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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 [42,43], conducted in Poland, were excluded because of severe validity concerns: a collaborating scientist questioned the alleged randomization of treatment allocation, and no information could be obtained from the authors to clarify this question. One further RCT (on Lektinol^® and breast cancer by Schwiersch et al.) might have met the inclusion criteria but was unpublished and unavailable. Thus it was possible to include 46 studies in this review: 19 RCTs, 16 non-RCTs, and 11 single-arm cohort studies. Of the 46 studies, 43 were published (4 of these only as an abstract), 1 study was retrieved as a doctoral dissertation, and 2 were unpublished reports.

1632 VAE-related references were checked by title, abstract or whole article, book chapter, or book regarding in vitro or animal studies. Experiments meeting the inclusion criteria were excluded if they were described in another publication, were not published in a scientific journal, scientific book or as a scientific dissertation, were unavailable (some dissertations from the 1950s and 60s), or if they did not present sufficient information.

Characteristics of included clinical studies

Tables ​Tables1,1, ​,2,2, ​,3,3, ​,4,4, ​,5,5, and ​and66 show characteristics of the clinical studies. Settings of the studies were mostly academic hospitals, large community hospitals, and specialized cancer hospitals. The studies were mainly conducted in Germany, but also in Austria, Switzerland, USA, Serbia, Russia, Bulgaria, Ukraine, Italy, Egypt, Israel, China, South Korea. Most studies were conducted in more than one centre. In 31 of the 32 studies published since 2000, the funding source was identifiable: three studies had public funding [44-46], 17 a combination of public and industry funding, and 11 industry funding alone.

Controlled studies

The 19 RCTs [47-63] (Table ​(Table1)1) encompassed 2420 participants, 16 non-RCTs [49-53,59,64-72] (Table ​(Table2)2) encompassed over 6399 participants (the sample size of one control group was not published). Cancer sites studied were breast (n = 20), uterus (n = 4), ovary (n = 6), cervix (n = 4), and genital (n = 1). One RCT investigated malignant pleural infusion. 4 studies not only investigated gynaecological or breast cancer but other cancer types as well.

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 [60,62,66]. In most studies VAE therapy was used at least partly in an adjuvant setting after surgery or radiotherapy.

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 [48,60,65]. Treatment duration was often not specified and depended on primary endpoint and related follow-up, ranging from one single application (in one trial [65]) to repeated applications over months and years. Control groups either received no further comparison treatment (n = 27), additional placebo application (n = 5), doxycycline (n = 1), Lentinan (n = 1) or radiation and hormones (n = 1). 4 trials had double-blinded treatment application.

Single-arm studies

11 prospective cohort studies [32,44-46,73-80] (Table ​(Table6)6) included 1,130 patients. Cancer sites studied were breast (n = 6), ovary (n = 1), CIN (n = 1), malignant pleural effusion (n = 2) and malignant ascites (n = 2). 8 studies investigated several cancer types. Tumour stages were advanced or inoperable except in three studies. In most studies patients had received conventional treatment some time previously. Directly preceding or concurrent anti-cancer treatment had been applied in two studies (gemcitabine [44], surgery [45]). Nine studies assessed tumour remission; seven reported QoL or symptomatic relief. Two studies primarily investigated the toxicity profile, pharmakokinetics and potential interactions of either the combination of gemcitabine and VAE [44,73] or of rML [32], and secondarily assessed tumour behaviour. The commercial VAE remedies were Abnobaviscum^®/Viscum fraxini, Iscador, Helixor, Lektinol or Aviscumine^® (rML). VAE were applied subcutaneously (n = 6), intratumourally (n = 1), intrapleurally (n = 2), intraperitoneally (n = 2) or as an intravenous infusion (n = 1). Dosage depended on the preparation and mode of application; some treated according to lectin content, others started with a low dosage and increased successively, or started with high dosage and applied it consistently once weekly. For intrapleural and intraperitoneal (repeated) application, VAE was diluted in 5 to 15 ml or 100 ml solution. Treatment duration and follow-up ranged from weeks to, most commonly, months or years.

Quality assessment

Table ​Table1,1, ​,22 and ​and66 summarize the validity assessment. Methodological quality differed substantially in the reviewed studies. 19 trials had randomized treatment allocation. The RCTs were mostly small (median sample size n = 60, range 23–692), particularly when investigating survival (median n = 52). Although RCTs investigating QoL were only slightly larger (median n = 68), they nevertheless encompass 4 trials that largely met modern standards of clinical trials and three of them had a sample size above 200. In four of the RCTs the patients and physicians were blinded; three further RCTs had an active or a placebo control-treatment. – 16 studies were non-randomized (median sample size n = 203, range 82–1442), 15 of them had controlled for confounding by close prospective (in one case retrospective) pair matching, by alternating treatment allocation and by multivariate analysis or propensity score (though in one study only for the main outcome parameter [69]). – Assurance of data quality according to ICH-GCP ("Good Clinical Practice") or GEP ("Good Epidemiological Practice") guidelines was reported in 5 RCTs and 4 non-RCTs. Eight of the RCTs and 8 of the non-RCTs were embedded in the same large epidemiological cohort study. Most studies did not present a clear documentation of co-interventions. Regarding the other quality aspects, most studies – especially the more recent ones – were reasonably well designed and conducted.

In the single-armed studies, study quality was reasonably good except in an unpublished report [80] and in an abstract publication [75] with too little information. Two studies had applied VAE in combination with or subsequent to conventional cancer treatment and one study had explored CIN, which has high spontaneous remission rates.

Characteristics of the preclinical studies

The in vitro cytotoxicity of different VAEs as well as isolated or recombinant lectins or their A-chain, viscotoxins, or other protein fractions were tested with different methods in a variety of human breast, ovarian, uterine, vulvar and cervical cancer cells [12,20,22,81-110] (Table ​(Table77).

Animal studies

43 studies were found. 9 of these were excluded as they investigated: tumour-bearing eggs [111], pre-incubation of tumour cells with VAE [112,113], different cancer types without differentiating the results accordingly [114], or isolated VAE proteins that were unstable [115]. Of the remaining 34 experiments [96,111,116-134] (Tables ​(Tables88 and ​and9),9), 28 had been conducted in mice and 6 in rats. 22 experiments had included 788 animals, (5–20 per treatment group), one included 282 VAE-treated animals (number of control animals were not reported), the other reports gave no details. 32 experiments investigated breast tumours (15 of these Ehrlich carcinoma, ECa), one uterus epithelioma and one ovarian cancer. 28 had used murine tumour models, 5 were of human origin and 1 an autochthonous model (methylnitrosurea-induced tumourigenesis). 24 experiments investigated whole VAE (two of these VAE-activated macrophages), two investigated isolated MLs, two rMLs, two investigated other isolated proteins, and four investigated polysaccharides ("Viscumsäure"). VAE were applied systemically in 17 experiments (subcutaneous, intraperitoneal, intratumoural on opposite site, intramuscular), local at the tumour site in 15 experiments (intraperitoneal, intratumoural, intramuscular), and without specification in two studies.

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 [135].

Results of controlled clinical studies are shown in Table ​Table33 (survival), Table ​Table44 (tumour behaviour) and Table ​Table55 (QoL and tolerability of conventional cancer treatment); results of single-arm studies are shown in Table ​Table66.

Results of the preclinical studies are presented in Tables ​Tables7,7, ​,88 and ​and99.

Breast cancer

Clinical studies: Survival (Table ​(Table3)3) was investigated by 4 RCTs and 3 non-RCTs (one of these is shown with three subgroups in Table ​Table3):3): Two RCTs reported a statistically significant benefit of VAE (of these one also included other tumour sites, and the other suffered from a major attrition rate without preventing bias by an intention-to-treat analysis), and two RCTs reported a small positive trend. The results of the latter two RCTs were also combined in an individual patient data meta-analysis; the result just missed significance (HR: 0.59, 95% CI: 0.34–1.02, p = 0.057) [135]. Two non-RCTs had observed a statistically significant benefit, and one a small positive trend. The results of two non-RCTs were additionally combined in an individual patient data meta-analysis, and showed highly significant results (HR: 0.43, 95% CI: 0.34–0.56, p < 0.0005) [135]. Tumour behaviour (Tables ​(Tables44 and ​and6)6) was investigated by two RCTs, four non-RCTs and 4 single-arm studies. Four of the controlled studies combined VAE and conventional cancer treatment. These studies partly reported a benefit regarding disease recurrence and time to disease relapse and partly no difference; none found a disadvantage. Two single-arm studies reported tumour remission in 44–62% of patients after local application of high dosage VAE. Another study found no remission after the application of rML. QoL and the reduction of side effects of chemotherapy, radiation and surgery (Tables ​(Tables55 and ​and6)6) were assessed by 11 RCTs, 6 non-RCTs and 4 single-arm studies: 19 of these 21 studies reported a benefit, mostly statistically significant, one study reported no QoL-benefit but a reduction of side effects, and the smallest of these studies found no difference. Three major pharmaco-epidemiological studies investigated patient charts and found reduced disease- and therapy-associated symptoms in VAE-treated groups.

In preclinical studies (Tables ​(Tables7,7, ​,8,8, and ​and9)9) VAE and VAE compounds showed cytotoxic effects in cancer cells. VAE also counteracted growth factor-induced proliferation and migration in breast cancer cells [95]. In mice, VAE inhibited tumour growth in most cases, especially when applied locally and in high dosage. Survival was prolonged in most cases, and numbers of metastases and local recurrences were reduced after application of VAE or of VAE-activated macrophages; one study found no benefit. All experiments using local VAE application found a benefit in relation to survival and tumour-growth inhibition. In rats, no clear benefit of VAE could be seen. Results from applying isolated or recombinant VAE compounds were inconsistent: some moderate effects of proteins (e.g. lectins) or polysaccharides were observed in relation to survival and tumour growth, while others observed none or possibly also adverse outcomes.

Cervical cancer

Clinical studies: Survival (Table ​(Table3)3) was investigated by one RCT and three non-RCTs: all four reported a beneficial outcome which, however, was statistically significant only in the non-RCTs. Tumour behaviour (Table ​(Table4)4) was investigated by one non-RCT, which could not find an effect on disease recurrence or metastases mainly because these events scarcely occurred. One single-arm study reported 41% complete and 27% partial remissions in CIN after VAE application. QoL (Table ​(Table5)5) was assessed in one RCT and one non-RCT; both reported a statistically significant benefit.

Regarding preclinical studies (Table ​(Table7),7), only HeLa cells were investigated; here VAE and protein fractions showed cytotoxic effects.

Uterus cancer

Clinical studies: Survival (Table ​(Table3)3) was investigated by two RCTs and two non-RCTs; three reported a statistically significant benefit while one found no difference. QoL (Table ​(Table5)5) was assessed by one RCT and one non-RCT; both found a statistically highly significant benefit.

Regarding preclinical studies (Tables ​(Tables77 and ​and9),9), VAE and isolated ML I showed cytotoxic effects in different human uterus cancer cells. Concerning animal experiments, a patent specification mentions "moderate" effects of mistletoe polysaccharides on tumour growth in uterusepithelioma.

Ovarian cancer

Clinical studies: Two RCTs and two non-RCTs investigated the influence of VAE on survival (Table ​(Table3)3) and reported a benefit, one of each with statistical significance. Tumour behaviour (Table ​(Table4)4) was investigated by two RCTs, each combining VAE and chemotherapy (plus radiotherapy in one study): these reported comparable outcomes. The influence of VAE on QoL and tolerability of chemotherapy and radiation (Table ​(Table5)5) was investigated by three RCTs and one non-RCT; all of them reported a statistically significant positive effect. In one trial using an aggressive chemotherapy protocol, higher dosages of Cisplatin and Holoxan could be given in the VAE group as the side effects were less intense [63]. One single-arm study applied recombinant lectins in ovarian cancer but found no remission.

Regarding preclinical studies (Tables ​(Tables77 and ​and9),9), VAE showed cytotoxic effects in various ovarian cancer cells. In SCID mice, rMLs led to increased survival and to more tumour-free animals at the highest and lowest dosage, while no effect was observed at the medium dosage.

Genital cancer

Clinical studies: One non-RCT (published in 1963) reported partly improved disease-specific survival (Table ​(Table3).3). Regarding preclinical studies (Table ​(Table7),7), VAE showed cytotoxic effects in vulvar cancer cells.

Malignant effusion

Clinical studies: One RCT and four single-arm studies investigated treatment of malignant pleural effusion and ascites (originating from breast or ovarian cancer, among other cancer sites), and all reported substantial remission rates (Tables ​(Tables44 and ​and66).

Safety

Tolerability was generally good. One case of urticaria and angioedema [56] and one case of "generalized reaction" [69] were described. Otherwise no major side effects or toxicity were reported. Frequent minor, dose-dependent and spontaneously subsiding symptoms included reactions at the injection site (swelling, induration, erythema, pruritus, local pain) and mild flu-like symptoms or fever. In one study, local reactions intensified during concomitant chemotherapy [64]. A higher prevalence of depression was documented in the unadjusted data of a retrolective non-RCT [69] in VAE-treated patients; these patients also had a higher prevalence of other treatments such as hormones. After intrapleural instillation, VAE induced significantly fewer side effects than doxycycline [60]. No indication for an interaction of VAE and chemotherapy could be found (i.e. remission rate) and VAE had no influence on the plasma concentration of gemcitabine [44,73]. No toxicity was observed in animal studies, except after application of high doses of an isolated protein complex with unknown constituents [132].

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