L .) . During the latest study, researchers were able to identify the most important ingredients of mistletoe (lectins, viskotoksiny and other components), during the pharmacological and toxicological tests its characteristics were examined. When carrying out experiments in the laboratory and in vivo have been proven immunomodulatory and cytotoxic action. So far on the prevention of tumor recurrence and increase survival spoke only a few isolated reports of small and random studies. Published clinical studies provide conflicting results and have methodological shortcomings. On the safety and potential toxicity of mistletoe extracts were controversial discussions. Practical and ethical doubt hindered research (the RCT) of the proof of the increase in life expectancy, as these studies are designed for the long term (5 to 10 years) and because of the relatively good prognosis in breast diseases, non-metastatic cancer must cover a fairly large amount of patients.

So we decided to spend a long period of controlled epidemiological cohort study according to Retrospect &trade concept; Institute of Applied Medicine (IFAG). This type of research finds acceptance among epidemiological studies and allows to EC to draw conclusions about the effectiveness and safety of medicines, which has long been present in the market („ well established use "). Detailed literature comparing the results of randomized and epidemiological studies have shown that a well-planned carried out and presented in a quantitative (digital) form of epidemiological studies have led mostly to similar results from randomized trials.

The goal of this study is to prove the efficacy and safety of a standardized extract of European mistletoe ( Viscum album L ., Iscador el ) , "mistletoe extract") under long-term monitoring of breast primary non-metastatic cancer as an adjunct along with traditional therapy. This extract of mistletoe has long been sold, and is often used as an adjunctive therapy in cancer, especially in Germany and Switzerland.

  1. research plan

This is a multicenter, controlled, long-term cohort study. In the study group were patients with non-metastatic breast cancer, who after surgery and conventional chemotherapy, radiotherapy and hormone therapy using mistletoe extracts were patients in the control group who received only traditional therapy.

  1. Choosing centers

It was a random choice of oncology clinics, outpatient clinics service patients in the stage of recovery (rehabilitation centers) in Germany and Switzerland, which are engaged in the treatment of patients with breast cancer and were ready to take part in the study. In the centers of applied mistletoe extract treatment or performed only conventional therapy along with conventional therapy. View conventional therapy or other additional activities did not matter.

  1. Patient Selection

In the centers of all of the documents have been studied patients who were treated for breast cancer between 1988 and 2000. At the beginning of the study treatment may have already been completed or still in progress. The study included a chronological, without any selection, the data of patients operated on in the investigation of histologically proven non-metastatic breast cancer (stage I-III), which at least 6 months were treated with conventional therapy (chemotherapy, radiation and hormone therapy) with or without additional application of mistletoe extract that could be observed for at least 3 years (or until death). Thus, the following data were recorded: a) basic data (age, menopause, the level of hormonal background, stage of the disease), b) the operation and condition of the tumor (date, type, location, multiplicity, the stage, the degree), c) carrying out treatment (conventional therapy, with an extract of mistletoe therapy, complementary therapies) and d) the patient's condition (Karnofsky index due to treatment or disease symptoms, the condition of the tumor, side effects of conventional therapies and mistletoe extract, recurrence, metastasis, or death).

  1. Study

The anonymous data of patients used in the study were recorded by control devices in the data curve (case report forms, CRFs). Data on treatment due to symptoms of disease and have been supplemented by the testimony of the doctor during the illness. These CRFs have been tested for accuracy and reliability, appropriate adjustments were made where necessary, text instructions (eg, medications, diagnoses, side effects) were transferred to the unambiguous code numbers (for example, Red List code &reg ;, ICD-10, WHO/CTC, etc.) and entered into the data bank system. Compliance with CRF data from patients were selectively monitored data (audit).

  1. Target and statistical evaluation

The primary endpoint was the rate of occurrence of adverse effects of conventional therapy. Secondary end points were due to the appearance of disease symptoms and treatment, as well as life expectancy. Therapy Security Defines the frequency of occurrence and severity of adverse reactions to mistletoe extract therapy and possible growth of the tumor. It should be borne in mind that the research and control groups had different initial conditions and treatment. During the statistical evaluation took into account differences in all material conditions and their effect on the objective function. The results were calculated based on the initial data, the treatment conditions and other factors the impact of using logistic regression or „ Cox pro ­ portional hazard regression ". Evaluation took place in accordance with the protocol "per protocol"

  1. Results

7.1. research and the number of patients Centers

The study involved 16 centers in Germany and Switzerland; 9 of them are hospital: 5 clinics primary survey, 4 outpatient clinics service patients in the recovery stage (rehabilitation centers) and 7 private clinics, where the focus is on the treatment of cancer. Four clinics were used along with conventional therapy mistletoe extract, used in 9 centers conventional therapy and only in some cases they have resorted to the use of mistletoe extract, and 3 centers have dealt only with conventional therapy.

Overall, the data were collected in 1442 patients. Of these, 710 were treated with conventional therapy and an extract of mistletoe therapy (research group) and 732 - only traditional therapy (control group).

Primary data

The basic data of patients, separately for the two treatment groups, contains Table. 1. Substantial and clinically important differences between the two groups can be traced time between diagnosis and surgery holding (1.32 to 0.14), estrogen receptor positive level (72% to 65%), as after menopause (62 to 82% %) and non-neoplastic diseases frequency (36% to 54%). Table. 2 includes data on transactions. Patients study group were significantly inferior to the projections of tumor stage (pT), its degree (pG) and in most cases have multilokulyarnuyu tumor (25% to 9%) than Control Commission patient. After the operation in 3% in the study group and 0.5% in the control had residual tumor site. In general, the patient study group suffered from a serious illness and had more facts to the risk of progression.

Table 1. Demographic and immunological data

Demographic and immunological data

The research team

control group

 

number = 710

number = 732

age (years), the average value

53

57

weight (kg), the average value

67

72

months between diagnosis and surgery, the mean value

1,32

0,14

the level of estrogen receptor (Pos.)

72,5%

65,1%

Postmenopause

61,6%

82,4%

allergy history

12,8%

7,6%

non-cancer diseases

36,0%

53,9%

Table 2 Data on surgery and tumor

Data on surgery and tumor

The research group number = 710

control group number = 732

stage pT2-4

61,4%

50,3%

lymph uzlovN > 0

46,3%

40,7%

degree pG3-4

36,1%

18,0%

Stage II + HI (UICC)

73,0%

62,0%

multilokulyarnaya tumor

25,0%

8,9%

operation with cleaning armpit

59,3%

76,0%

reoperation

7,7%

1,6%

residual tumor after surgery

2,7%

0,5%

     

Basic mistletoe treatment (conventional therapy)

The average duration of the observations made in the study group was 66 months, while the control group - 60 Tab. 3 provides an overview of basic oncological treatment. At the same time become visible clinically relevant differences between the study groups. 156 patients (22%) and 42 of the study group (6%) controls were not treated by traditional therapy. Radiotherapy was used in the research group in 44% of cases and the control – 76%; Chemotherapy – 33% and 23% respectively, and hormone therapy used in both groups 50% of patients.

The average length of treatment of mistletoe extract is 52 months, the mean cumulative dose - 4,367 mg.

Table 3 Traditional and additional oncologic therapy

Traditional Therapies

The research team

number = 710

The control group

number = 732

unconventional therapy

22,0%

5,7%

Radiotherapy

43,9%

75,7%

Chemotherapy

32,8%

23,2%

Hormone Therapy

50,1%

50,3%

antiemetic

8,6%

4,9%

analgesic agents

4,5%

6,0%

Other (eg. Vitamins)

24,8%

7,9%

Physical Therapy

18,9%

35,1%

months between surgery and initiation of therapy

   

(average value)

1,4

1,2

7.4. The reduction of side effects of conventional therapy

Among the 112 patients study group (16% of all, 20% of patients with performed traditional therapy) were recorded in whole 152 cases among 395 control group patients (54% of all, 57% of patients with performed traditional therapy) - in overall 780 cases of side effects from conventional therapy. Indicator side effects of the base treatment was significantly lower in the patients study group (relative ratio (Odds Ratio, 95% confidence index): OR = 0,47 (0,32-0,67), p < 0.0001) (Fig 1. ). Side effects were pronounced in patients, past radio and chemotherapy. Among 152 cases of side effects in patients Study Group 40 (27%) were from radiotherapy (including 17 base reactions), 89 (60%) from chemotherapy (42 cases of nausea/vomiting and 10 leukopenia/leukocytosis), 8 (5% ) of hormone therapy, and 12 (8%) of other therapies. 3 cases of side effects were not correlated anywhere. Among 782 cases of side effects of conventional therapy for patients in the control group 541 (69%) occurred by radiotherapy (including - 243 base reactions), 184 (24%) from chemotherapy (of this 71 case of nausea/vomiting, 6 - leukopenia/leukocytosis), 15 (2%) of hormone therapy, and 40 (5%) of other types of therapies. 2 cases of side effects were not correlated anywhere.

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