Омела белая Viscum album Mistletoe
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- Бұл бет үшін навигация:
- Mistletoe therapy
- Participants
- Randomization
- Sample size
- Statistical methods
- Adherence to regulations
IntroductionBackgroundQuality of life is frequently deteriorated during and after chemotherapy for cancer.1 Besides nausea, emesis and pain, fatigue is a frequent complaint, reported by 70%–100% of the patients.2 Recent research has shown that fatigue lasts for months after the last cycle of chemotherapy.2 Three types of fatigue are distinguished: general, physical, and mental; the latter being related to reduced activity, depression, anxiety, and mood disorders.3,4 Fatigue, insomnia and daytime sleepiness are augmented during and after chemotherapy with cyclophosphamide and 5-FU combined with methotrexate (CMF) or anthracyclines (CAF).5 One can conclude that fatigue is one of the major concerns for patients with cancer.6,7 Mistletoe therapyPhysicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy, compared to patients receiving chemotherapy alone.8–12 Mistletoe preparations also have immunostimulant and DNA-protecting properties13,14 and might therefore have protective effects against chemotherapy-induced neutropenia.15 In Central Europe, mistletoe preparations are widely used for adjuvant cancer therapy, especially by breast cancer patients. In Germany, 70% of cancer patients use unconventional treatments, and randomized trials of mistletoe preparations are difficult to conduct because of non-compliance and low recruitment rates due to therapy preferences.16–19 Mistletoe preparations10,16 as adjunct to CMF12,16 or other chemotherapies for breast cancer and other types of cancer10 have been examined in a few clinical studies showing a benefit in EORTC-QLQ-C3016 and other quality of life scores.10,12 This randomised clinical trial assessed mistletoe effects during CAF chemotherapy for breast cancer. The aim was to explore whether the EORTC-QLQ-C30 is a suitable instrument to detect differences between patients with early breast cancer receiving CAF with and without additional mistletoe therapy and whether such study is feasible in Serbia, a country where mistletoe preparations are not available.
MethodsObjectivesThe objectives of this pilot study were to determine the clinical response (quality of life including fatigue) and neutropenia in breast cancer patients during CAF. Our hypotheses were: Breast cancer patients receiving mistletoe preparations during six cycles of consecutive treatment with CAF will show a better quality of life including fatigue, and less neutropenia compared to patients receiving CAF alone. Design
We conducted a prospective randomized open label study with equal-size randomization into three groups. All three groups received six cycles of CAF. In addition, one group received Iscador® M special (IMS), another group received a different mistletoe preparation and a control group had no additional therapy. Here we report the comparison IMS vs. control. ParticipantsBreast cancer patients in the stages T1–3N0–2M0 treated at the Institute of Oncology and Radiology, National Cancer Research Centre of Serbia in Belgrade (IORS) and prescribed six consecutive cycles of CAF after surgery were assessed for eligibility. Additional inclusion criteria were female gender, age ≥18 years, Karnofsky-Index ≥60, leucocytes ≥3‚000/mm3, thrombocytes ≥100‚000/mm3, serum creatinine ≤2 mg%, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) ≤2.5 × the upper institutional limits. Exclusion criteria were pregnancy or lactation, metastases, planned radiation or hormone therapy during six consecutive cycles of CAF, use of immunostimulant or immunosuppressive agents (e.g. corticosteroids) except for nausea and emesis; current use of other investigational agents, clinically relevant physical or mental illness such as serious infections, hepatic, renal or other organ dysfunction or major depression; alcohol abuse, alcoholism, oral or parenteral drug abuse, and methadone treatment.
RandomizationThe chance to be allocated to any of the three groups (IMS, other mistletoe preparation, control) was 1:1:1. For randomization variable block sizes were used. No stratification took place prior to randomization. The randomization sequence was generated by Clinical Research Dr. Tröger (CRDT), using SPSS® (SPSS® 14.0.1, SPSS Inc., Chicago, Ill, USA). Allocation concealment was implemented by using sealed envelopes, prepared by CRDT. Patients were enrolled by investigators at the Outpatient Clinic, IORS, while the sealed randomization envelopes were stored in the Department of Study Coordination, IORS and released consecutively for each enrolled patient. Interventions CAF was administered in six cycles with a three-week interval between each cycle. The scheduled dosage was 500 mg Cyclophosphamide, 50 mg Adriamycin, and 500 mg 5-FU per 1 m2 skin surface applied at one day. All patients received antiemetic therapy with a single dose of Ondansetrone chloride 8 mg, Dexamethasone 8 mg, and Ranitidine 50 mg, respectively, administered prior to each CAF cycle. One dropout patient in the control group received only three CAF cycles, while all other patients received the six scheduled CAF cycles. The applied dose intensities (DI) of Cyclophosphamide, Adriamycin, and 5-FU (DI in mean mg/m2 per week; ± standard deviation) were 160.8 ± 5.5 mg, 16.1 ± 0.5 mg, and 160.8 ± 5.5 mg, respectively, in the IMS group and 157.1 ± 15.6 mg, 15.7 ± 1.6 mg, and 157.1 ± 15.6 mg, respectively, in the control group. The results correspond to 99% of planned DI in the IMS group and 96% of planned DI in the control group. No other antineoplastic or immunomodulating therapies were applied during the study. Patients randomly allocated to additional therapy with IMS received Iscador® M special (IMS; fermented aqueous extract of Viscum album from apple tree, fresh plant material, ratio of plant to extract = 1:5). IMS was manufactured by Weleda AG, Schwäbisch Gmünd, Germany and prepared in 1 ml ampoules for injection, each ampoule containing the fermented extract of 0.01, 0.1, 1, 2, or 5 mg of fresh mistletoe herb, respectively, in isotonic saline solution. IMS was administered by subcutaneous injections of 1 ml IMS into the upper abdominal region three times per week (i.e. Monday, Wednesday, Friday). The patients were instructed to inject IMS themselves. The dosage of IMS was increased stepwise: 2 × 0.01 mg, 2 × 0.1 mg, 11 × 1 mg, 8 × 2 mg, remaining doses 5 mg. Dose-dependent inflammatory reactions at the injection site (redness, swelling, sometimes accompanied by itching) were monitored. If such reactions exceeded 5 cm in diameter, the dosage was decreased or the therapy was paused until the reactions had ceased. An average of 54.1 ± 2.3 injections with altogether 174.80 ± 26.34 mg of IMS per patient were administered in the IMS group.
OutcomesOutcomes were quality of life and neutropenia. Quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) in the official Serbian translation.20 The EORTC-QLQ-C30 has 30 questions and is analysed in 15 scores: six scores for functioning and nine symptom scores (Table 2). The EORTC-QLQ-C30 was documented by the patients at seven visits: before each CAF cycle and three weeks after the 6th CAF cycle. Neutropenia was defined as neutrophil count <1,000/μl in the peripheral blood and assessed one day before each CAF cycle and three weeks after the 6th CAF cycle. Assessment of adverse events (AE) Adverse events were assessed by interviewing the patients and by analysing the laboratory results at each visit. Local reactions to IMS less than 5 cm in diameter were not considered as adverse events. Sample sizeA sample size of 90 patients (30 per group) was considered to be sufficient for this pilot study. BlindingThe study was not placebo controlled because the typical and time-dependent reactions following s.c. injections of mistletoe extracts (reactions at the injection site, increased body temperature, flu-like symptoms) cannot be imitated by a pseudo-placebo. Statistical methodsStatistical analysis (SPSS® 14.0) was performed on the intention-to-treat-population. An alternative analysis of the per-protocol sample, excluding one dropout patient in the control group, yielded very similar results (data not shown). All results of the statistical analysis have exclusively hypothesis-generating character. For each quality of life score (EORTC QLQ-C30), the mean change from baseline during follow-up in each group was compared between the IMS group, the group with the other mistletoe preparation and the control group, using nonparametric marginal models according to Brunner21 with therapy as whole-plot factor and time as sub-plot factor and a possible interaction between these two factors (results not shown). As a sensitivity assessment, a parametric covariance pattern model was also applied and found to qualitatively concur with the nonparametric results. For a better representability, the estimates of this parametric model will be shown. Post-hoc analyses of differences between the IMS group and control group were performed using the Dunnett T3-Test. Neutropenia was assessed by measuring the number of patients with neutrophils <1,000/μl during the study. For neutropenia, the group difference between IMS group and control group was analysed by Fisher’s exact test according to the sequential rejective Holm procedure. Adherence to regulationsThe study was approved by the Ethics Committee of the National Cancer Research Center of Serbia without modifications (date: 3 October 2005) and by the Serbian Drug Agency (date: 01 November 2005). Due to its pilot character, this study was not registered in a public study registry. The study was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and national laws. A patient insurance was provided for all participants. All patients provided signed informed consent prior to inclusion. CRDT was responsible for planning, conduct, monitoring, and analysis of the study. Two audits at CRDT and one at the study site were performed by the two sponsors during the study. No violation of Good Clinical Practice was detected. |