Quality of life of cancer patients is frequently reduced during and after chemotherapy [
Because 70% of cancer patients use mistletoe products in Germany, randomized clinical trials are difficult to conduct: low recruitment rates and noncompliance because of therapy preferences are the consequences [
This randomized clinical pilot trial was carried out to assess the effects of two different mistletoe products on quality of life and on neutrophil count when administered during CAF chemotherapy for breast cancer. The aim was to identify promising outcome measures and methods for future studies in Serbia and to use the results for sample size calculation for a following confirmative study. Here we present the results with the mistletoe product Helixor A (HxA).
The objectives of this pilot study were to determine the clinical response (primary: quality of life, and secondary: neutropenia) of breast cancer patients to an additional mistletoe therapy during CAF. Our primary hypotheses were: breast cancer patients receiving mistletoe products during six cycles of consecutive treatment with CAF will show a better quality of life and less neutropenia compared to patients receiving CAF alone.
We conducted a prospective randomized open-label pilot study with equal-size randomization into three groups. All three groups received six cycles of CAF. In addition, one group received Helixor A (HxA), another group received Iscador M, and a control group had no additional therapy. The study was not placebo-controlled because currently no active placebo is known that can imitate the typical and time-dependent reactions following subcutaneous injections of mistletoe products (reactions at the injection site, increased body temperature, and flu-like symptoms). Here we report the comparison of HxA versus control. The other part of this combined pilot study has been published elsewhere [
At the Institute of Oncology and Radiology, National Cancer Research Centre of Serbia in Belgrade (IORS), breast cancer patients in the stages
Additional inclusion criteria were female gender, age ≥ 18 years, Karnofsky-Index ≥ 60, leukocytes ≥ 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, distant metastases, planned radiation or hormone therapy during the CAF treatment period, 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.
The chance to be allocated to any of the three groups (HxA, other mistletoe product, and 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 of the IORS, while the sealed randomization envelopes were stored in the Department of Study Coordination of the IORS and released consecutively for each enrolled patient.
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 administered at one day. All patients received antiemetic therapy with a single dose of ondansetron chloride 8 mg, dexamethasone 8 mg, and ranitidine 50 mg, respectively, administered prior to each CAF cycle.
No other antineoplastic or immunomodulatory therapies were permitted during the study. Patient compliance was examined by account of the questionnaires and patient diaries and at each visit.
Patients randomly allocated to the first group with additional therapy received Helixor A (HxA; aqueous extract of
The primary objective of the study was quality of life and the secondary objective neutropenia. Quality of life was documented with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in the official Serbian translation [
Adverse events (AE) were assessed by interviewing the patients and by analysing laboratory data at each visit. The Common Terminology Criteria of Adverse Events (v3.0) were used for grading. Local reactions to HxA less than 5 cm in diameter were expected reactions and therefore not classified as adverse events.
Neutropenia was one of the study objectives and was not classified as AE.
Statistical analysis (SPSS 14.0) was performed on the intention-to-treat population, a population consisting of all patients randomised into one of the three groups. Missing data were not replaced. Because of the pilot character of this study, all results of the analysis are explorative and do not have a confirmatory character. Therefore no sample size calculation was performed. A sample size of 90 patients (30 per group) was considered to be sufficient. For calculation of the EORTC QLQ-C30 scores, missing data within one scale were replaced according to the manual [
Quality of life (EORTC QLQ-C30) was analysed as follows: for each EORTC QLQ-C30, the mean change from baseline during follow-up in each group was compared among the HxA group, the group with the other mistletoe product, and the control group, using nonparametric marginal models according to Brunner and Langer [
For the incidence of neutropenia, the difference between the HxA and control groups was analysed by chi-square test according to the sequential rejective Holm procedure.
The study was approved by the Ethics Committee of the National Cancer Research Centre 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 the CRDT office and one at the study site were performed by the two sponsors during the study; no violation of Good Clinical Practice was detected.
This publication followed the CONSORT-PRO statement for reporting of randomized trials [
From 14 December 2005 to 15 February 2007 a total of 123 breast cancer patients were scheduled for treatment with CAF and assessed for eligibility at the IORS study centre. 28 patients did not fulfil the eligibility criteria (reasons: see Figure
Detailed flow chart of the patient disposition.
In the HxA group, 5 patients dropped out; reasons were withdrawal of informed consent (
The EORTC QLQ-C30 was evaluable for 86.9% (207 of 238) of planned visits in the HxA group, and for 97.2% (211 of 217) of planned visits in the control group. None of the expected questionnaires were missing in the follow-up phase of the study (Table
Baseline status.
Group |
|
||
---|---|---|---|
HxA |
Control | ||
Age in years (mean ± SD; |
|
|
0.228 |
Tumor status ( |
|||
Tumor classification | 0.619 | ||
T1 | 9 | 9 | |
T2 | 24 | 19 | |
T3 | 1 | 2 | |
T |
0 | 1 | |
Pos. lymph nodes | 0.849 | ||
N0 | 16 | 16 | |
N1 | 16 | 14 | |
N2 | 2 | 1 | |
Tumor grade | 0.474 | ||
G1 | 3 | 1 | |
G2 | 28 | 24 | |
G3 | 3 | 6 | |
Menopause status ( |
0.475 | ||
Premenopausal | 18 | 13 | |
Perimenopausal | 2 | 1 | |
Postmenopausal | 13 | 17 | |
Unknown | 1 | 0 | |
Receptor status estrogen | 0.507 | ||
Positive | 21 | 17 | |
Negative | 9 | 12 | |
unknown | 4 | 2 | |
Receptor status progesterone | 0.620 | ||
Positive | 22 | 19 | |
Negative | 8 | 10 | |
Unknown | 4 | 2 | |
Body Mass Index (mean ± SD; |
|
|
0.709 |
Karnofsky-Index (mean ± SD) |
|
|
— |
Abnormal findings on physical examination ( |
0 | 0 | — |
Vital signs (mean ± SD; |
|||
Blood pressure systolic (mmHg) |
|
|
0.139 |
Blood pressure diastolic (mmHg) |
|
|
0.209 |
Pulse (/min) |
|
|
0.945 |
Temperature (°C) |
|
|
1.000 |
Primary outcomes | |||
EORTC QLQ-C30 |
|||
Global health status |
|
|
0.713 |
Physical functioning |
|
|
0.872 |
Role functioning |
|
|
0.443 |
Emotional functioning |
|
|
0.274 |
Cognitive functioning |
|
|
0.23 |
Social functioning |
|
|
0.226 |
Fatigue |
|
|
0.894 |
Nausea and vomiting |
|
|
0.285 |
Pain |
|
|
0.273 |
Dyspnea |
|
|
0.839 |
Insomnia |
|
|
0.902 |
Appetite loss |
|
|
0.704 |
Constipation |
|
|
0.914 |
Diarrhoea |
|
|
0.498 |
Financial difficulties |
|
|
0.661 |
Secondary outcomes | |||
Incidence of neutropenia | 0 | 0 | — |
The HxA group and the control group did not differ significantly regarding age, tumour stage, body mass index, physical status, vital signs, previous diseases, EORTC QLQ-C30 scores, and neutrophil counts (Table
Number of patients and compliance in the completion of QoL forms by visit and groups.
Group Visit | Time schedule (days) | Time window (days) | Dropout | Forms expected | Forms received |
---|---|---|---|---|---|
Control | |||||
1 | 0 | 0-0 | 0 | 31 | 29 (94%) |
2 | 21 | 21–25 | 0 | 31 | 31 (100%) |
3 | 42 | 42–49 | 0 | 31 | 31 (100%) |
4 | 63 | 63–74 | 1 | 30 | 30 (100%) |
5 | 84 | 84–98 | 1 | 30 | 30 (100%) |
6 | 105 | 105–122 | 1 | 30 | 30 (100%) |
7 |
|
126–143 | 1 | 30 | 30 (100%) |
|
|||||
Helixor: | |||||
1 | 0 | 0-0 | 0 | 34 | 34 (100%) |
2 | 21 | 18–28 | 2 | 32 | 32 (100%) |
3 | 42 | 39–51 | 5 | 29 | 29 (100%) |
4 | 63 | 63–75 | 5 | 29 | 29 (100%) |
5 | 84 | 84–96 | 5 | 29 | 29 (100%) |
6 | 105 | 105–117 | 5 | 29 | 29 (100%) |
7 |
|
126–155 | 5 | 29 | 29 (100%) |
During chemotherapy with CAF, a deterioration of the quality of life occurred in 14 of 15 EORTC QLQ-C30 mean scores in the control group of which 4 were clinically relevant; whereas a deterioration occurred in 5 of 15 scores in the HxA group, of which 2 were clinically relevant.
In the adjusted analyses, mean differences from baseline were compared between the two groups for each EORTC QLQ-C30 score: 14 of 15 comparisons favoured the HxA group and one comparison (financial difficulties) favoured the control group. Ten of 14 comparisons favouring the HxA group showed significant differences (Figures
Differences of the mean of six follow-up values to baseline values of the EORTC QLQ-C30 function scores (mean ± sd), sorted by between-group group differences. All patients with at least one follow-up visit are displayed.
Differences of the mean of six follow-up values to baseline of the EORTC QLQ-C30 symptom scores (mean ± sd) sorted by group differences. All patients with at least one follow-up visit are displayed.
In explorative analyses, the differences from baseline for each of the 15 scores at each of the six follow-up assessments were compared between the two groups. 80 out of 90 differences favoured the HxA group, while 10 differences favoured the control group (data not shown). Furthermore, moderate differences of at least 10 points were found once in nine scores (role function, emotional function, social function, and global health: pain, insomnia, nausea/emesis, appetite loss, and diarrhoea), small differences of 5–10 points were found in three scores (cognitive function, fatigue, and constipation), and differences <5 points were found in the remaining three scores.
Neutropenia (neutrophil count < 1,000/
List of patients experiencing a neutropenia.
Group | ID | Visit number | Date (Visit) | Age | Stage | T | N | M | G | Leuco-cytes/nL | Neutro-phils/nL |
---|---|---|---|---|---|---|---|---|---|---|---|
HxA | 18 | 2 | 26.04.2006 | 43 | 2 | 2 | 1 | 0 | 2 | 10.2 | 0.6 |
61 | 2 | 18.09.2006 | 50 | 2 | 2 | 0 | 0 | 2 | 2.6 | 0.9 | |
42 | 7 | 03.11.2006 | 47 | 2 | 2 | 1 | 0 | 2 | 1.4 | 0.5 | |
53 | 7 | 06.12.2006 | 44 | 2 | 2 | 1 | 0 | 2 | 1.6 | 0.4 | |
57 | 7 | 22.12.2006 | 64 | 2 | 2 | 1 | 0 | 3 | 1.5 | 0.3 | |
58 | 7 | 22.12.2006 | 37 | 2 | 2 | 0 | 0 | 3 | 2.5 | 0.7 | |
75 | 7 | 07.03.2007 | 55 | 2 | 2 | 0 | 0 | 2 | 3.2 | 0.9 | |
|
|||||||||||
Control | 13 | 3 | 26.04.2006 | 32 | 2 | 2 | 1 | 0 | 2 | 2.8 | 0.9 |
33 | 5 | 29.08.2006 | 60 | 2 | 2 | 0 | 0 | 2 | 2.4 | 0.9 | |
87 | 6 | 26.03.2007 | 45 | 2 | 2 | 1 | 0 | 2 | 3.3 | 0.3 | |
90 | 6 | 29.03.2007 | 52 | 2 | 1 | 0 | 0 | 3 | 2.6 | 0.8 | |
51 | 7 | 08.12.2006 | 66 | 2 | 2 | 1 | 0 | 2 | 1.3 | 0.3 | |
56 | 7 | 21.12.2006 | 53 | 2 | 2 | 1 | 0 | 2 | 3.5 | 0.9 | |
62 | 7 | 31.01.2007 | 62 | 2 | 1 | 1 | 0 | 2 | 2.5 | 0.8 | |
66 | 7 | 23.01.2007 | 44 | 1 | 1 | 0 | 0 | 2 | 2.4 | 0.8 | |
90 | 7 | 19.04.2007 | 52 | 2 | 1 | 0 | 0 | 3 | 2.7 | 0.9 |
Seven patients of the HxA group and eight patients of the control group experienced a neutropenia (
Altogether 1
In the control group, 12 AEs and one serious adverse event (SAE: acute hospitalization because of dehydration upon severe emesis; see Table
List adverse events.
Group |
Code* | Number | Grade**number | Relation | Duration | Outcome | |
---|---|---|---|---|---|---|---|
Helixor A | Adverse events | ||||||
Localized skin reaction at |
10022096 | 42 | Mild |
1 |
Definite | Median 4 days |
Resolved without sequelae |
Conjunctivitis | 10010741 | 1 | Moderate | 1 | Probable | Unknown | Unknown |
Febrile temperature | 10021113 | 1 | Severe | 1 | Unrelated | 2 days | Resolved without sequelae |
Sting | — | 1 | Severe | 1 | Unrelated | Unknown | Unknown |
|
|||||||
Control | Adverse events | ||||||
Urticaria (localized) | 10046749 | 1 | Mild | 1 | Unrelated | 3 days | Resolved without sequelae |
Wound infection | 10048038 | 1 | Severe | 1 | Unrelated | 6 days | Resolved without sequelae |
Nausea/emesis | 10028813 | 3 | Severe | 3 | Unrelated | 2 days | Resolved without sequelae |
|
|||||||
Control | Serious adverse events: | ||||||
Nausea/emesis*** | 10028813 | 1 | Severe | 1 | Unrelated | 4 days | Resolved without sequelae |
*Code according to the Medical Dictionary for Regulatory Activities.
**Grading according to the Common Terminology Criteria of Adverse Events (v3.0).
***Patient was hospitalized to treat dehydration. According to the ICH 2A Guidelines hospitalization is defined as “serious adverse event”.
Abbreviations: lq: lower quartile; uq: upper quartile; ICH: International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use.
In this randomized pilot study quality of life (EORTC QLQ-C30) and incidence of neutropenia were investigated in breast cancer patients undergoing adjuvant CAF chemotherapy. Patients receiving HxA in addition to CAF had significantly better quality of life, compared to patients receiving CAF alone. HxA therapy was well tolerated.
Strengths of this study include a high recruitment rate, detailed assessments of therapy implementation, high therapy compliance, and very low dropout rates.
Due to the open-label design, the study cannot distinguish between direct drug effects on quality of life and possible indirect effects from therapy expectations, therapy administration, and so forth, in the HxA group.
Generally, medication trials are blinded to separate pharmacological effects from placebo effects. However, the lack of blinding may not necessarily have had relevant effects on the results of this study: an updated Cochrane review of randomized trials comparing placebo to no treatment found no significant placebo effects on eight out of ten evaluable indications, small effects on self-reported pain, and moderate effects on phobia. Even these effects might have been confounded by biases [
This study was designed as a pilot study, and the limited sample size of 30 patients per group does not allow for hypothesis confirmation. Moreover dropout patients or patients with missing data were more frequent in the HxA-group. As the results were calculated using data from all included patients (ITT), data of two patients in each group were missing. The remaining differences are additional three patients (ITT) in the HxA-group, which may lead to a biased result. Nevertheless, significant differences in 10 of 15 EORTC QLQ-C30 scores favouring the HxA group were found. All of these scores showed a clinically relevant difference of at least 5 points. The latter scores include role function, emotional function, pain, nausea, emesis, appetite loss, and diarrhoea, which are relevant symptoms in patients during chemotherapy with CAF.
These results are consistent with findings from another randomized phase III trial, wherein the administration of HxA to patients undergoing chemotherapy for breast cancer, lung cancer, or ovarian cancer was associated with significant beneficial effects on quality of life [
On the other hand, in a trial of early breast cancer patients receiving radiochemotherapy (CMF schedule), no influence of adjunctive therapy with HxA on any of the EORTC QLQ-C30 scores was found [
On the whole, there is some evidence that mistletoe extracts may have an impact on quality of life and reduction of side effects of chemotherapy especially in case of breast cancer patients as concluded in two recent comprehensive systematic reviews [
In this pilot study, the effects of HxA on quality of life increased over time with the largest effects observed at the last follow-up visit. A longer follow-up period might show additional long- term benefits of HxA therapy.
In this randomized pilot study of patients receiving adjuvant CAF chemotherapy for breast cancer, additional treatment with mistletoe therapy (Helixor A) was associated with significant and clinically relevant improvements of quality of life. Although the open design may be a limitation, the findings show the feasibility and justification of a phase III study using the methods described here.
5-Fluorouracil
Adverse event
Cyclophosphamide, adriamycine, and 5-fluoro-uracil
Clinical Research of Dr. Tröger
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
Helixor A
Institute of Oncology and Radiology of Serbia
Intention to treat
Serious adverse event.
The sponsor, Helixor Heilmittel GmbH & Co. KG, had no influence on study design, planning, conduct, or analysis. The authors declare that they have no conflict of interests.
Miodrag Matijašević was the responsible principal investigator. Zdravko Ždrale was the coinvestigator. Nevena Tišma carried out the blood analysis. Wilfried Tröger was principal author of the paper, wrote the study protocol, coordinated the study, had full access to all data, and is guarantor. All authors read and approved the final manuscript.
The authors would like to thank Petra Siemers, Anja Glockmann, and Claudia Bihl for monitoring and data management, Biostatistik Fischer for statistical analyses, and Dusanka Jelecanin for the coordination of patients in the centre. Special thanks go to the study nurses Milijana Sokol and Zorica Randelović and the participating patients. The part of the study that is reported here was financially supported by Helixor Heilmittel GmbH & Co. KG, Rosenfeld, Germany.