Institute for Applied Epistemology and Medical Methodology, Zechenweg 6, D-79111 Freiburg, Germany
Verein Filderklinik e.V, Research Department, Im Haberschlai 7, D-70794 Filderstadt, Germany
Abstract
Background
Methods
Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality.
Results
19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 single-arm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3 RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results.
Conclusion
VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted.
Background
Breast and gynaecological cancers (i.e. ovarian, endometrial, cervical, vaginal, vulval, and fallopian cancers) account for a significant amount of morbidity and mortality in women. In Europe an estimated 429,900 cases were diagnosed as breast cancer in 2006 (13.5% of all cancer cases) and 131,900 died from it, despite substantially improved treatment options (surgery, chemotherapy, radiation, hormonal and targeted therapies)
40% to 80% of these patients use complementary therapies additionally to well-established treatments
Across Europe,
For clinical application VAE are made from mistletoes grown on different host trees [Host trees of VAE: Fir (
Clinical effects of VAE in cancer have been investigated in a variety of studies and assessed in systematic reviews
Methods
Design
Systematic review of clinical and preclinical studies investigating the influence of VAE on breast or gynaecological cancer.
Search strategy
We used a systematic process to search the following databases for clinical trials – AMED, Biosis Previews, Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, The NHS Economic Evaluation Database, Health Technology Assessment Database), Embase, Medline/Premedline, NLM Gateway, private databases – from inception of these databases to December 2008 using the terms (MISTLETOE OR VISCUM? OR MISTEL? OR ISCADOR? OR ISCAR OR HELIXOR OR ABNOBA? OR ISCUCIN OR ISOREL OR VISOREL OR ?SOREL OR WELEDA OR WALA OR EURIXOR OR LEKTINOL OR PLENOSOL OR AVISCUMINE) AND (STUDY? OR STUDIE? OR TRIAL OR EVALUAT? OR RANDOM? OR INVESTIG? OR COHORT? OR KOHORT? OR OUTCOME?). The reference list from each potentially eligible study, relevant review article and textbook was checked, and experts in the field and manufacturers of mistletoe preparations were contacted for additional reports.
Regarding
Selection
The following selection criteria were used for inclusion of studies in the analysis: (I) prospective randomized or non-randomized controlled clinical trial, or prospective single-arm cohort study (e.g. phase II trial) or pharmaco-epidemiological cohort study; (II) study population with breast or gynaecological cancer, i.e. ovary, uterus, cervix, genital cancer, or cervical intraepithelial neoplasm (CIN); (III) intervention group treated with VAE preparation; (IV) clinically relevant outcome (i.e. survival, disease-free interval, remission, relapse, QoL, or reduction of side effects or immune suppression during cytoreductive therapy); (V) completion of study; (VI) published or unpublished. Studies were excluded if they: only measured toxicity or tolerability (phase I trial), only measured stimulation of immunological parameters, were not conducted on cancer patients, or had a retrospective design (except pharmaco-epidemiological cohort studies). There were no restrictions on language.
For
Validity assessment and data abstraction
Criteria-based analysis was performed on the selected clinical studies to assess their methodological quality. Analyses were performed independently by two reviewers (GK, HK). There were no major differences in study assessment; disagreements were resolved by discussion. Criteria for assessing strength of evidence in controlled trials were adapted from the National Health Service Centre for Reviews and Dissemination
Regarding animal experiments we extracted data on study size, animal model, tumour type, tumour transfer, intervention, treatment schedule, outcome, physiological monitoring, side effects, dose-response, randomization, control treatment, blinding of outcome assessment, publication in a peer-reviewed journal, and funding source.
Results
Result of literature search
The literature search identified 306 references describing potential clinical studies (after deletion of duplicates). After deleting references only describing studies on immune modulation or toxicity or tolerability (phase I trial), or only on cancer sites other than breast or gynaecological, with retrospective evaluation, without quantification of results, or only investigating complex treatment regimes, or describing studies already published elsewhere, 48 potential studies were identified that met the inclusion criteria. Two trials
1632 VAE-related references were checked by title, abstract or whole article, book chapter, or book regarding
Characteristics of included clinical studies
Tables
Randomized Controlled Clinical VAE Trials on Breast and Gynaecological Cancer: Quality Assessment
Author, Year
Quality Criteria Fulfilled in Studies I
Participants
AR II
A)
B)
C)
D)
E)
F)
G)
H)
I)
J)
K)
Tröger 2009
+
-
-
(+)
+
+
+
+
(+)
(+)
+
95
6%
Büssing 2008
+III
-III
-III
-III
(-)III
-III
(-)III
(-)III
(-)III
(-)III
-III
65
No data
Grossarth 2008a
+
+
-
(-)
+
(-)
+
(+)
+
+
-
76
21%
Grossarth 2008b
+
+
-
(-)
+
+
+
(+)
+
+
-
52
0%
Grossarth 2007a
+
+
-
(-)
+
(-)
+
(+)
+
+
-
50
16%
Grossarth 2007b
+
+
-
(-)
+
(-)
+
(+)
+
+
-
48
17%
Grossarth 2007c
+
+
-
(-)
+
+
+
(+)
+
+
-
38
0%
Grossarth 2006a
+
+
-
(-)
+
(-)
+
(+)
+
+
-
118
36%
Semiglasov 2006
+
-
(+)
(+)
+
+
+
+
+
+
+
352
4%
Auerbach 2005
+
-
(+)
(+)
+
-
+
(+)
+
(+)
+
23
30%
Piao 2004
+
+
-
(-)
+
+
+
(+)
+
+
+
233
4%
Semiglasov 2004
+
-
(+)
(+)
+
+
+
+
+
+
+
272
4%
Borrelli 2001
+
-
(+)
(+)
+
+
(+)
+
(-)
(+)
-
30
0%
Grossarth 2001a
+
+
-
(-)
+
+
+
(-)
+
+
-
34
0%
Grossarth 2001b
+
+
-
(-)
+
(-)
+
(-)
+
+
-
98
20%
Kim 1999
+
-
-
-
(-)
-
(+)
(+)
(-)
(-)
-
30IV
13%
Heiny 1991
+
-
(-)
(-)
+
(+)
+
(+)
+
+
-
46
13%
Gutsch 1988
+
-
-
(-)
+
(-)
+
+
(+)
+
-
692
20%
Lange 1985
+
+
-
(-)
+
(-)
+
(+)
+
+
-
68
35%
I A) Protection against selection bias, especially by adequate randomization
B) Minimization of heterogeneity by pre-stratification or matching
C) Protection against observer bias by blinding of patient, care provider, and outcome assessor
D) Protection against performance (treatment) bias by standardization of care protocol, documentation of all co-interventions, blinding of patients and care providers
E) Protection against measurement (detection) bias by standardization of outcome assessment
F) Protection against attrition (exclusion) bias, lost patients <10% or by intention-to-treat analysis (including non-adherers as randomized) plus per-protocol analysis (excluding non-adherers) in combination with sensitivity analysis, and by comparison of prognostic characteristics of lost patients and compliers
G) Effect measurement relevant and well described
H) Well-described intervention, patient characteristics, disease (diagnosis, stage, duration), previous therapy
I) Well-described study design
J) Well-described results
K) Data quality assured by ICH-GCP guidelines, especially by monitoring
+ = adequately fulfilled, (+) = partly fulfilled, (-) = little fulfilled, - = not fulfilled
II AR: attrition rate (dropouts, protocol deviations, withdrawals, patients did not receive treatment as allocated).
III Assessment based only on an abstract
IV Discrepancy in patient numbers in two presentations (30 and 33), with corresponding discrepancy of results
Non-Randomized Controlled Clinical VAE Studies on Breast and Gynaecological Cancer: Quality Assessment
Author, Year
Quality Criteria Fulfilled in Studies I
Participants
AR II
Design/control for confounding
A)
B)
C)
D)
E)
F)
G)
H)
I)
J)
K)
Grossarth 2008c
(+)
+
-
(-)
+
+
+
(+)
+
+
-
200
5%
Prospective pair-matching
Grossarth 2008d
(+)
+
-
(-)
+
(-)
+
(+)
+
+
-
282
27%
Prospective pair-matching
Loewe-Mesch 2008
-
-
-
(-)
+
(-)
+
+
(+)
+
-
82
20%
Self-selected treatment allocation, no adjustment
Grossarth 2007d
(+)
+
-
(-)
+
(-)
+
(+)
+
+
-
198
24%
Prospective pair-matching
Grossarth 2007e
(+)
+
-
(-)
+
+
+
(+)
+
+
-
132
6%
Prospective pair-matching
Grossarth 2007f
(+)
+
-
(-)
+
+
+
(+)
+
+
-
212
4%
Prospective pair-matching
Grossarth 2007g
(+)
+
-
(-)
+
+
+
(+)
+
+
-
140
6%
Prospective pair-matching
Grossarth 2006b
(+)
+
-
(-)
+
(-)
+
(+)
+
+
-
210
20%
Prospective pair-matching
Büssing 2005
(-)
-
-
(-)
+
+
(+)
(+)
(+)
+
+
105
7%
Comparison of two different hospitals. Pair-matching for analysis
Grossarth 2001c
(+)
+
-
(-)
+
+
+
-
+
+
-
792
4%
Prospective pair-matching
Salzer 1987
(+)
-
-
(-)
+
-
+
-
-
(+)
-
155
not shown
Alternating treatment allocation
Fellmer 1966
-
-
-
(-)
+
-
+
+
-
-
-
924
15%
Treatment allocation by neutral attending physician
Majewski 1963
(+)
-
-
(-)
+
-
+
-
-
-
-
III
not shown (15%)IV
Alternating treatment allocation
Retrolective pharmaco-epidemiological cohort studies
Beuth 2008
-
(+)
-
-
(-)
-
(+)
(-)
(+)
(+)
+
681
V
Multivariate adjustment only for one main outcome ("complaints")
Bock 2004
-
(+)
-
-
(-)
-
(+)
+
(+)
(+)
+
1442
V
Multivariate adjustment
Schumacher 2003
-
(+)
-
-
(-)
-
(+)
+
(+)
(+)
+
689
V
Propensity score adjustment
I–II Abbreviations as in Table 1.
III Number of study patients not indicated; mistletoe group included 155 patients.
IV Numbers given only for mistletoe group.
V Not applicable for retrolective studies.
Controlled Clinical Studies on VAE Treatment in Breast and Gynaecological Cancer: Survival
Site
Stage
Intervention (evaluable patients)
Survival Outcomes
Author, year, reference
Years (median)
Hazard ratio
5-year survival and others
P-value
95% CI
Randomized controlled trials
Breast
T1a-3, N0, M0
Iscador (38)
14.8
0.65
0.2
0.34–1.25
Grossarth 2006a
None (38)
13.8
IIIA–IIIB
Iscador (17)
6.3
0.46
0.13
0.16–1.31
Grossarth 2001a
None (17)
2.3
T1-3, N0-3, M0, local recurrence
Surgery, radiationI, Helixor (192)
Not applicableII
69.1% 5-year survival
0.048
Gutsch 1988
Surgery, radiationI, CMF (177)
67.7% 5-year survival
0.025
Surgery, radiationI (274)
59.7% 5-year survival
Breast, others
All stages
Iscador (39)
3.5 (mean)
0.04
Grossarth 2001b
None (39)
2.5 (mean)
Cervix
IVA-B
Iscador (19)
1.83
0.46
0.12
0.18–1.21
Grossarth 2007c
None (19)
1.92
Uterus
IA-C
Iscador (30)
6.29
0.36
0.014
0.16–0.82
Grossarth 2008a
None (30)
5.17
IVA-B
Iscador (26)
1.5
1
0.99
0.46–2.16
Grossarth 2008b
None (26)
2.0
Ovary
IA–IC
Iscador (21)
6.75
0.40
0.058
0.15–1.03
Grossarth 2007a
None (21)
5.58
IV
Iscador (20)
2.75
0.33
0.033
0.12–0.92
Grossarth 2007b
None (20)
1.58
Non-randomized controlled studies
Breast
T1-3, N0, M0
Iscador (84)III
11.75
0.42
0.0002
0.27–0.68
Grossarth 2006b
None (84)
10.13
Local recurrence, N0, M0
Iscador (29)IV
5.17
0.0025
Grossarth 2001b
None (29)
4.33
T1-4, N>1, M0
Iscador (38)IV
4.04
0.0516
Ø same study
None (38)
3.17
TX, NX, M1
Iscador (53)IV
3.08
0.0056
Ø same study
None (53)
2.17
I–III
Iscador, (76)
29% alive 1985, after 11–14 years
not shown
Salzer 1987
Radiation, hormone (79)
24% alive 1985, after 11–14 years
Cervix
IB-IVA
Iscador (102)III
7.17
0.41
<0.0001
0.27–0.63
Grossarth 2007f
None (102)
5.92
IV
Iscador (66)III
2.33
0.54
0.015
0.32–0.89
Grossarth 2007g
None (66)
1.83
I–III
Radiation, Iscador (81)
83% 5-year survival
0.05
Fellmer 1966
Radiation (709)
69% 5-year survival
Uterus
IIIA–IVB
Iscador (95)III
2.75
0.61
0.023
0.39–0.93
Grossarth 2008c
None (95)
1.67
IA-C
Iscador (103)III
8.75
0.41
<0.0001
0.26–0.63
Grossarth 2008d
None (103)
6.67
Ovary
IA–IC
Iscador (75)III
6.83
0.47
0.0002
0.31–0.69
Grossarth 2007d
None (75)
5.83
IV
Iscador (62)III
1.79
0.62
0.077
0.37–1.05
Grossarth 2007e
None (62)
1.17
Genital
All stages
SurgeryI, radiationI, Iscador (155)
Disease-specific survival partly improved
not shown
Majewski 1963
SurgeryI, radiationI,(not shown)
Retrolective pharmaco-epidemiological cohort studies
Breast
I–III
Conventional therapy, Iscador (710)
0.46
0.038
0.22–0.96
Bock 2004
Conventional therapy (732)
I–IV
Conventional therapy, Eurixor (219)
No difference observedV
Schumacher 2003
Conventional therapy (470)
I Co-intervention (i.e. radiation) applied to part of the group
II Not applicable since more than 50% alive at study termination
III Data from complete set of patient pairs reported
IV Data only from patient pairs with strict matching reported
V No difference could be found due to limited observation time (median < 10 months)
CMF: Cyclophosphamide, methotrexate, 5-fluorouracil
P-value, 95% CI (confidence interval): Statistical significance of difference between mistletoe (or other verum) and control group.
Controlled Clinical Studies on VAE Treatment in Breast and Gynaecological Cancer: Tumour Behaviour or Pleurodesis
Site
Stage
Intervention (evaluable patients)
Outcome
P-value
95% CI
Author, year, reference
R
Randomized controlled trials
Breast, ovary, lung
T1–4, N0–3, M0–1
ChemotherapyI, Helixor A (115)
Remission rate: no difference
Piao 2004
ChemotherapyI, Lentinan (109)
Ovary, others
Inoperable
Radiation, cisplatin, holoxan, Helixor (23)
10% complete remission
48% partial remission
5% progress
Lange 1985
Radiation, cisplatin, holoxan (21)
17% complete remission
48% partial remission
4% progress
Pleural effusionII
Advanced
Helixor (11)
82% complete remission
9% partial remission
<0.05 III
Kim 1999
Doxycycline, meperidine, lidocaine (15)
40% complete remission
27% partial remission
D
Randomized controlled trials
Breast
T1a-3, N0, M0
Iscador (38)
Time to local recurrences: 0.44
lymphatic metastases: 0.27
distant metastases: 0.50
all events (incl.death) 0.65
0.18
0.0048
0.061
0.012
0.14–1.44
0.11–0.67
0.24–1.03
0.47–0.91
Grossarth 2006a
None (38)
Non-randomized controlled trials
Breast
T1–3, N0, M0
Iscador (84)
Time to local recurrences: 0.42
lymphatic metastases: 0.22
distant metastases: 0.36
all event (incl.death) 0.66
0.21–0.83
0.10–0.47
0.21–0.62
0.55–0.79
Grossarth 2006b
None (84)
Cervix
IB-IVA
Iscador (102)
Time to local recurrences: 1.42
lymphatic metastases: None
distant metast.:1 in Iscador group
all event (incl.death) 0.32
0.61
n.a.
n.a.
<0.0001
0.37–5.39
n.a.
n.a.
0.22–0.48
Grossarth 2007f
None (102)
Retrolective pharmaco-epidemiological cohort study
Breast
I–III
Conventional therapy, Helixor (167)
Recurrence, metastases, reoperation: no difference
Beuth 2008
Conventional therapy (514)
I–III
Conventional therapy, Iscador (710)
Recurrence: 0.98
Dist. metast. 0.65
0.947
0.172
0.60–1.62
0.35–1.21
Bock 2004
Conventional therapy (732)
I–IV
Conventional therapy, Eurixor (219)
Time to relapse: 0.28
0.012
0.10–0.76
Schumacher 2003
Conventional therapy (470)
I Chemotherapy: see table 5
II Plural effusion indicates treatment site (primary cancer site: 4 × breast, 1 × cervix, 23 × lung, 1 × stomach, 1 × unknown primary)
III Side effects in Helixor and doxocycline group: pain in 6 and 14, fever in 3 and 6, burning sensation in 0 and 5 patients respectively; difference statistically significant (p < 0.05)
P-value, 95% CI (confidence interval): Statistical significance of difference between mistletoe (or other verum) and control group.
Controlled Clinical Studies on VAE Treatment in Breast and Gynaecological Cancer: Reduction of side effects of chemotherapy, radiation or surgery; QoL
Site
Stage
Intervention (evaluable patients)
Reduction of side effects of chemotherapy, radiation or surgery
QoL (*during chemotherapy, radiation)
Author, year, reference
Outcome
P-value
Measurement scale and outcome
P-value
95% CI
Randomized controlled trials
Breast
T1–3, N0–2, M0
CAF, Iscador or Helixor (59)
Neutropenia
15%
0.195
EORTC QLQ-C30* (Pain*, diarrhoea*, role*, insomnia*, nausea/vomiting*)
0.0438 to
0.0003
Tröger 2009
CAF (30)
27%
No data
(F)EC, Iscador M (32)
EC-associated inhibition of granulocyte function: no difference.
Reduction of EC-related side effects (nausea, constipation, pain, stomatitis).
Lymphocytes, retching, emesis: no difference
>0.27
EORTC QLQ-C30*, BR 23*, Rhodes Index*: no difference
No data
No data
Büssing 2008
(F)EC (33)
"significant"
T1a-3, N0, M0
Iscador (38)
Self-regulation questionnaire,
Hazard-ratio
0.35
0.05–0.60
Grossarth 2006a
None (38)
T1–3, N0-N+, M0
CMF, Lektinol 15 ng ML (169)
Haematological parameters, hospitalization, paracetamol, metoclopramid: no difference.
Leucopenia ↓ (trend)
FACT-G*
↑ 4.4
GLQ-8* sum
↓ 28.9
Spitzer uniscale*
↓ 12.2
KPS*
No difference
<0.0001
Semiglasov 2006
CMF, placebo (168)
FACT-G*
↓ 5.11
GLQ-8* sum
↑ 94.8
Spitzer uniscale*
↑ 10.8
T1–2, N0–1, M0
CMF, radiation, Helixor A (11)
CMF-induced NK-cell decrease ↓ SCE-increase ↓
other immune markers: no difference
0.005
n.s.
EORTC QLQ-C30*
No difference, data not shown
not shown
Auerbach 2005
CMF, radiation, placebo (9)
T1–3, N0-N+, M0
CMF, Lektinol 5 ng ML (66)
Haematological parameters, hospitalization, paracetamol, metoclopramid: no difference. immune markerers: CD4, CD4/CD8, NK-cell-activity: significant ↑
GLQ-8* sum
No difference
Spitzer uniscale*
No data
QLQ C-30*
No difference
<0.05
Semiglasov 2004
CMF, Lektinol 15 ng ML (65)
GLQ-8* sum
Superior 60,8mm
Spitzer uniscale*
Superior 16,4 mm
CMF, Lektinol 35 ng ML (64)
GLQ-8* sum
No difference
Spitzer uniscale*
No data
CMF, placebo (66)
IIIA–IIIB
Iscador (17)
Self-regulation questionnaire (score 1–6)
2.92 → 3.7
0.13
Grossarth 2001a
None (17)
2.87 → 2.99
IV
Iscador spezial (20)
Spitzer score questionnaire
~5 → 7.2
<0.05
Borrelli 2001
Placebo (10)
~5.2 → 4.8
Advanced
VEC, Eurixor (21)
Leukopenia ↓
Platelets: no difference
≤ 0.001
QoL index* (superior)
Anxienty scale* (superior)
≤ 0.01
Heiny 1991
VEC, placebo (19)
Breast, others
All stages
Iscador (39)
Self-regulation questionnaire
(score 1–6)
3.41 → 3.87
0.02
Grossarth 2001b
None (39)
3.85 → 3.62
Breast, ovary, lung
T1–4, N0–3, M0–1
ChemotherapyI, Helixor A (115)
Chemotherapy-related adverse events
28
not shown
FLIC-score*
↑ 9
TCM-score*
↑ -1
KPS* increase in % of patients
50%
FLIC 0.014
TCM 0.0007
KPS 0.002
Piao 2004
ChemotherapyI, Lentinan (109)
Chemotherapy-related adverse events
77
FLIC-score*
↑ 4,7
TCM-score*
0
KPS* increase in % of patients
32%
Ovary
IA–IC
Iscador (21)
Self-regulation questionnaire, (score 1–6) median difference
0.58
0.0002
0.30–0.90
Grossarth 2007a
None (21)
Ovary, others
Inoperable
Radiation, cisplatin, holoxan, Helixor (23)
Nausea ↓,
vomiting ↓,
depression of leucopoiesis ↓
0.005, 0.08,
0.003
KPS*
67% → 76% (p = 0.0008II)
not shown
Lange 1985
Radiation, cisplatin, holoxan (21)
70% → 74% (p = 0.12II)
Cervix
IVA-B
Iscador (19)
Self-regulation questionnaire, (score 1–6) median difference
0.7
0.014
0.15–1.05
Grossarth 2007c
None (19)
Uterus
IA-C
Iscador (30)
Self-regulation questionnaire, (score 1–6) median difference
0.4
0.0012
0.15–0.70
Grossarth 2008a
None (30)
Non-randomized controlled studies
Breast
T1–3, N0, M0
Iscador (84)
Self-regulation questionnaire
Hazard-ratio
0.20
0.031
0.00–0.35
Grossarth 2006b
None (84)
I–II
Surgery, CMF/EC, Iscador (33)
CMF/EC-induced lymphocyte decrease ↑,
platelet decrease ↓
n.s,
0.01
EORTC QLQ-C30*, BR 23*
Reduced increase of nausea/vomiting, general side effects of CMF/EC
0.02
0.02
Loewe-Mesch
Surgery, CMF/EC (33)
Breast (suspected)
Surgery, Iscador M spezial (47)
Prevention of surgery-associated inhibition of granulocyte function (PMA- and E.coli-stimulated oxidative burst)
<0.0001,<0.001
Büssing 2005
Surgery (51)
Ovary
IA–IC
Iscador (75)
Self-regulation questionnaire, (score 1–6) median difference
0.30
<0.026
0.10–0.60
Grossarth 2007d
None (75)
Cervix
IB-IVA
Iscador (102)
Self-regulation questionnaire, (score 1–6) median difference
0.25
<0.0005
0.15–0.35
Grossarth 2007f
None (102)
Uterus
IA-C
Iscador (103)
Self-regulation questionnaire, (score 1–6) median difference
0.65
<0.0005
0.4–0.95
Grossarth 2008d
None (103)
Retrolective pharmaco-epidemiological cohort study
Breast
I–III
Conventional therapy, Helixor (167)
Odds ratio for occurrence of disease- or treatment associated symptoms: 0.508
0.319–0.811
Beuth 2008
Conventional therapy (514)
I–III
Conventional therapy, Iscador (710)
Adverse drug reactions ↓, Odds ratio: 0.47
95% CI 0.32–0.67
Odds ratio for being symptom-free 3.56 (vomiting, headache, exhaustion, depression, concentration, sleep, dizziness, irritability) ↑
2.03–6.27
Bock 2004
Conventional therapy (732)
I–IV
Conventional therapy, Eurixor (219)
Symptom mean score improved (nausea, appetite, stomach pain, tiredness, depression, concentration, irritability, sleep)
<0.0001
Schumacher 2003
Conventional therapy (470)
I Chemotherapy (referring to the study by Piao et al.) – breast cancer: CAP, CAF (CAP: Cyclophosphamide, doxorubicin, cisplatin; CAF: Cyclophosphamide, doxorubicin, 5-fluorouracil); ovarian cancer: CP, IcP (CP: Cyclophosphamide, cisplatin, IcP: Ifosfamid, carboplatin); non-small cell-lung cancer: VP, MViP (VP: Vinorelbine, cisplatin; MViP: Mitomycin, vindesine, cisplatin).
II Statistical significance of pre-post difference within each group
QoL: Quality of life; KPS: Karnofsky Performance Status Scale SCE: Sister chromatid exchange; ↑: increase; ↓: decrease. P-value, 95% CI: Statistical significance of difference between mistletoe (or other verum) and control group; n.s.: not statistically significant; EC: Epirubicin, cyclophosphamide (F: 5-fluorouracil); VEC: Vindesine, epirubicin, cyclophosphamide; CMF: Cyclophosphamide, methotrexate 5-fluorouracil; CAF: Cyclophosphamide, doxorubicin, 5-fluorouracil.
Single-Arm Cohort Studies (e.g. Phase II Trials) on VAE Treatment in Breast and Gynaecological Cancer
Author, Year
Treatment I
Site II
Outcome III
N IV
Quality Criteria Fulfilled VI
Preparation
Injection site
Dosage
Escalating dosage
Duration
CR
PR
NC
PD
QoL
L
M
N
O
P
Q
Breast, Ovary, CIN
Mansky 2008
Helixor
(& gemcitabine)
sc
Up to 250 mg, daily
Yes
9 w
Breast, others
0%
10%
47%
43%
27
(+)
+
+
-V
(+)
(+)
Schink 2006
Helixor
(& surgery)
sc
3/week, varying individually
Yes
Up to 2 years
Breast, colon
-
-
-
-
↗IIIa
40
+
+
(+)
(+)V
(+)
-
Schöffski 2004
Aviscumine
iv
10 – 6400 ng/kg, 2/w
Yes
3–24 w, median 6 w
Ovary, breast, others
0%
0%
30%
70%
37
+
(+)
+
+
+
+
Mahfouz 1999
Viscum fraxini
sc or it
1 × 45 mg/w
No
16–136 w
Breast
8%
54%
35%
4%
↗
26
(+)
(+)
+
(+)
+
+
Mahfouz 1998
Abnobaviscum Fr
sc
1 × 45 mg/w
No
17 w
Breast
0%
44%
33%
22%
↗
9
-
(-)
(+)
-
-
(+)
Finelli 1998
Lektinol
sc
2,5 μl/kg, 2/w
No
Up to 12 w
Breast, others
-
-
-
-
↗
884
+
+
+
-
+
+
Portalupi 1995
Iscador M
sc
2 × 1 ng MLI/kg bw × w
No
16 w
CIN I–III
41%
27%
27%
5%
22
+
+
+
+
+
(+)
Malignant effusion
Bar-Sela 2006
Iscador M
ip
10 mg
No
repeatedly
Ascites (ovary, others)
Increase of interval between two successive paracenteses from 7 to 12 days, p = 0.001IIIb
↗IIIc
23
(+)
(+)
+
(+)
+
+
Werner 1999
Abnobaviscum Fr
ipl
1 × 75 mg/w
No
3–8 w
Pleural effusion (breast, others)
88%
↗
32
+
+
+
-
(+)
(+)
Stumpf 1994
Helixor A, M or P
ipl
100–1000 mg
Yes
repeatedly
Pleural effusion (breast, others)
61%
11%
22%
18
+
+
+
(+)
+
+
Friedrichson 1995
Helixor A, M
ip
100–1000 mg, 2/w
Yes
repeatedly
Ascites (ovary, others)
70%
↗
12
(+)
(-)
+
-
(-)
+
I sc: subcutaneous, it: intratumoural, ipl: intrapleural, ip: intraperitoneal; iv: intravenous infusion; bw; body weight; w: week
II CIN: cervical intraepithelial neoplasia. Stage: advanced, except in Portalupi 1995, and partly Schink 2006 and Finelly 1998; plural effusion and ascites indicates treatment site
III CR: complete, PR: partial remission, NC: no change, PD: progredient disease, QoL: quality of life, ↗: improved, ↘ impaired
IIIa Especially physical functioning, role, fatigue, appetite
IIIb Median values, comparable abdominal circumference and symptom score or drained fluid before or during each paracentesis respectively
IIIcTrend improvement in symptom score, especially abdominal pain, abdominal pressure, and waking up at night due to shortness of breath
IV N: Number of participants
V Concomitant conventional oncological cytoreductive therapies in some of the patients
VI L Well-described patient characteristic and disease (diagnosis, stage, duration), prognostic factors
M Outcome parameter relevant and well described
N Well-described intervention
O Concomitant therapies well described
P Outcome clearly described, temporal relationship between applied therapy and observed outcome precisely described
Q Selection of patients excluded
+ = adequately fulfilled, (+) = partly fulfilled, (-) = little fulfilled, - = not fulfilled
Controlled studies
The 19 RCTs
Stages ranged from early-detected to advanced disease. 33 studies had two arms, one trial had three, and one four arms. Endpoints were: survival (22 studies), tumour remission, recurrence or time to recurrence or metastases (8 studies), pleurodesis (1 study), QoL or coping with disease (11 studies), QoL or tolerability of concomitant chemotherapy, radiotherapy or surgery (13 studies). Length of follow-up varied from three days in one trial to – usually – months or years.
All treatment groups received conventional care when indicated, and most patients had undergone prior surgery. In 16 studies (9 RCTs and 7 non-RCTs) the combination of VAE treatment and concurrent chemotherapy, radiotherapy or surgery was investigated. 13 of these studies assessed reduction of side effects from these cytoreductive therapies. Three trials directly compared VAE treatment versus chemotherapy treatment or versus radiation and hormones
The commercial VAE applied were Iscador®, Helixor®, Eurixor® or Lektinol®. VAE dosage mostly followed general recommendations, starting with low doses and increasing to an individually still well-tolerated dosage, or treating according to lectin-content (in 6 trials) or leaving treatment modalities to the physician's discretion, which, it can likewise be assumed, followed general recommendations. VAE was injected subcutaneously except in three trials employing intravenous infusion or intrapleural instillation
Single-arm studies
11 prospective cohort studies
Quality assessment
Table
In the single-armed studies, study quality was reasonably good except in an unpublished report
Characteristics of the preclinical studies
The
Tumour cell
VAE
Result
Reference
Breast cancer
MFM-223
Iscador Qu, M, A
Iscador P
ML I
IC50
0.05–0.12 mg/ml
1.89 mg/ml
38 ng/ml
Iscador M, Qu,
Abnobaviscum Fr
Inhibition of proliferation
0.1–1 mg/ml
0.01–1 mg/ml
KPL-1
Iscador Qu, M, A
Iscador P
ML I
IC50
0.1–0.3 mg/ml
1.94 mg/ml
141 ng/ml
Iscador M, Qu,
Abnobaviscum Fr
Inhibition of proliferation
1 mg/ml
0,1–1 mg/ml
Iscucin® A, M, P, C, Po, T, Qu, S
Cytotoxicity
0.1 mg/ml
Iscador M
ML I
No stimulation of cell proliferation
0.05–5 ng ML/ml
0.01–5 ng/ml
MCF-7
Iscador Qu, M, A
Iscador P
ML I
IC50
0.09–0.12 mg/ml
1.61 mg/ml
410 ng/ml
Lektinol
IC50
>10 ng ML I/ml
Iscador Qu, M, P
(max. 1 or 1.5 mg/ml)
Inhibition of S-phase progression
Induction of apoptosis
Iscador M
Iscador P
ML I
Iscador Qu
IC50
No influence
185 μg/ml
no activity
0.003 μg/ml
0.0015–15 μg/ml
Viscotoxin isoforms (A1, A2, A3, B, 1-PS)
Viscotoxin isoform U-PS
GI50
LC50
0.02–0.8 μg/ml
0.6 to >1 μg/ml
no activity
ML I A chain
Inhibition of proliferation
0.5 μg/ml
ML I, ML II, ML III
Inhibition of proliferation
1–10 ng/ml
TNF & ML I (100 ng/ml)
Potentiation of TNF-cytotoxicity
Lektinol
IC50
0.003 μg/ml
Helixor P
ML I
IC50
> 150 μg/ml
0.086 μg/ml
Iscucin M, P, C, Po, T, Qu, S
Iscucin A, Pi
Cytotoxicity
0.1 mg/ml
no activity
MCF-7/ADR
Lektinol
IC50 (SRB assay)
0.3 E-4 μg/ml
MAXF 401NL
Helixor P
ML I
IC50
0.66 μg/ml
0.003 μg/ml
Iscador M
Iscador P
ML I
Iscador Qu
IC50
>70% growth inhibition
< 3 μg/ml
no activity
0.353 E-4 μg/ml
10 μg/ml
MAXF 401
Lektinol
IC50
< 0.1 E-4 μg/ml
MAXF 1162
Lektinol
IC50
< 0.1 E-4 μg/ml
MAXF 449
Lektinol
IC50
0.2 E-4 μg/ml
MAXF MX1
Lektinol
IC50
< 0.1 E-4 μg/ml
MDA-MB-231
Lektinol
IC50
0.7 E-4 μg/ml
Helixor P
ML I
IC50
135 μg/ml
0.041 μg/ml
MDA-MB-468
Helixor P
ML 1
IC50
47 μg/ml
0.006 μg/ml
MDA-MB-486-HER2
Iscador M
Inhibition of epidermal growth factor-induced proliferation
0.5 μg/ml
Colo-824
Iscador M
ML I
No stimulation of cell proliferation
0.05–5 ng ML/ml
0.01–5 ng/ml
HCC-1937
Iscador Qu, M, A
Iscador P
ML I
IC50
0.1 to 0.3 mg/ml
2.14 mg/ml
320 ng/ml
Iscucin A, M, P, C, Po, T, Qu, S
Cytotoxicity
0.1 mg/ml
BT474
Helixor M, A
Cytotoxicity (WST-1)
Maximum (80 and 100%) with 25 mg/ml
Primary breast cancer
Iscador M, Qu
Abnobaviscum Fr
Mitochondrial activity (MTT)
50–80% with 0.1–0.001 mg/ml
Abnobaviscum M
Inhibition of proliferation
0.5–50 μg/ml
ML I
Inhibition of proliferation
1–50 ng/ml
T47D
ML I, II, III
IC50
> 0.1 – 1 ng/ml
ML I A-chain
Inhibition of proliferation
10 ng/ml
BT549
ML I A-chain
Inhibition of proliferation
500 ng/ml
HBL100
ML I A-chain
Inhibition of proliferation
100 ng/ml
Breast cancer cells
ML II, ML III, viscotoxins
Cytotoxicity
Ovarian cancer
OVXF 1619L
Helixor P
ML I
IC50
119 μg/ml
0.100 E-3 μg/ml
OVXF 899L
Helixor P
ML I
IC50
>150 μg/ml
0.229 μg/ml
SKOV-3 (HER-2 expression)
Recombinant ML I
IC50
Induction of apoptosis
0.033 ng/ml
OVCAR3
Iscador Qu, M
(max. 1 or 1.5 mg/ml)
Inhibition of S-phase progression,
Induction of apoptosis
No clear effect
OVXF 899
Lektinol
IC50
0.3 E-3 μg/ml
OVXF 1353
Lektinol
IC50
0.01 μg/ml
OVXF 1023
Lektinol
IC50
< 0.1 E-4 μg/ml
SKOV3
Lektinol
IC50
< 0.1 E-4 μg/ml
Primary ovarian cancer
Abnobaviscum M
Inhibition of proliferation
5 μg/ml
Uterine cancer
UXF 1138L
Iscador M
Iscador P
ML I
Iscador Qu
IC50
Growth inhibition >30%
6.8 μg/ml
No activity
0.16 E-4 μg/ml
15 μg/ml
UCL SK-UT-1B
Helixor P
ML I
IC50
> 150 μg/ml
0.038 μg/ml
SK-UT-1B
Lektinol
IC50
0.6–5.5 ng ML I/ml
ML I
Inhibition of proliferation
0.5–500 ng/ml
Iscador M
ML I
No stimulation of cell proliferation
0.05–5 ng ML/ml
0.01–5 ng/ml
SK-UT-1
ML I
Inhibition of proliferation
0.5–500 ng/ml
MES-SA
ML I
Inhibition of proliferation
0.5–500 ng/ml
Primary uterus cancer
Abnobaviscum M
Inhibition of proliferation
5–50 μg/ml
Vulvar cancer
SK-MLS-1
Lektinol
IC50
2 to >5 ng ML I/ml
ML I
Inhibition of proliferation:
0.5–500 ng/ml
Iscador M
ML I
No stimulation of cell proliferation
0.05–5 ng ML/ml
0.01–5 ng/ml
Cervical cancer
HeLa
TNF & ML I (100 ng/ml)
Potentiation of TNF-cytotoxicity
ML I
Inhibition of protein synthesis
100 μg/ml
Protein fractions
Complete inhibition of DNA-, RNA-synthesis
Proliferation
1 μg/ml
no effect
Viscotoxins
IC50
0.2–1.7 μg/ml
Helixor M
Growth inhibition
≥ 0.01 mg/ml
Isorel®
Cytotoxicity
30 μg/μl
Isorel A, M, P,
ML I
Cytotoxicity
> 1 μl/ml
> 1 μg/ml
Iscador M
Helixor M
VAE M
LC50
16 μg/ml
35,4 μg/ml
3,9 μg/ml
Iscador M, Qu
Abnobaviscum Fr
Growth inhibition
0.1–1 mg/ml
0.01 mg/ml
GI50: 50% growth inhibitory concentration
LC50: 50% lethal concentration
IC50: 50% inhibitory concentration
MCF-7/ADR: adriamycin(doxorubicin)-resistant MCF-7 cell line
HER: human epidermal growth factor receptor
Animal studies
43 studies were found. 9 of these were excluded as they investigated: tumour-bearing eggs
Animal Studies of VAE on Breast or Gynaecological Cancer (transplanted human or murine tumours or primary autochthonous tumour)
Tumour, site
Animal
VAE, application and dosage
Tumour growth
T/C
Survival
ILS
Other outcomes
Reference
Human breast
Mice
MAXF 449, sc
Nude mice
Local Abnobaviscum Qu 8 or 4 or 2 mg/kg, it, qd * 3
6 to 20%
Systemic Abnobaviscum Qu 8 mg/kg, it, qd * 3
78%
MAXF 449, sc
Nude mice
Abnobaviscum M 8 mg/kg, sc, qd * 3 * 2 w
68%
BT474, sc
Mice (BALB/c)
Helixor M or A 5 mg, it, qd * 3 * 2 w
29 to 52%
Murine breast
Carcinoma, sc, iv
Mice (CBA/HZgr)
Isorel M, 3 mg, sc, qod * 21
No difference
Lung-metastases: VAE vs. control: 13.4 vs. 37.5
Carcinoma, sc
Mice (CBA/HZgr)
Isorel M, 1400 mg/kg, 2 w
20%
Carcinoma, sc
Mice (CBA/HZgr)
Isorel M, 140 mg/kg
Recurrence after resection, VAE vs. control: 47% vs. 78%
Carcinoma, iv
Mice (CBA/HZgr)
Isorel M, 140 mg/kg, ip
52 lung-metastases
Endoxan, 50 mg/kg
23 lung-metastases
Isorel M, 140 mg/kg & Endoxan 50 mg/kg
10 lung-metastases
Control
76 lung-metastases
C3H adenocarcinoma, 16/C
Mice (B6C3F1)
Iscador M, 50 or 100 mg/kg, ip, qd, day 1–14
28%
15 to 20%
RC adenocarcinoma, sc
Mice (DBA)
VAE I, sc
20 to 40%
ECa, ip
Mice (NMRI)
VAE (supracritical CO2 extraction), 2 mL/kg, ip, qd, starting day -7, day 0, or day 7
65 to 100%II
ECa, ip
Mice (BALB/c)
Iscador, 15 μg, ip, day -1
108%
Sodium caseinate & Iscador, 15 μg, ip, day -1
no death
Sodium caseinate, day -1
0%
ECa, ip
Mice (BALB/c)
Iscador, 15 μg, ip, day 6
82%
Sodium caseinate, day 6
7%
ECa, ip
Mice (BALB/c)
Iscador-activated macrophages, ip, day 6
49%
Non-activated macrophages, ip, day 6
4%
ECa, ip
Mice (BALB/c)
Iscador activated macrophages, ip, day 6, 10, 14
98%
Non-activated macrophages, ip, day 6, 10, 14
9%
ECa, sc
Mice (BALB/c)
Iscador, 15 μg, it, day 7
Severe necrosis, infiltration of lymphocytes and macrophages
ECa, sc
Mice (Swiss)
Iscador M, 1.66 mg, im, qod * 5 or 10
3 to 10%
ECa, ip
Mice (Swiss)
Iscador M, 1.66 mg, ip, qod * 10
76%
ECa, ip
Mice (Swiss)
Iscador M, 25 or 50 mg/kg, ip, qd * 14
69 to 97%
No tumour-free mice
ECa, ip
Mice (Swiss)
Iscador M, sc, cumulative dose 4, 5, 150, or 200 mg
-4 to 0%
ECa, sc
Mice
VAE, it, 0.1–0.2 ccm, qod * 6–10
Complete remission & no recurrence: 27%
Murine breast
Rats
Walker carcinosarcoma 256; sc
Rats (Sprague Dawley)
Iscador M, sc, cumulative dose 11, 16, 500, or 750 mg or combination of Iscador M, sc, cumulative dose 11 or 500 mg & Cetraria praeparata, cumulative dose 3 or 164 mg
93 to 115%
-16 to 8%
Dunning DMBA-5A; sc
Rats
Iscador M, 2.5–15 mg, ip, qd
No difference
Less tumour viability
Walker carcinosarkoma 256
Rats
Iscador M, 0.005–0.5 mg, im, qd
No difference
Metastases: no difference
Autochthonous
Methylnitrosurea-induced
Rats (Sprague Dawley)
Iscador M c. Arg., sc, 0,2 ml/day, 50 mg/week * 6 weeks
75%
-16%
sc: subcutaneous; im: intramuscular; it: intratumoural; ip: intraperitoneal; iv: intravenous; w: week;
qod: every other day; qd: every day; T/C: treated tumour/control tumour; ILS: increase in life span
All experiments did have control groups, but these were only mentioned if necessary for results
I Part of a screening programme for substances with anticancer activity (1,000 plant extracts from 107 plant species)
II Relating to volume of ascites; effects greatest with therapy started on day -7
Animal Studies of VAE Compounds in Breast or Gynaecological Cancer (transplanted human or murine tumours)
Tumour, site
Animal
VAE
Tumour growth
T/C (%)
Survival
Other outcomes
Reference
Human breast tumour
Breast
Mice
rML 0,3 ng/kg – 3 μg/kg, ip, qd * 5 * 2–4 w
No effect
Murine breast tumour in mice
C3L5, adenocarcinoma; sc
Mice (C3H7HeJ)
ML I, 1 ng/kg, sc, q3d, day 7–19
160
27.6 lung-metastases
IL-2, twice 6 × 104 IU/mouse, ip q8h 2 * qd * 5
43
2.3 lung-metastases
Combination of ML 1 & IL-2
37
2.3 lung-metastases
Control
7.5 lung-metastases
ECa, ip
Mice (ICR)
ML I, 80 ng, ip, day 1
70% died after 50 days
A-chain of ML I, 100 μg, ip, day 1
80% died after 57 days
B-chain of ML I, 10 μg, ip, day 1
80% died after 58 days
Control
100% died after 20 days
ECa, sc
Mice (BALB/c)
VAE 5 kDa peptides, 2 μg, it, day 7
Severe necrosis, infiltration of lymphocytes and macrophages
ECa, ip
Mice (CD-1)
Vester' Proteins, ip, 0.1 or 1 or 10 μ/kg, qd * 10
ILS: 0, 33, and -33%I
ECa
Mice
Polysaccharide („Viscumsäure“), ip, qd * 6
Slight effect
Adenocarcinoma EO 771
Mice
Polysaccharide („Viscumsäure“), ip, qd * 6
Moderate effect
Murine breast tumour in rats
Walker Carcinosarcoma
Rats
Polysaccharide („Viscumsäure“), ip, qd * 6
Moderate effect
Other gynaecological tumour
Ovary, SoTü 3, ip
Mice (SCID)
rML 30 ng/kg, ip, qd * 5 * 12
35% mice alive at day 84
40% tumour-free mice at day 84
rML 150 ng/kg, ip, qd * 5 * 12
10% mice alive at day 84
10% tumour-free mice at day 84
rML 500 ng/kg, ip, qd * 5 * 12
75% mice alive at day 84
65% tumour-free mice at day 84
Control
15 mice alive at day 84
10% tumour-free mice at day 84
Uterusepithelioma T-8 Guérin
Rats
Polysaccharide ("Viscumsäure"), ip, qd * 6
Moderate effect
All experiments did have control groups, but these were only mentioned if necessary for results.
sc: subcutaneous; it: intratumoural; ip: intraperitoneal; iv: intravenous; w: week;
qod: every other day; qd: every day; T/C: treated tumour/control tumour; ILS: increase in life span.
I Application of 10 μg/kg of proteins had toxic effects
These experiments had been conducted in Germany, Switzerland, Austria, USA, India, Croatia and Serbia. 9 of the 34 experiments reported the funding source, 8 of these had public funding and one a combination of public and industry funding. 19 had been published since 1990 and 15 before (1938–1989). 21 were published in peer-reviewed and 2 in other journals, 6 were published in scientific reference books, 1 as a conference abstract, and 4 in a patent specification. Published information was often insufficient and sometimes extremely sparse. 6 experiments reported randomized treatment allocation. Regarding the control group, placebo treatment was described in 13 experiments – five of these with identical application schedule to the verum treatment -, no treatment in 11 experiments, and 9 experiments gave no information. None of the experiments reported a blinded outcome assessment (but randomized treatment allocation and blinded outcome assessment are generally routine practice).
Outcome
We found substantial heterogeneity of the studies in terms of intervention, patient characteristics, clinical diagnosis, measured outcomes, design, methodological quality and potential positive and negative biases. We therefore regarded quantification of effect size by combining results as unreliable and decided on a non-quantitative synthesis and discussion. A subgroup of studies (2 RCTs, 2 non-RCTs on breast cancer), with a comparable design (all originating in the same epidemiological cohort study) had already been analysed in a quantitative meta-analysis
Results of controlled clinical studies are shown in Table
Results of the preclinical studies are presented in Tables
Breast cancer
In
Cervical cancer
Regarding
Uterus cancer
Regarding
Ovarian cancer
Regarding
Genital cancer
Malignant effusion
Safety
Tolerability was generally good. One case of urticaria and angioedema
Discussion
A variety of clinical studies and experiments have investigated the potential therapeutic effects of VAE and its compounds in breast and gynecological cancer, and predominantly reported positive effects. Nevertheless they have to be interpreted with caution and within their context.
The strongest and most consistent results from VAE in clinical studies concern
Concerning
Regarding
Apart from the discussed issues, the following validity aspects have to be considered: An attrition rate above 10% was present in 10 RCTs. In 5 of these RCTs
To reduce publication bias we also included unpublished studies and conducted a thorough literature search with extensive expert consultations. One unpublished RCT (Lektinol in breast cancer by Schwiersch et al.) could not be included as it was not released by the manufacturer. Beyond this, we cannot rule out the existence of unpublished and unknown RCTs, but we presume that no well-conducted, large-size and valid trials escaped our attention. – Regarding preclinical studies achieving completeness is nearly impossible. These experiments are usually explorative, for instance when plant extracts are chemically analysed for active compounds or for cytotoxic effects; in general only relevant results are published, but not results of non-relevant or non-working models or unstable chemicals. (Even in the reviewed experiments, often not all but only the noteworthy results were presented in detail.)
Regarding funding, 27 of 28 controlled studies published since 2000 reported their funding source: 11 studies received funding from the pharmaceutical industry alone, 16 studies (all by Grossarth et al.) had both industry and public funding. There was no difference of results depending on funding source.
Regarding non-RCTs, bias by self-selecting the treatment is usually present in raw data. In particular, patients who choose complementary treatments differ substantially from patients not choosing them
In
In general, the predictive reliability of the preclinical studies for clinical application is fairly limited in most instances. Clinical cancer disease is insufficiently mimicked by animal models, with major differences regarding age, general condition, co-morbidity, invasiveness, metastases, antigenicity, immune system etc. The results of preclinical screening, especially for treatment of solid tumours, have therefore been largely disappointing. The models currently regarded as best for cytotoxic substances use patient-derived tumours that grow subcutaneously or orthotopically in nude mice, as in several cases reviewed here. Immuno-active substances may however still be insufficiently assessed in immune-deficient animals, as the main components of the immune system are missing (nude mice, for instance, cannot generate mature T-lymphocytes). Nevertheless, these preclinical experiments can provide important additional information for detecting the possible anti-cancer effects of medicinal plants, their active compounds, their mode of action and potential risks
Safety aspects
Mistletoe therapy was well tolerated in the reviewed studies. Mild flu-like symptoms and local reactions at the injections sites are frequent, dose-dependent and self-limited. Allergic reactions can occur, and a few case reports of anaphylactic reactions exist
Conclusion
Preclinical and clinical studies investigating the influence of VAE and its isolated compounds on breast or gynaecological cancer suggest a benefit, with the strongest evidence in relation to QoL and tolerability of conventional anti-cancer treatments. Regarding survival, evidence is less conclusive; most of the clinical studies had a very small sample size (RCTs) and were embedded in the same large cohort study; therefore an independent trial would be needed. Tumour-growth inhibition has been insufficiently assessed in prospective clinical trials. Tumour regression seems not to have been connected with regular low-dose subcutaneous VAE treatment, but with high dose and local application. The latter has not yet been thoroughly assessed and is not generally recommended.
Abbreviations
AMED: Allied and Complementary Medicine; CI: confidence interval; CIN: cervical intraepithelial neoplasia; DNA: deoxyribonucleic acid; ECa: Ehrlich carcinoma; EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer; EORTC QLQ-BR23: European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Questionnaire; FACT-G: Functional Assessment of Cancer Therapy-General; FLIC: Functional Living Index – Cancer; GCP: Good Clinical Practice; GEP: Good Epidemiological Practice; GLQ-8: Global Life Quality; GM-CSF: granulocyte macrophage colony-stimulating factor; HeLa cells: immortal cell line from Henrietta Lacks; HR: hazard ratio; ICH: International Conference on Harmonisation; IFN-γ: interferon-gamma; IL: interleukin; kDa: kilodalton; KPS: Karnofsky performance status scale; MDR+: multidrug resistant; ML: mistletoe lectin; NCCAM: National Center for Complementary and Alternative Medicine; NCI: National Cancer Institute; NHS: National Health Service; NK: neutral killer (cell); NLM: National Library of Medicine; non-RCT: non-randomized controlled trial; QoL: quality of life; RCT: randomized controlled trial; rML: recombinant mistletoe lectin; SCE: sister chromatid exchange; SCID mice: Severe Combined Immunodeficiency mice; T-cells: lymphocytes matured in thymus; TCM: Traditional Chinese Medicine Index; TNF-α: tumor necrosis factor-alpha; TNM: tumor, node, metastasis; VAE:
Competing interests
IFAEMM has received restricted research grants from Weleda, Abnoba and Helixor for other projects not connected to this review.
Authors' contributions
The study protocol was written by GK and HK. Studies were read by GK, HK, AG. Study quality was assessed by GK and HK. Data were extracted by GK and checked by AG and HK. MS contributed substantially to data acquisition, analysis and interpretation of preclinical studies. GK wrote the paper which was critically revised and finally approved by HK, MS and AG.
Acknowledgements
This review was funded by the Gesellschaft für Biologische Krebsabwehr and the Software AG Stiftung. We thank Dr. Renatus Ziegler for providing additional data on the studies by Grossarth-Maticek & Ziegler.