complementary cancer therapy a s r … · 2012-07-17 · complementary and alternative medicine...

EUROPEAN JOURNAL OF MEDICAL RESEARCH 103

AbstractBackground: Anthroposophic Mistletoe therapy is awidely used complementary cancer treatment.Objective: To evaluate prospective clinical trials on theeffectiveness of anthroposophic mistletoe therapy forcancer.Design: Systematic review.Material and Methods: Search of 9 electronic databases,reference lists and extensive expert consultations. Cri-teria-based assessment of methodological study quali-ty. Results: 16 randomized (RCT) and 9 non-randomized(N-RCT) controlled trials were identified that investi-gated mistletoe treatment of malignant diseases. Statis-tically significant benefit for survival was reported in 8of 17 trials (in 5 of 10 RCTs), for disease-free survivaland tumour recurrence in none of 2 RCTs, for remis-sion of tumour and malignant effusion in 1 RCT and 1N-RCT of 4 controlled trials, for quality of life (QoL)in 3 of 5 RCTs, and for QoL and reduction of side ef-fects of cytoreductive therapies (chemotherapy, radia-tion or surgery) in 5 of 7 trials (3 of 5 RCTs). Method-ological quality of the controlled trials differed sub-stantially; some had major limitations while otherswere reasonably well conducted. 12 single-arm cohortstudies were identified. 5 of 7 studies found substantialtumour remission in various cancers, one study report-ed remission of CIN, and 4 studies remission of malig-nant pleural effusion or ascites. Quality of reporting incohort studies was mostly reasonably good. Mistletoeapplication was well tolerated.Conclusions: Regarding quality of studies and consis-tency of results, the best evidence for efficacy ofmistletoe therapy exists for improvement of QoL andreduction of side effects of cytotoxic therapies(chemotherapy, radiation). Survival benefit has beenshown but not beyond critique. Tumour remissionsare described in cohort studies that investigate the ap-plication of high dose or local mistletoe extracts. Asseveral reasonably well-conducted studies indicatebeneficial effects, further properly designed trialsshould be encouraged to investigate clinical efficacyand its possible dependency on the mode of applica-tion.

Key words: Clinical trials, systematic review, mistletoe,Viscum album, neoplasms

INTRODUCTION

Complementary and alternative medicine (CAM) ispopular among cancer patients; across Europe 40%(15-73%) use some form of CAM, mostly herbal med-icine. [1] Mistletoe extracts (Viscum album L., VAE)are the most frequently prescribed CAM cancer thera-pies in Central Europe [2]. Up to two thirds of cancerpatients in Germany and Austria receive CAM, pri-marily mistletoe extracts. [3;4]

Mistletoe treatment for cancer was introduced in1920 by Steiner and Wegman, founders of Anthropo-sophic Medicine (AM). [5] AM is a CAM system, andis practised worldwide, particularly in Central Europe.[6;7] AM mistletoe preparations – Abnobaviscum, He-lixor, Iscador (labelled as “Iscar” in the US), Iscucin,Isorel – are used not only within but also widely out-side AM. They are extracts from defined parts of Vis-cum album L., i.e. fresh leafy shoots and berries. Thesepreparations are available from different host treessuch as fir (Abies, A), oak (Quercus, Qu), apple tree(Malus, M), pine (Pinus, P), elm (Ulmus, U), and oth-ers. Route of application and dosage are varied individ-ually, depending on the patient’s reaction and stage ofdisease. AM mistletoe is used in all stages of disease,either alone or in combination with chemotherapy, ra-diation therapy, or hormone therapy.

Biological and pharmacological properties of VAEhave been subject to extended scientific investigations(overview in [8;9]). Several pharmacologically activecompounds have been isolated, such as mistletoelectins (ML I, II and III) [10], viscotoxins [11;12], oli-go- and polysaccharides [13;14], lipophilic extracts[15] and several others [8]. The most prominent prop-erties of VAE are their cytotoxic and growth-inhibit-ing effects on a variety of human tumour cell lines,lymphocytes and fibroblasts in vitro [8]. The cytotoxiceffects of VAE are mainly due to the apoptosis-induc-ing mistletoe lectins [16-18], while the viscotoxins in-duce necrotic cell death [18;19]. VAE are also recog-nized for their immune modulating activity. In vitroand in vivo studies have demonstrated activation ofmonocytes/macrophages, granulocytes, natural killer(NK) cells, T-cells (especially T-helper-cells) and theinduction of various cytokines [8]. VAE also possessDNA stabilizing properties. [20-22] In animals, VAEdisplays potent antitumoural effects when adminis-

March 26, 2007

Eur J Med Res (2007) 12: 103-119 © I. Holzapfel Publishers 2007

Review

COMPLEMENTARY CANCER THERAPY: A SYSTEMATIC REVIEW OF PROSPECTIVE CLINICAL TRIALS ON

ANTHROPOSOPHIC MISTLETOE EXTRACTS

G. S. Kienle, H. Kiene

Institute for Applied Epistemology and Medical Methodology, Bad Krozingen, Germany

tered either directly into the tumour or systemically.[8; 9]

Clinical efficacy of mistletoe therapy has been thesubject of controversial debate. Because of its wide-spread use and because of increasing research activity,systematic review of clinical mistletoe studies is impor-tant. Most reviews are outdated or incomplete (e.g.[23-28]). Of the recently published reviews, one fo-cused on non-AM mistletoe extracts only [27], onemissed most of the RCTs on AM mistletoe extracts[28], and one [29] is being incorporated into the fol-lowing.

This review was initiated by the ComplementaryMedicine Evaluation Programme (Programm Evalua-tion der Komplementärmedizin – PEK), a researchinitiative of the Swiss Parliament, covering HTA re-ports on five CAM methods, including AM [6;7]. Outof 197 clinical studies on AM therapies, 97 prospectiveand retrospective studies investigated mistletoe in can-cer and other neoplasms [7]. The present review is re-stricted to prospective clinical studies on AM mistletoeapplication in cancer only, addressing the followingquestions:

Do prospective clinical trials provide evidence forthe effectiveness of mistletoe therapy in relation to sur-vival, tumour remissions (including malignant effusion),quality of life (QoL), or reduction of side effects fromcytoreductive therapies in cancer patients? Can the ef-fect size be estimated by quantitative data synthesis?

MATERIAL AND METHODS

Methods were predefined in a protocol.

SEARCH STRATEGY

We used a systematic process to search the followingdatabases for clinical trials: AMED, Biosis Previews,Cinahl, Cochrane Library (Cochrane Database of Sys-tematic Reviews, Cochrane Controlled Trials Register,The NHS Economic Evaluation Database, HealthTechnology Assessment Database), Embase, Med-line/Premedline, NLM Gateway, Science Citation In-dex, National Centre for Complementary and Alterna-tive Medicine, private databases; from inception ofthese databases to June 2006 using the terms (AN-THROPOS? OR MISTLETOE OR VISCUM? ORMISTEL? OR ISCADOR? OR ISCAR OR HE-LIXOR OR ABNOBA? OR ISCUCIN OR ISORELOR VISOREL OR ?SOREL OR WELEDA ORWALA) AND (STUDY? OR STUDIE? OR TRIALOR EVALUAT? OR RANDOM? OR INVESTIG?OR COHORT? OR KOHORT? OR OUTCOME?OR REVIEW OR UEBERSICHT OR MET-ANALYS? OR META(W)ANALYS?) The referencelist from each potentially eligible study, relevant reviewarticle and textbook was checked, and experts in thefield and manufacturers of mistletoe preparations werecontacted for additional reports.

SELECTION

The following selection criteria were used for inclu-sion of studies in the analysis: (I) prospective random-

ized or non-randomized controlled clinical trial, orprospective single-arm cohort study (e.g. phase II tri-al); (II) study population with cancer, including cervi-cal intra-epithelial neoplasm (CIN); (III) interventiongroup treated with anthroposophic mistletoe prepara-tion; (IV) clinically relevant outcome (i.e. survival, dis-ease-free interval, remission, relapse, QoL, or reduc-tion of side effects or immune suppression during cy-toreductive therapy); (V) completion of study; (VI)published or unpublished. Studies were excluded ifthey: only measured toxicity or tolerability (phase I tri-al), only measured stimulation of immunological para-meters, or were not conducted on cancer patients.There were no restrictions on language.

VALIDITY ASSESSMENT AND DATA ABSTRACTION

Criteria-based analysis was performed on the selectedstudies to assess their methodological quality. Analyseswere performed independently by two reviewers (GK,HK). There were no major differences in study assess-ment; disagreements were resolved by discussion. Cri-teria for assessing strength of evidence in controlledtrials were adapted from the National Health ServiceCentre for Reviews and Dissemination [30] and fromcriteria for good methodology as already applied inearlier reviews on mistletoe trials [24;29]. Quality crite-ria were adjusted for cohort studies [6]. Criteria wererated as “+” = adequately fulfilled, “(+)” = partly ful-filled, “(-)” = little fulfilled, “-” = not fulfilled. Datawere abstracted by one reviewer (GK) and checked bythe second reviewer (HK). When necessary, primaryauthors of the trials were contacted for additional in-formation.

For ranking the quality of the studies (cf. Table 1and Table 2) we computed a summary score with 3 for+, 2 for (+), 1 for (-), and 0 for - respectively. Thefunction of this ranking is only to provide a quick,summary reference to the methodological quality ofthe studies. It does not claim precision since it neitherpresupposes equivalence of rating intervals nor nu-merical equality among the different criteria.

RESULTS

Figure 1 summarizes the process of identifying eligibleclinical trials (for more details see [6;7]). 37 trials metthe inclusion criteria: 16 RCTs, 9 N-RCTs, and 12 sin-gle-arm cohort studies. Of the 37 trials, 34 were pub-lished (three of these only as an abstract [31-33]), onestudy was retrieved as a doctoral dissertation [34], andtwo were unpublished reports [35;36]. Two further tri-als [37;38], conducted in Poland, were excluded fromthis review because of severe validity concerns: a col-laborating scientist questioned the alleged randomiza-tion of treatment allocation, and no information couldbe received from the authors to clarify this question.

CHARACTERISTICS OF INCLUDED TRIALS

Table 1 - Table 6 show characteristics of the trials. Set-tings of the trials were academic hospitals, large com-munity hospitals, and specialized cancer hospitals;three trials were done in cancer rehabilitation centres.

EUROPEAN JOURNAL OF MEDICAL RESEARCH104 March 26, 2007

The studies were conducted in Germany (n = 14),Austria (n = 6), Egypt (n = 4), Italy (n = 2), Israel (n =2), Switzerland (n = 2), Romania (n = 2), China (n =1), Denmark (n = 1), South Korea (n = 1), or in morethan one European country (n = 2). 22 trials wereconducted in one, 15 in more than one centre. One ofthe controlled [39] and four of the cohort studies[33;36;40;41] were conducted in an AM hospital, theother ones in non-AM institutions.

Controlled trials:16 RCTs (see Table 1) included 2602 participants, 9 N-RCTs (see Table 2) included more than 2512 partici-pants (the sample size of one control group was notpublished). Cancer sites studied were: breast (n = 10),lung (n = 8), colon and rectum (n = 5), stomach (n =3), melanoma (n = 2), ovary (n = 2), genital (n = 2),head and neck (n = 1), gastrointestinal (n = 1), andmalignant pleural effusion (n = 1). Stages ranged fromearly detected to advanced disease. 20 trials had twoarms, four trials had three arms, one trial consisted oftwo overlapping parts with three and four arms re-spectively, with two of the four arms used for analysisof mistletoe efficacy. Endpoints were: survival (n =

17), tumour remission or recurrence (n = 5), pleurode-sis (n=1), quality of life or coping with disease (QoL, n= 5), QoL, physical condition and reduction of sideeffects of chemotherapy, radiotherapy or surgery (n =7). Length of follow-up depended on primary out-come, varying from three days in one trial [39] to usu-ally months or years (survival).

All treatment groups received conventional care(COM) when indicated. In nine trials mistletoe was ad-ministered concurrently with chemotherapy, radiother-apy or surgery [35;39;42-48]; seven of the trials as-sessed reduction of side effects from these cytoreduc-tive therapies [35;39;44-48]. In 18 trials mistletoe ther-apy was used at least partly in an adjuvant setting aftersurgery or radiotherapy [39;44-46;48-60].

The applied mistletoe remedies were Iscador, He-lixor, or Isorel. Host tree specification of these reme-dies (usually depending on cancer site, and sex of pa-tient) was often not mentioned. Dosage mostly fol-lowed recommendations of the manufacturer, startingwith low doses and increasing to the maximum tolerat-ed dosage; one trial treated according to lectin-content(1ng/kgKG) [61]. Mistletoe was injected subcuta-neously except in three studies employing intravenous

EUROPEAN JOURNAL OF MEDICAL RESEARCHMarch 26, 2007 105

Fig. 1. Identification of eligible prospective clinical cancer trials on anthroposophic mistletoe preparations (updated HTA-re-port [6; 7] )

infusion [39;44] or intrapleural instillation [32]. Treat-ment duration depended on primary endpoint and re-lated follow-up, ranging from one single application(in one trial [39]) to repeated applications over monthsand years, often with individually varying length withintrials. Exact treatment duration, however, was oftennot specified. Control groups received either no fur-ther treatment (n = 18), additional placebo application(n = 3), doxycyclin (n = 1), Lentinan (n = 1), BCG (n= 1), or partly hormones (n = 1). Two trials had dou-ble-blinded treatment application [46;61]. Besides themistletoe extracts, AM was not part of any study treat-ment except perhaps in one N-RCT on surgery-associ-ated inhibition of granulocyte function [39] that waspartly conducted in an AM hospital.

We found substantial heterogeneity of the studies interms of intervention, patient characteristics, clinicaldiagnosis, measured outcomes, design, methodologicalquality and potential positive and negative biases. Wetherefore considered a quantification of effect size bycombining results to be unreliable and decided on anon-quantitative synthesis and discussion.

Single-arm cohort studies:Twelve prospective cohort studies (see Table 6) includ-ed 251 patients. Cancer sites studied were colorectal (n= 1), pancreas (n = 1), hepatocellular carcinoma (HCC,n = 1), breast (n = 2), brain (n = 1), kidney (n = 1), fol-licular Non-Hodgkin’s lymphoma (FL, n = 1), and CIN(n = 1). Furthermore, malignant pleural effusion (n =2) and malignant ascites (n = 2) were investigated. Tu-mour stages were advanced or inoperable, except in FL(all stages) or CIN. Six trials were on solid tumours andone on FL; four of these included patients who all[31;62;63], or some of whom [41], had received conven-tional pre-treatment, and had mostly been resistant es-pecially to chemotherapy; the two other trials includedpatients with inoperable or disseminated disease whohad received no prior chemo- or hormone therapy[64;65]. One trial combined mistletoe extract with gem-citabine in inoperable pancreatic cancer [33]. All 12studies assessed remission of solid tumours, of FL, orof malignant effusion; eight of them also reported QoLor symptomatic relief. The mistletoe remedies were Ab-nobaviscum (partly Viscum fraxini), Iscador, or He-


Table 1. Quality of Randomized Controlled Mistletoe Trials (ordered by decreasing quality).

Author, Year Quality Criteria Fulfilled in StudiesI Partici- ARII

pants

A) B) C) D) E) F) G) H) I) J) K)

Piao 2004 [45] + + - (-) + + + (+) + + + 233 4%Auerbach 2005 [46] + - (+) (+) + - + (+) + (+) + 23 17-30%Grossarth 2001 [59] + + - (-) + + + (-) + + - 34 0%Dold 1991 [66] + + - - + (-) + (+) + + (-) 408 17%Lange 1985 [35] + + - (-) + (-) + (+) + + - 68 35%Borrelli 2001 [61] + - (+) (+) + + (+) + (-) (+) - 30 0%Grossarth 2001 [59] + + - (-) + (-) + (-) + + - 98 20%Kleeberg 2004 [60;67] + + - (-) (-)III (-) (+) + (+) (+) (+) 204 24%

(830)Salzer 1991 [49] + (+) - (-) (+) (-) + (+) (+) + - 218 16%Douwes 1986 [42] + - - (-) + + + + - (+) - 60 0%Gutsch 1988 [51] + - - (-) + (-) + + (+) + - 692 20%Salzer 1979, 1983 [56-58] + - - (-) + - + + (+) (+) - 320 57%Cazacu 2003 [44] (+) - - (-) + + (+) (+) (-) - - 64 not shownSalzer 1987 [55] + (+) - (-) + - + - - - - 50 48%Enesel 2005 [47]IV + - - - (+) - (+) (-) (-) (-) - 70 45%Kim 1999 [32] + - - - (-) - (+) (+) (-) (-) - 30V 13%

I A) Protection against selection bias, especially by adequate randomization B) Minimization of heterogeneity by pre-stratification or matchingC) Protection against observer bias by blinding of patient, care provider, and outcome assessorD) Protection against performance (treatment) bias by standardization of care protocol, documentation of all co-interven-

tions, blinding of patients and care providersE) Protection against measurement (detection) bias by standardization of outcome assessmentF) 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 com-parison of prognostic characteristics of lost patients and compliers

G) Effect measurement relevant and well describedH) Well described intervention, patient characteristics, disease (diagnosis, stage, duration), previous therapyI) Well described study designJ) Well described results K) Data quality assured by GCP-ICH-guidelines, especially by monitoring

II AR: attrition rate (dropouts, protocol deviations, withdrawals, patients did not receive treatment as allocated). III Primary endpoint (disease-free survival) was prone to measurement bias (see discussion or [29]); secondary endpoints were

resistant to measurement bias (overall survival), or were not published (quality of life).IV Essential information in a supplementary statementV Discrepancy in patient numbers in two presentations (30 and 33), with corresponding discrepancy of results

lixor. They were applied subcutaneously (n = 7), intra-tumourally (n = 2), intrapleurally (n = 2), or intraperi-toneally (n = 2). Dosage depended on mode of applica-tion. Of the seven trials on solid tumours or FL, threestarted with high dosage and applied it constantly onceper week; three other trials started with low dosages, in-creasing them successively, and the seventh trial appliedincreasing dosages intratoumorally by endoscopic, ul-trasound-guided, fine-needle injection [33]. The trial onCIN constantly applied a lower dosage. For intrapleuraland intraperitoneal (repeated) application, mistletoe ex-tracts were diluted in 5-15 or 100 ml solution respec-tively. Treatment durations and follow-up ranged fromweeks to, most commonly, months or years.

QUALITY OF STUDIES

Table 1, Table 2 and Table 6 summarize the validity as-sessment. Methodological quality differed substantially.Some studies had major limitations in quality of design,conducting and reporting, while others were reasonablywell conducted (Table 1, Table 2). During recent yearsstudy quality has markedly increased in most trials. Inthe cohort studies, study quality was reasonably goodexcept in an unpublished report [36] and in the abstractpublications [31;33] with too little information.

STUDY RESULTS

Main study results are shown in Table 3 - Table 6. On survival (Table 3): Out of 17 controlled trials, eight

(5 of 10 RCTs) had statistically significant positive re-sults [44;51;53;54;56-59], eight (4 of 10 RCTs) positivetrends [42;43;49;50;52;55;66], one RCT no effect [60].

On disease-free interval and recurrence (Table 4):Out of two RCTs, one had a negative trend [60], oneno effect [49].

On remission of tumour and malignant ef fusion(Table 4): Out of four controlled trials (3 RCTs, 1 N-RCT), one N-RCT reported a statistically significantpositive effect [43], one RCT a positive trend [66], oneno effect [42]; one trial on malignant pleural effusionfound significantly higher remissions with mistletoethan with doxycyclin [32]. Of 12 cohort studies (Table6), five reported remission of solid tumours or of FLin 22-62% of patients, three reported remission of ma-lignant effusion in 70-88% of patients, one an increaseof interval between two successive paracenteses aftermistletoe instillation, one reported remission of CINin 68% of patients, and two reported stable and pro-gressive disease, but no tumour remission. Time to re-mission (CR) of solid tumours was 4-6 months in twotrials [63;64]. Concurrent conventional cytoreductivetherapy was explicitly given in only two cohort studies,one with substantial [33] and one with no tumour re-mission [65].

On QoL and coping (Table 5): Out of five RCTs,three found a statistically significant benefit [59;61;66],one RCT did not report the results [60;67]. (Six fur-ther trials investigated QoL related to chemotherapyand radiation – see below.) Of eight cohort trials, fivereported improved, one reported decreasing QoL, and


Table 2. Quality of Non-randomized Controlled Mistletoe Trials (ordered by decreasing quality).

Author, Year Quality Criteria Fulfilled in StudiesI Partici- ARII Design/control for pants confounding

A) B) C) D) E) F) G) H) I) J) K)

Grossarth 2001 [59] (+) + - (-) + + + - + + - 792 3.5% Prospective pair -matching

Büssing 2004 [39] (-)VI - - (-) + + (+) (+) (+) + + 105 7% Comparison of two differenthospitals. Pair-matching foranalysis

Salzer 1978 [53] - - - (-) + + + (+) + (+) - 77 0% Treatment allocation by typeof hospital referring the patient to surgery

Douwes 1988 [43] - - - (-) + + + + - + - 40 3% Planned as an RCT, however,computer error occurred

Von Hagens 2005 [48] - - - (-) + (-) + + (+) (+) - 66 11% Self-selected treatment allocation

Schuppli 1990 [52] (+) - - (-) + (-) + (-) - - - 198 not shown Prognostic disadvantage for mistletoe group at study begin

Salzer 1987 [55] (+) - - (-) + - + - - (+) - 155 not shown Alternating treatment allocation

Fellmer 1966 [54] - - - (-) + - + + - - - 924 16% Treatment allocation by neutral attending physician

Majewski 1963 [50] (+) - - (-) + - + - - - - VII not shown Alternating treatment (I: 15%) VIII allocation

Abbreviations as in Table 1. VI Propensity Score and Matching for final analysis VIINumber of study patients not indicated;mistletoe group included 155 patients VIIINumbers are given only for mistletoe group


Tab

le 3

. Con

trol

led

Tria

ls o

n M

istle

toe

Tre

atm

ent i

n C

ance

r: Su

rviv

al (R

CT

s an

d N

-RC

Ts

each

ord

ered

by

decr

easi

ng q

ualit

y. S

ee T

able

1 a

nd T

able

2).

Au

thor

, Yea

rSi

teSt

age

Inte

rven

tion

(ev

alu

able

pat

ien

ts)

Surv

ival

Ou

tcom

es

Mea

n (

Mon

ths)

Med

ian

H

azar

d

5-ye

ar

Oth

ers

P o

r C

Ip

artl

y ce

nsu

red

(M

onth

s)ra

tio

surv

ival

Ran

dom

ized

con

trol

led

tri

als

Gro

ssar

th

Bre

ast

IIIA

-III

B•

Isca

dor

(17)

• 57

.5

• 75

P=0.

0220

01 [5

9]•

Non

e (1

7)•

28.9

•

28

Dol

d Lu

ngA

ll •

Isca

dor

U o

r Q

u, c

.Hg.

(114

)•

9.1

• n.

s. (p

=0.

24)

1991

[66]

stag

es•

Plac

ebo

(vita

min

B) (

113)

• 7.

6 •

Poly

erga

(110

)•

9.0

• n.

s. (p

=0.

13)

Gro

ssar

th

Bre

ast,

lung

, col

on, r

ec-

All

• Is

cado

r (3

9)•

42

• 30

P=0.

0420

01 [5

9]tu

m, s

tom

ach

stag

es•

Non

e (3

9)•

29

• 29

Kle

eber

g M

elan

oma

Hig

h ris

k •

Surg

ery,

Isc

ador

M (1

02)

• 1.

21

• n.

s. (C

I: 0

.84-

1.75

)20

04 [6

0;67

]pr

imar

y •

Surg

ery,

IFN

-α(2

40)

• 0.

96

• n.

s. (C

I: 0

.76-

1.21

)(≥

3MM

)•

Surg

ery,

IFN

-γ(2

44)

• 0.

87

• n.

s. (C

I: 0

.69-

1.10

)or

LN

+•

Surg

ery

(244

/102

)

Salz

er

Lung

I-

IV•

Surg

ery,

Isc

ador

(87)

• 33

n.

s.19

91 [4

9]•

Surg

ery

(96)

• 31

Res

pond

er |

non

-Res

pon.

Dou

wes

C

olon

, rec

tum

Adv

ance

d•

5FU

/FA

, Hel

ixor

(20)

• 27

| 1

2no

t sho

wn

1986

[42]

• 5F

U/F

A, N

ey T

umor

in (2

0)•

24 |

12

• 5F

U/F

A (2

0)•

14 |

5

Gut

sch

Bre

ast

T1-

3, N

0-3,

•

Surg

ery,

rad

iatio

nI, H

elix

or (1

92)

• 69

.1%

• P=

0.04

819

88 [5

1]M

0•

Surg

ery,

rad

iatio

nI, C

MF

(177

)n.

a.II

• 67

.7%

• (P

=0.

025)

• Su

rger

y, r

adia

tionI

(274

)•

59.7

%

Salz

er 1

979,

St

omac

h19

83 [

56-5

8]II

-III

• Su

rger

y, I

scad

or (6

2)Ly

mph

nod

e +

| _

LN +

| _

LN +

| _

• Su

rger

y (7

5)•

25

|

55•

22 |

n.a

.IIP<

0.05

| n

.s.

• 1

8

| 45

• 11

| 4

0

Duk

es D

Duk

es C

Caz

acu

[44]

Col

on, r

ectu

mD

ukes

C

• Su

rger

y, 5

-FU

, Iso

rel A

(29)

• 17

• 2

5P<

0.05

(for

D

or D

• Su

rger

y, 5

-FU

(21)

• 7

• 1

8an

d C

)•

Surg

ery

(14)

• 15

• 1

7

Salz

er 1

987

[55]

Lung

I (I

I)•

Surg

ery,

Isc

ador

(12)

• 1

17no

t sho

wn

• Su

rger

y (1

4)•

34

.5


Tab

le 3

. (co

ntin

ued)

Au

thor

, Yea

rSi

teSt

age

Inte

rven

tion

(ev

alu

able

pat

ien

ts)

Surv

ival

Ou

tcom

es

Mea

n (

Mon

ths)

Med

ian

H

azar

d

5-ye

ar

Oth

ers

P o

r C

Ip

artl

y ce

nsu

red

(M

onth

s)ra

tio

surv

ival

Non

-ran

dom

ized

con

trol

led

tri

als

Gro

ssar

th

Bre

ast,

lung

, col

on,

All

stag

es•

Isca

dor

(396

)•

50.8

• 44

P<0.

001

2001

[59]

rect

um, s

tom

ach

• N

one

(396

)•

36.6

• 32

Salz

er

Lung

I-II

I•

Surg

ery,

Isc

ador

(37)

• 6

36-

year

•

38%

P<0.

0119

78 [5

3]•

Surg

ery

(40)

• 10

surv

ival

• 15

%

Dou

wes

[43]

C

olon

, rec

tum

Adv

ance

d•

5FU

/FA

, Hel

ixor

(19)

• 26

n.s.

(P=

0.06

3)•

5FU

/FA

(20)

• 14

Schu

ppli

Mel

anom

aN

ot s

peci

fied

• Su

rger

y, I

scad

or P

c. H

g (8

4)n.

a.II

• ~

86%

not s

how

n19

90 [5

2]•

Surg

ery,

BC

G (1

14)

• ~

72%

Salz

er

Bre

ast

I-II

I•

Surg

ery,

Isc

ador

, (76

)A

live1

985

• 29

%no

t sho

wn

1987

[55]

• Su

rger

y, r

adia

tion,

hor

mon

e (7

9)(a

fter

11-1

4•

24%

year

s)

Fellm

er

Cer

vix

I-II

I•

Rad

iatio

n, I

scad

or (8

1)•

83%

P=0.

0519

66 [5

4]•

Rad

iatio

n (7

09)

• 69

%

Maj

ewsk

i G

enita

l A

ll st

ages

• Su

rger

yI, r

adia

tionI

, Isc

ador

(155

)D

isea

se-s

peci

fic

not s

how

n19

63 [5

0]•

Surg

eryI

, rad

iatio

nI(n

ot s

how

n)su

rviv

al p

artly

im

prov

ed

CM

F: C

yclo

phos

pham

id, M

etho

trex

at, 5

FU; 5

FU: 5

-Flu

orou

raci

l; FA

: Fol

ic a

cid;

P (

p-va

lue)

, CI

(95%

-con

fiden

ce in

terv

al):

Stat

istic

al s

igni

fican

ce o

f di

ffer

ence

bet

wee

n m

istle

toe

(or

othe

r ve

rum

)an

d co

ntro

l gro

up; n

.s.:

not

stat

istic

ally

sig

nific

ant;

I C

o-in

terv

entio

n (i.

e. r

adia

tion)

app

lied

to p

art

of t

he g

roup

; II

n.a.

: not

app

licab

le s

ince

mor

e th

an 5

0% a

live

at s

tudy

ter

min

atio

n; “

•”-o

utco

mes

rela

te to

cor

resp

ondi

ng “

•”-t

reat

men

t gro

up.


Tab

le 4

.Con

trol

led

Tria

ls o

n M

istle

toe

Tre

atm

ent i

n C

ance

r: T

umou

r B

ehav

iour

or

Pleu

rode

sis

(RC

Ts

and

N-R

CT

s ea

ch o

rder

ed b

y de

crea

sing

qua

lity.

See

Tab

le 1

and

Tab

le 2

)

Au

thor

, Si

teSt

age

Inte

rven

tion

(ev

alu

able

pat

ien

ts)

Tu

mou

r or

ple

ura

l eff

usi

onY

ear

Rem

issi

onD

isea

se-f

ree

inte

rval

, R

ecu

rren

ce

P o

r C

IH

azar

d r

atio

Ran

dom

ized

con

trol

led

tri

als

Com

plet

e re

sp.|

over

all r

egre

ssio

nID

old

Lung

All

• Is

cado

r U

or

Qu,

c.H

g. (1

14)

• 4

% |

26%

• n.

s. (p

=0.

1)19

91 [6

6]st

ages

• Pl

aceb

o (v

itam

in B

) (11

3)•

3%

| 2

0%•

Poly

erga

(110

)•

2%

| 1

9%•

(n.s

. p=

0.5)

Kle

eber

gM

elan

oma

Hig

h ris

k pr

imar

y •

Surg

ery,

Isc

ador

M (1

02)

• 1.

32•

n.s.

(0.9

3-1.

87)

2004

[60;

67]

(≥3M

M) o

r LN

+•

Surg

ery,

IFN

-α(2

40)

• 1.

04•

(n.s

. 0.8

4-1.

30)

• Su

rger

y, I

FN-γ

(244

)•

0.96

• (n

.s. 0

.77-

1.2)

• Su

rger

y (2

44/1

02)

Salz

er

Lung

I-

IV•

Surg

ery,

Isc

ador

(87)

• 50

%n.

s.19

91 [4

9]•

Surg

ery

(96)

• 55

%

Com

plet

e re

sp.|

par

tial r

espo

nse

Dou

wes

C

olon

, rec

tum

Adv

ance

d•

5FU

/FA

, Hel

ixor

(20)

• 15

%|

35%

not s

how

n19

86 [4

2]•

5FU

/FA

, Ney

Tum

orin

(20)

• 15

%|

25%

• 5F

U/F

A (2

0)•

15%

| 3

0%

Com

plet

e re

sp.|

part

ial r

espo

nseI

II

Kim

Pl

eura

l eff

usio

nII

Adv

ance

d•

Hel

ixor

(11)

• 81

%|

9%

P<0.

05

1999

[32]

• D

oxyc

yclin

, Mep

erid

in, L

idoc

ain

(15)

• 40

%|

26%

Non

-ran

dom

ized

con

trol

led

tri

als

Com

plet

e |

part

ial |

min

imal

res

p.D

ouw

es

Col

on, r

ectu

mA

dvan

ced

• 5F

U/F

A, H

elix

or (1

9)16

%|

37%

|

26%

“s

igni

fican

t”,

1988

[43]

• 5F

U/F

A (2

0)0%

| 3

0%

| 2

0%p-

valu

e no

t sho

wn

5FU

: 5-F

luor

oura

cil;

FA: F

olic

aci

d; P

(p-v

alue

), C

I (9

5%-c

onfid

ence

inte

rval

): St

atis

tical

sig

nific

ance

of

diff

eren

ce b

etw

een

mis

tleto

e (o

r ot

her

veru

m) a

nd c

ontr

ol g

roup

; n.s

.: no

t sta

tistic

ally

sig

nifi-

cant

; IN

ot c

orre

spon

ding

to W

HO

-def

initi

on o

f tu

mou

r re

spon

se; I

I plu

ral e

ffus

ion

indi

cate

s tr

eatm

ent s

ite; I

IIsi

de e

ffec

ts in

Hel

ixor

and

dox

ocyc

lin g

roup

: pai

n in

6 a

nd 1

4, f

ever

in 3

and

6, b

urn-

ing

sens

atio

n in

0 a

nd 5

pat

ient

s, r

espe

ctiv

ely;

diff

eren

ce s

tatis

tical

ly s

igni

fican

t (p<

0.05

).“•

”-ou

tcom

es r

elat

e to

cor

resp

ondi

ng “

•”-t

reat

men

t gro

up.

two reported symptomatic relief (reduction of nausea,vomiting, fatigue, diarrhoea, constipation, dyspnoea,and symptoms of ascites).

On reduction of side ef fects of surger y, chemotherapyand radiation and related improvement of QoL (Table5): Of seven controlled trials, two RCTs and two N-RCTs showed a statistically significant positive effect[35;39;45;48], one RCT found improved QoL and pre-vention of lymphopenia, however, without computingstatistical significance of the difference between thetwo comparison groups [47]; one small pilot RCT re-ported mixed results (no effect on QoL, a significantreduction of suppression of activatedCD56+/CD69+/CD45+NK-cells, no effect on otherimmune cells) [46]; one RCT mentioned fewer side ef-fects of 5-FU and a positive effect on QoL withoutgiving details [44]. Furthermore, one of these trials re-ported that with additional mistletoe therapy thedosage of Cisplatin and Holoxan could be increasedbecause of less intensive side effects. [35]

Tolerability was generally good. One case of ur-ticaria and angioedema was described [45]. Otherwise,no major side effects or toxicity were reported. Minordose-dependent and spontaneously subsiding symp-toms included reactions at the injection site (swelling,induration, erythema, pruritus, local pain) and mildflu-like symptoms or fever. After intrapleural instilla-tion mistletoe extract induced significantly fewer sideeffects than doxycyclin ([32], see Table 5)

DISCUSSION

Mistletoe therapy, especially AM preparations, is wide-ly used to treat cancer patients in Central Europe.Most of the clinical trials report a benefit for survival,QoL, side-effects of toxic conventional therapies, ortumour remissions. Quality of the trials varies substan-tially; however, even most of the better-conducted andpublished trials show a beneficial effect. In detail:

Survival benefit (see Table 3) was assessed by mostof the controlled trials. Half of them found a signifi-cant positive result; the other half did not reach or didnot calculate significance or found no benefit, whilenone found a disadvantage. All of these trials receivedsome amount of critique [29]: Among the best trialswith significant positive effects (by Grossarth-Maticeket al. [59]) were two RCTs embedded in a large cohortstudy that were small and had an epidemiologicalrather than a clinical trial design (for more details see[29]). This methodological approach is not well estab-lished, unfamiliar to most clinical researchers, andtherefore raised concern [7;68]. Other trial publica-tions mentioned major difficulties in patient recruit-ment or protocol violations [51;56-58], or had smalland unequally distributed groups of patients [44]. Sev-eral trials had non-randomized designs, some of themcarefully controlling for confounders. (Whether care-fully conducted N-RCTs can be sufficient to yieldvalid results, is still the subject of controversial discus-sion. [69-71]) Survival benefit was usually reported un-der long treatment duration (several years) while theonly trial with no benefit had a short treatment dura-tion (months, with the maximum of one year onlycompleted by 40% of the patients; for more details see

[29]). Dependency of survival benefit on length ofmistletoe therapy was reported in one of the trials. [59](This was also mentioned by two recent retrolectivepharmaco-epidemiological cohort studies of mistletoein breast cancer and melanoma. [72;73]) Furthermore,variability of results might be explained by differencesin design, methodology and quality of the studies aswell as differences in cancer sites and stages investigat-ed. Whether possible survival benefit also depends onthe type of mistletoe preparation, host tree, or dosage,cannot be seen in the reviewed trials; they often lackeddetailed information and homogeneity for reliable in-ter-study comparison. These issues need further clari-fication.

Tumour remission (see Table 4) was investigated bythree controlled trials. Two of them [42;43], an RCTand an N-RCT, adding mistletoe to chemotherapy andfinding higher remission rates, lacked sufficient qualityand transparency in design and presentation. Onethree-arm study [66], conducted by the German Can-cer Research Centre, investigating sole mistletoe treat-ment, found surprisingly high tumour remission ratesin all groups, even with placebo alone (20%). Howev-er, as the diagnosis was advanced lung cancer, thespontaneous remission rate of 20% seems unlikely[74], suggesting insufficient documentation or undoc-umented additional therapy. (Unnoticed co-interven-tion that contaminates results might be an underesti-mated and widely neglected hazard for the validity ofclinical trials; for instance up to 90% of patients en-rolled in conventional cancer trials also use CAM ther-apies [75].) Disease-free interval was investigated inone trial [60], which, however, may have been influ-enced by detection bias [29]. Overall, questions of tu-mour behaviour remain unclear in these controlled tri-als.

More reliable information on tumour remission isdelivered by the cohort studies (see Table 6). Seven ofthese cohort studies were on solid tumours or on FL,four of them reporting substantial remission with nosimultaneous conventional cytoreductive therapy (in-operable HCC, breast cancer pre-treated withchemotherapy, intracranial malignant tumour, FL). Ina trial on pancreatic carcinoma, the intratumoural, en-doscopic, ultrasound-guided, fine-needle injection ofHelixor was combined with Gemcitabine treatment,and achieved tumour remission in 58% of patients, ex-ceeding remission rates known with chemotherapyalone [33]. Notably, all four trials that documented re-missions in solid tumours [31;33;63;64], other than thetwo trials with no remission [62;65], deviated from thecommon low escalating dosage and used high mistle-toe doses from the beginning, and (in three studies)only once per week (due to chronobiological consider-ations; H. Werner, personal communication). Single-arm cohort studies, including phase II trials, that haveno control group, need – besides careful outcome as-sessment and comprehensive documentation of allmajor covariables with potential influence on the tu-mour – an appraisal of spontaneous remissions.[76;77] Spontaneous remissions are common in a fewtumour sites (e.g. CIN, renal cancer, melanoma, andlymphomas) but are extremely rare in most commoncancers. [78;79] Accordingly, among the cohort studies



Tab

le 5

.Con

trol

led

Tria

ls o

n M

istle

toe

Tre

atm

ent i

n C

ance

r: R

educ

tion

of s

ide

effe

cts

of c

hem

othe

rapy

, rad

iatio

n or

sur

gery

; QoL

(RC

Ts

and

N-R

CT

s ea

ch o

rder

ed b

y de

crea

sing

qua

lity.

See

Tab

le 1

and

Tab

le 2

).

Au

thor

, Si

teSt

age

Inte

rven

tion

(ev

alu

able

pat

ien

ts)

Red

uct

ion

of

sid

e ef

fect

s of

Q

oL (

*du

rin

g c

hem

oth

erap

y, r

adia

tion

) ye

arch

emot

her

apy

or r

adia

tion

Ou

tcom

eP

or

CI

Mea

sure

men

t sc

ale

and

ou

tcom

eP

or

CI

Ran

dom

ized

con

trol

led

tri

als

Che

mot

hera

py-r

elat

ed

*Inc

reas

e in

*

Incr

ease

in*K

PI in

crea

se in

ad

vers

e ev

ents

FLIC

-sco

reT

CM

-sco

re%

of p

atie

nts

Piao

B

reas

t, T

1-4,

N0-

3,•

Che

mot

hera

pyI ,

Hel

ixor

A (1

15)

• 28

not

• ↑

9• ↑

-1•

50 %

P=0.

014

2004

[45]

ovar

y, lu

ng

M0-

1•

Che

mot

hera

pyI ,

Lent

inan

(109

)•

77sh

own

• ↑

4.7

• 0

• 32

%P=

0.00

07(N

SCLC

)(p

=0.

014)

(p=

0.00

07)

(p=

0.00

2)P=

0.00

2

Aue

rbac

h B

reas

tT

1-2,

N0-

1, M

0•

CM

F, r

adia

tion,

Hel

ixor

A (1

1)C

MF-

indu

ced

NK

-cel

l dec

reas

e ↓

p=0.

005

*EO

RT

C

No

diff

eren

ce, d

ata

not s

how

nno

t sho

wn

2005

[46]

• C

MF,

rad

iatio

n, p

lace

bo (9

)SC

E-in

crea

se ↓

n.s.

QLQ

-C30

othe

r im

mun

e m

arke

rs: n

odi

ffer

ence

Gro

ssar

th

Bre

ast

IIIA

-III

B•

Isca

dor

(17)

Self-

regu

latio

n •

2.92

→3.

7P=

0.13

20

01 [5

9]•

Non

e (1

7)qu

estio

nnai

re

• 2.

87 →

2.99

(sco

re 1

-6)

Dol

d [6

6]Lu

ngA

ll st

ages

• Is

cado

r U

or

Qu,

c.H

g. (1

14)

Patie

nts

• 59

%

• P=

0.01

8•

Plac

ebo

(vita

min

B) (

113)

subj

ectiv

ely

• 45

%•

Poly

erga

(110

)im

prov

ed•

43%

• (P

=0.

4)

Lang

e Lu

ng, h

ead

Inop

erab

le•

Rad

iatio

n, c

ispl

atin

, hol

oxan

,

Nau

sea ↓

(p=

0.00

5), v

omiti

ng ↓

p=0.

005,

*K

PI•

67%

→76

% (p

=0.

0008

II)

not s

how

n19

85 [3

5]an

d ne

ck,

Hel

ixor

(23)

(p=

0,08

), de

pres

sion

of m

yelo

poie

sis

p=0.

08,

ovar

y•

Rad

iatio

n, c

ispl

atin

, hol

oxan

(21)

↓(le

ucoc

ytes

p=

0,0

03)

p=0.

003

• 70

% →

74%

(p=

0,12

II)

Bor

relli

B

reas

tIV

• Is

cado

r sp

ezia

l (20

)Sp

itzer

sco

re

• ~

5 →

7.2

P<0,

0520

01 [6

1]•

Plac

ebo

(10)

ques

tionn

aire

• ~

5.2

→4.

8

Gro

ssar

th

Bre

ast,

lung

, A

ll st

ages

• Is

cado

r (3

9)Se

lf-re

gula

tion

• 3.

41 →

3.87

P=0,

0220

01 [5

9]co

lon,

rec

tum

,•

Non

e (3

9)qu

estio

nnai

re•

3.85

→3.

62st

omac

h(s

core

1-6

)

Kle

eber

g M

elan

oma

Hig

h ris

k •

Surg

ery,

Isc

ador

M (1

02)

“Qua

lity

of

Res

ult n

ot s

how

nno

t sho

wn

2004

[60;

67]

prim

ary

• Su

rger

y, I

FN-α

(240

)lif

e (≥

3MM

) or

• Su

rger

y, I

FN-γ

(244

)ev

alua

tion”

LN+

• Su

rger

y (2

44/1

02)

5-FU

sid

e ef

fect

s (%

of p

atie

nts)

not

*“Q

ualit

y “I

mpr

ovem

ent”

;no

t sho

wn

Caz

acu

Col

on,

Duk

es C

•

Surg

ery,

5-F

U, I

sore

l A (2

9)•

0%

show

nof

life

”da

ta n

ot s

how

n20

03 [4

4]re

ctum

or D

• Su

rger

y, 5

-FU

(21)

• 19

%•

Surg

ery

(14)

*KPI

*Sco

re o

f Anx

iety

Ene

sel

Gas

tro-

II-I

II•

Surg

ery,

Iso

rel A

(40)

Prev

entio

n of

Sur

gery

-indu

ced

not

• ↑

22%

(p<

0.01

II)

• ↓

2,9

(p<

0.01

II)

not s

how

n20

05 [4

7]in

test

inal

• Su

rger

y (3

0)ly

mph

ocyt

e re

duct

ion

show

n• ↓

13%

(p<

0.05

II)

• ↑

1.5

(p<

0.01

II)

reviewed, spontaneous remissions might have oc-curred in CIN [34] or in FL [41].

Tumour remission under mistletoe therapy may de-pend on mode of application (local subcutaneous, in-tratumoural, intravenous, intrapleural), on chronobio-logical aspects (e.g. application once versus three timesper week), and on dosage (slowly increasing versushigh dosage from the beginning, as, for instance, anti-bodies against active ingredients are induced withinweeks or months of treatment). These links are alsosuggested by anecdotal therapeutic reports, and are bi-ologically plausible considering the substantial antitu-moural, cytotoxic and pro-apoptotic VAE activity invivo and in vitro that is partly inhibited by serum pro-teins and ML antibodies. [8;9] These issues should beinvestigated in more detail.

All seven trials investigating reduction of side ef fectsof toxic conventional treatments (chemotherapy, radia-tion, surgery) (see Table 5) found a benefit. Themethodologically best trial, an RCT conducted in Chi-na, investigated side effects of various chemotherapeu-tics and found significantly less adverse effects, betterQoL and physical condition with mistletoe comparedto the phytopharmacon Lentinan. [45] An unpublishedGerman trial, small-sized but otherwise reasonablywell-designed, showed fewer side effects of Cisplatin,Holoxan and radiotherapy with additional mistletoetherapy (less nausea and vomiting, better physical con-dition) and a positive effect on Holoxan and Cisplatindosage (fewer dose reductions were necessary becauseof reduced side effects). [35] A small Austrian pilot tri-al reported no effect on QoL, less suppression of acti-vated NK-cells and a trend towards less chromatindamage. This trial, well designed in many aspects, wasseverely underpowered for effect estimation, and thetested laboratory markers (SCE: Sister Chromatid Ex-change, immune parameters) are more of experimentalrelevance than clinically well-established, and displayhigh inter-individual variability. [46] The latter also ap-plies to the N-RCT on surgery-associated inhibition ofgranulocyte function [39]; here, outcomes in two dif-ferent hospitals (an AM hospital applying pre-opera-tive mistletoe infusion, a COM hospital applying rou-tine surgery only) were compared, matching for pa-tient characteristics and length of surgery. Despitematching, residual differences of the two self-selectedpatient populations and settings (AM, COM) mightalso have affected the investigated immune function.[39] Biological plausibility of these side-effect reduc-tions might lie in DNA-stabilizing properties of VAE[20-22]. These properties, however, seem not to atten-uate the cytoreductive effects of radiotherapy andchemotherapy [35;42;43]; they were, rather, enhancedby VAE in vitro and in vivo. [9]

QoL (see Table 5) was investigated altogether ineleven controlled trials: Seven trials (one double blind[61]) found a benefit for mistletoe treatment, one re-ported a trend [59], one study (small, double-blind butunblinded by most patients [46]) found no difference,one did not present the results of an “improvement”[44]; one RCT cited “quality of life evaluation” in apre-publication report [67] but did not mention it anymore in the final publication [60]. Since assessment ofQoL might be influenced by patients’ expectations,


Tab

le 5

(co

ntin

ued)

.

Au

thor

, Si

teSt

age

Inte

rven

tion

(ev

alu

able

pat

ien

ts)

Red

uct

ion

of

sid

e ef

fect

s of

Q

oL (

*du

rin

g c

hem

oth

erap

y, r

adia

tion

) ye

arch

emot

her

apy

or r

adia

tion

Ou

tcom

eP

or

CI

Mea

sure

men

t sc

ale

and

ou

tcom

eP

or

CI

Non

-ran

dom

ized

con

trol

led

tri

als

Büs

sing

B

reas

t •

Surg

ery,

Isc

ador

M s

pezi

al (4

7)Pr

even

tion

of s

urge

ry-a

ssoc

iate

d P<

0.00

01,

2004

[39]

(sus

pect

ed)

• Su

rger

y (5

1)in

hibi

tion

of g

ranu

locy

te fu

nctio

n

P<0.

001

(PM

A- a

nd E

.col

i-stim

ulat

ed

oxid

ativ

e bu

rst)

Von

Hag

ens

Bre

ast

I–II

• Su

rger

y, C

MF/

EC

, Isc

ador

(33)

CM

F/E

C-in

duce

d *

EO

RT

C

Red

uced

incr

ease

of

2005

[48]

• Su

rger

y, C

MF/

EC

(33)

lym

phoc

yte

decr

ease

↓,

n.s,

Q

LQ-C

30,

naus

ea/v

omiti

ng, g

ener

al s

ide

p=0.

02pl

atel

et d

ecre

ase ↓

p=0.

01B

23

effe

cts

of C

MF/

EC

p=0.

02

QoL

: Qua

lity

of li

fe; K

PI: K

arno

fsky

Per

form

ance

Ind

ex. S

CE

: Sis

ter

Chr

omat

id E

xcha

nge;

↑: I

ncre

ase;

↓: d

ecre

ase.

P (

p-va

lue)

: Sta

tistic

al s

igni

fican

ce o

f di

ffer

ence

bet

wee

n m

istle

toe

(or

othe

r ve

rum

)an

d co

ntro

l gro

up; n

.s.:

not s

tatis

tical

ly s

igni

fican

t; C

MF:

Cyc

loph

osph

amid

, Met

hotr

exat

, 5FU

; 5FU

: 5-F

luor

oura

cil;

FA: F

olic

aci

d;

I Che

mot

hera

py: B

reas

t C

ance

r: C

AP,

CA

F; O

varia

n ca

ncer

: CP,

IcP

; NSC

LC: V

P, M

ViP

. Cyc

loph

osph

amid

(C

), A

dria

myc

in (

A),

Cis

plat

in (

P), 5

-Flu

orou

raci

l (F)

, Vin

orel

bine

(V

), M

itom

ycin

(M

), If

os-

fam

id (I

), V

inde

sine

(Vi),

Car

bopl

atin

(cP)

. II

stat

istic

al s

igni

fican

ce o

f pre

-pos

t-di

ffer

ence

with

in e

ach

grou

p;

“•”-

outc

omes

rel

ate

to c

orre

spon

ding

“•”

-tre

atm

ent g

roup

.


Tab

le 6

.Sin

gle-

Arm

Coh

ort S

tudi

es (e

.g. P

hase

II

Tria

ls) o

n M

istle

toe

Tre

atm

ent i

n C

ance

r (o

rder

ed c

hron

olog

ical

ly).

Au

thor

, Yea

rT

reat

men

tISi

teII

Res

ult

III

nIV

Qu

alit

y C

rite

ria

Fu

lfil

led

V

Pre

par

atio

nIn

ject

ion

D

osag

eE

scal

atin

gD

ura

tion

CR

PR

NC

PD

QoL

LM

NO

PQ

site

dos

age

Soli

d t

um

ours

or

lym

ph

oma

Kue

hn 2

005

[41]

Isca

dor

P (M

, Qu

sc0.

01-3

0mg

Yes

mea

n 24

Fo

llicu

lar

17 %

25

%

–38

%24

(+)

(+)

++

o (+

)+

occa

sion

ally

)m

onth

sly

mph

oma

IIIa

IIIa

IIIa

Mat

thes

200

5 [3

3]

Hel

ixor

MitI

a30

0-10

00 m

gY

esre

peat

edly

Panc

reas

8%50

%33

%8

%�

12(-

)(+

)(+

)-o

(+)

+

Bar

-Sel

a 20

04 [6

2]A

bnob

avis

cum

Qu

sc3

x 0,

15-1

5 m

g/w

Yes

med

. 14

wC

olon

, Rec

tum

00

84%

16%

�II

Ib25

++

+(+

)+

+

Mab

ed 2

004

[64]

Vis

cum

frax

ini

sc1

x 30

mg/

wN

om

ed. 1

7 w

HC

C13

%9%

(39%

)III

c39

%23

++

+(-

)+

+

Mah

fouz

199

9 [6

3]V

iscu

m fr

axin

isc

or

it1

x 45

mg/

wN

o18

-136

wB

reas

t8%

54%

35%

4%�

26(+

)(+

)+

(+)

++

Mah

fouz

199

8 [3

1]A

bnob

avis

cum

Fr

sc1

x 45

mg/

wN

o17

wB

reas

t, B

rain

27%

27%

27%

20%

�15

-(-

)(+

)-

-(+

)

Kja

er 1

989

[65]

Isca

dor

Qu

or M

,sc

Var

ying

Yes

med

. 13/

47K

idne

y0

014

%86

%↓

14+

(+)

++

o(+

)+

c.C

uw

CIN

Port

alup

i 199

5 [3

4]Is

cado

r M

sc2

x 1

ng M

LI /

kg

No

16 w

CIN

I-I

II41

%27

%27

%5%

27+

++

++

(+)

bw/w

Mal

ign

ant

effu

sion

Bar

Sel

a 20

06 [1

00]

Isca

dor

Mip

e10

mg

No

repe

ated

lyA

scite

sIn

crea

se o

f int

erva

l bet

wee

n �

IIIe

23(+

)(+

) +

(+)

++

two

succ

essi

ve p

arac

ente

ses

from

7 to

12

days

, p=

0.00

1III

d

Wer

ner

1999

[101

]A

bnob

avis

cum

Fr

ip1

x 75

mg/

wN

o3-

8 w

Pleu

ral e

ffus

.88

%�

32+

++

-(+

)(+

)

Stum

pf 1

994

[40]

Hel

ixor

A, M

or

Pip

100-

1000

mg

each

Yes

repe

ated

lyPl

eura

l eff

us.

61%

11%

22%

18+

++

(+)

++

Frie

dric

hson

198

5 H

elix

orip

e10

0-10

00 m

g ea

chY

esre

peat

edly

Asc

ites

70%

�12

(+)

(-)

+-

(-)

+[3

6]

Isc

: sub

cuta

neou

s, it

: int

ratu

mou

ral,

ip: i

ntra

pleu

ral,

ipe:

intr

aper

itone

al; w

: wee

k, m

ed.:

med

ian.

IaE

ndos

copi

c ul

tras

ound

-gui

ded

fine-

need

le in

ject

ion.

IIH

CC

: hep

atoc

ellu

lar

carc

inom

a, C

IN: c

ervi

cal i

ntra

epith

elia

l neo

plas

ia, e

ffus

.: ef

fusi

on (m

alig

nant

). St

age:

adv

ance

d, e

xcep

t CIN

; plu

ral e

ffus

ion

and

asci

tes

indi

cate

s tr

eatm

ent s

ite.

III

CR

: com

plet

e, P

R: p

artia

l rem

issi

on, N

C: n

o ch

ange

, PD

: pro

gred

ient

dis

ease

, QoL

: qua

lity

of li

fe, �

: im

prov

ed, ↓

impa

ired;

IIIa

resp

onse

s un

der

mis

tleto

e m

onot

hera

py, w

ithou

t con

com

itant

onc

olog

-ic

cyt

ored

uctiv

e th

erap

ies;

III

bsy

mpt

omat

ic r

elie

f (4

0% o

f pa

tient

s); I

IIc

unde

term

ined

res

pons

e du

e to

ear

ly d

eath

; III

dm

edia

n va

lues

, com

para

ble

abdo

min

al c

ircum

fere

nce

and

sym

ptom

sco

re o

rdr

aine

d flu

id b

efor

e or

dur

ing

each

para

cent

esis

,res

pect

ivel

y; II

IeT

rend

impr

ovem

ent i

nsy

mpt

omsc

ore,

espe

cial

lyab

dom

inal

pain

,abd

omin

alpr

essu

re,a

ndw

akin

gup

atni

ghtd

ueto

shor

tnes

s of

bre

ath.

IVn:

Num

ber

of p

artic

ipan

ts.

VL

Wel

l des

crib

ed p

atie

nt c

hara

cter

istic

and

dis

ease

(dia

gnos

is, s

tage

, dur

atio

n), p

rogn

ostic

fact

ors

MO

utco

me

para

met

er r

elev

ant a

nd w

ell d

escr

ibed

N

Wel

l des

crib

ed in

terv

entio

nO

Con

com

itant

ther

apie

s w

ell d

escr

ibed

(o: c

onco

mita

nt c

onve

ntio

nal o

ncol

ogic

cyt

ored

uctiv

e th

erap

ies

in s

ome

of th

e pa

tient

s)P

Out

com

e cl

early

des

crib

ed, t

empo

ral r

elat

ions

hip

betw

een

appl

ied

ther

apy

and

obse

rved

out

com

e pr

ecis

ely

desc

ribed

QSe

lect

ion

of p

atie

nts

excl

uded

blinding is a relevant issue. However, due to local skinreaction (rubor, pruritus, induration) and mild flu- likesymptoms, blinded subcutaneous mistletoe applica-tions are usually unblinded by 80% - 100% of patientsand physicians, as confirmed in two recent double-blind RCTs [46;80]. For this reason, the ethics com-mittee for an RCT on non-anthroposophic mistletoeextracts [81] did not approve a double-blind design.When reliable blinding is questionable, a possibility isto apply active or pseudo-active control treatmentsthat might generate similar expectations. This wasdone in the trial conducted in China when the controlgroup received Lentinan, a polysaccharide cancer drugpopular in China and Japan [45]; it was also done in athree-arm trial when two study groups received eithervitamin B or Polyerga [66]. In both trials, QoL resultsin the mistletoe groups were rated significantly higherthan in the control groups. – Besides, blinding of out-come assessment should be conducted whenever pos-sible, or QoL assessment should be combined withother biological parameters that are less prone to sub-jectivity, as done in some of the mistletoe trials. Final-ly, the possibility of blinding of other applicationroutes, like intravenous infusions, should be checkedin future trials and done if possible.

Safety aspects: Mistletoe therapy was well toleratedin the reviewed trials. Impairment of QoL in one co-hort study was due to progressive cancer disease. [65]Good tolerability was also shown in other investiga-tions. [82] Currently, a phase I study at the NC-CAM/NCI is investigating safety, toxicity and drug in-teractions between mistletoe extract and Gemcitabine.[83] A first interim report found good tolerability, withneither dose-limiting toxicity of the mistletoe extractnor any effects on the plasma concentration of gemc-itabine. [84] Allergic reactions can occur, and a fewcase reports of anaphylactic reactions exist [82;85;86].Recently, a list of serious side effects of mistletoe ther-apy was published [87;88] but turned out to be erro-neous interpretations of reports not referring tomistletoe therapy (for details see [89] or [7]). Enhance-ment of brain metastases was discussed in preliminaryreports [90;91] on the melanoma trial by Kleeberg etal. 2004 [60]. The data were not confirmed in the finalpublication [60], and may have resulted from detectionbias [29;92]. Still, they gave rise to an elaborate GEP-conform, retrolective multi-centre study in Germanyand Switzerland, conducted by the Dermatology De-partment of the University of Freiburg: in 686 consec-utive patients (329 mistletoe, 357 controls) withmelanoma stage II or III, treated in 35 randomly cho-sen centres, no tumour enhancement could be ob-served in mistletoe-treated patients, while incidence ofbrain metastases (multiple adjusted analysis), brainmetastases-free survival, disease-free survival, andoverall survival were all statistically significant infavour of the mistletoe group. [72] Regarding initialhigh-dose therapy, as reported in the Egyptian trials[31;63;64], safety aspects might have to be taken intoaccount because high dosages might produce muchstronger local reactions and flu-like symptoms. Fur-thermore, especially in Central Europe, prior mistletoeexposure through the widespread use of mixed herbalremedies or teas is possible and often not known to

the patients; therefore adverse reactions to initial highmistletoe dosages are a theoretical possibility.

Strength and weakness of the reviewThe validity of this review largely depends on the pri-mary trials. There are substantial weaknesses in severalof the reviewed studies; however, some of the morerecent ones, in particular, were reasonably well con-ducted. Strengths and weaknesses of most of the re-viewed trials, such as potential performance bias, de-tection bias, attrition bias etc., have been describedpreviously (see [29]) and are summarized and updatedin Table 1, Table 2 and Table 6. Blinding of therapywas attempted in only two trials [46;61]; however,blinded application of mistletoe extracts is unblindedby most of the patients [46;80], which is why reliabilityof pro forma blinding might be questionable (seeabove).

In order to minimize publication bias, all unpub-lished trials were included and a comprehensive searchwas conducted, including personal contacts with ap-proximately 150 experts in the field worldwide, mostof them from Europe [6;7]. We consider it unlikelythat important rigorous trials, especially RCTs, re-mained unnoticed, at least in Europe; however, wecannot exclude that we missed trials in distant, non-European countries, or small cohort studies unknownto our contacted experts and not listed in the screeneddatabases. The two trials that were excluded becauseof validity concerns (see result section) reported re-sults in favour of mistletoe treatment; therefore nopositive bias is induced by these exclusions. One fur-ther N-RCT, a feasibility trial, not included in this re-view because it did not present quantifiable results,also reported results in favour of mistletoe therapy(fewer side effects and improved QoL in breast cancerpatients undergoing chemotherapy with CMF or EC)[93]. Inclusion of different sorts of trials (RCT, N-RCT, cohort study) does not bias this review, sincethey are clearly indicated in Table 2 - Table 6 and ex-plicitly identified in the text.

For this review, blinded quality assessment was im-possible, since most trials were previously known tothe authors.

Clinical relevance and further research recommendationsAll reported endpoints are clinically relevant. Someapplication and dosage modalities, especially in cohortstudies, deviated from general recommendations.

In the reviewed trials, mistletoe therapy was mostlyapplied in non-AM and non-CAM settings. In AM set-tings, mistletoe therapy is usually part of a complexclinical approach that may include, besides COMremedies, further AM medicines, art and movementtherapy, therapeutic massage and counselling for phys-ical, mental, social and spiritual issues. [6;7;94] Thesemulti-modal treatments claim to focus on the “whole”patient, trying to improve his or her inherent self-heal-ing abilities. Comprehensive prospective trials on thewhole system of AM cancer treatment were recentlyconducted by the Universities of Uppsala and Bern.The Swedish study compared QoL of breast cancerpatients in AM and COM settings. A prospectivematched-pair design was chosen because an RCT was


not feasible (funding from the Swedish Cancer Societyand other sources did not cover expenses that wouldhave included patients staying in an AM clinic). WhileAM patients had lower QoL-scores at study entrance,they significantly improved during AM therapy and,after one year, were superior compared to COM-treat-ed patients, who showed no significant change ofQoL. [95] The Swiss AM cancer study, a project by theSwiss National Science Foundation, consisted of threestudy modules including a three-armed randomizedcontrolled trial investigating the benefit of additionalAM or psychosocial treatment. This RCT had to bestopped as not enough patients at the Institute ofMedical Oncology in Bern could be enrolled. [96]

Common difficulties with patient recruitment seemto be frequent in European mistletoe trials. [9] In afeasibility study by the University of Heidelberg, out of1,922 patients receiving surgical treatment for breastcancer only 29 (1,5%) could have participated in anRCT. [97] Two larger RCTs that were finally broughtto completion took eight and nine years of patient re-cruitment despite multi-centre designs and sample sizere-calculation to reduce the required number of pa-tients. [60;66] Reasons for hampered patient recruit-ment were multiple, e.g. not fulfilling inclusion criteria,preference or objection towards mistletoe treatment,general rejection of study participation or of random-ized treatment allocation, participation in other stud-ies, or logistical reasons. This issue has to be carefullyconsidered in future trials.

Regarding the widespread use and the potentialanti-tumour benefit of VAE, widely investigated espe-cially in vitro and in animal models [8;9], clinical re-search should be further intensified and its quality fur-ther improved. This process would clearly benefitfrom public funding to enable more extensive andclinically detailed research. Future studies should takeinto account the methodological limitations and po-tential biases of the reviewed mistletoe trials (see also[29]). They should further explore the results of thecohort studies, and clarify the impact of differentmodalities of mistletoe applications (dosage, location,intervals, duration) on the outcome in different thera-peutic situations. Furthermore, since a biomedical par-adigm – viewing mind and body as separate – has beenperceived as an additional violation by patients undmay increase their suffering [98], multimodal systems(see above) should also be investigated and patients’perspectives evaluated in order to gain insights intoways of meeting their need of holistic, multimodalcare. Appropriate research methods may include com-parison trials of different complex treatment systems,high quality observational studies, or carefully per-formed qualitative research. [99] These complex ap-proaches, however, require strong commitment by theresearch community, and often require more prepara-tory effort than conventional clinical trials. [99]

CONCLUSION

Quality of clinical trials on mistletoe therapy variessubstantially, but has improved during recent years.With regard to quality of studies and consistency of re-sults, the best evidence concerning efficacy of mistle-

toe therapy seems to exist for improvement of QoLand reduction of side effects of cytoreductive thera-pies (chemotherapy, radiation) – limited by the factthat the interventions are not blinded, and cannot bereliably blinded. Survival benefit is possible; conven-tional RCTs on this issue had varying results and bestevidence relies mostly on small trials using epidemio-logical methodology unfamiliar to most scientists andless widely accepted [59;72;73]. In relation to tumourremission, the controlled trials are inconclusive; co-hort studies describe tumour remissions mostly withhigh dosage and local application; they should be fur-ther explored. Tumour remission seems to depend ondosage and on mode of application. Mistletoe applica-tion seems safe except for rare allergic reactions.

As several reasonably well-conducted studies indi-cate beneficial effects, and results of preclinical re-search are promising, further properly designed trialsshould be encouraged to investigate clinical efficacyand its possible dependency on mode of application.Also, considering the widespread use of mistletoeamong cancer patients as well as many patients’ appar-ent need for complementary medicine and holisticcare, research activities should be increased. Futurecontrolled studies should take into account themethodological limitations and potential biases ofthese previous mistletoe trials.

Acknowledgements: We are grateful to the contacted AM ex-perts for valuable help with literature searches, to authors ofmistletoe trials for providing additional information, and toHarald J. Hamre for helpful comments. We are also gratefulto the colleagues of our international working group that pre-pared the preceding mistletoe review [29] partly incorporatedinto this study. This study was funded by the ComplementaryMedicine Evaluation Program (PEK) of the Swiss FederalOffice for Public Health; updating and manuscript prepara-tion was funded by IFAEMM e.V. Freiburg/Bad Krozingen.

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Received: August 3, 2006 / Accepted: January 23, 2007

Address for correspondence:Dr. med. Gunver S. KienleInstitut für angewandte Erkenntnistheorie und medizinischeMethodologie e.V.Schauinslandstraße 6D-79189 Bad KrozingenTel.: +49-7633-806682Fax: +49-7633-806696e-mail: [email protected]


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