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Discussion

Concerning survival (Table ​(Table3),3), some of the RCTs show a statistically significant benefit while others show a statistical trend or no difference. Most of the non-RCTs (which included larger patient numbers) show a major impact. The validity of the studies is limited because of their small sample size (median only 52 participants per RCT), and because 8 of the 9 RCTs were imbedded in the same (large) epidemiological cohort study. This study was started in the 1970s, before modern standards of data quality control (ICH-GCP, GEP) were established, and it therefore does not fulfil modern standards in this respect. The 9^th RCT had enrolled more patients but was conducted even earlier, and suffers from a major attrition rate due to protocol violation [62]; the subsequent analysis followed the "as treated" instead of the "intention-to-treat" principle [145]. Hence bias cannot be excluded. None of the survival studies was blinded, but survival is generally not easily affected by observer bias or suggestive effects [138-140]. Seen altogether, although results were consistent, questions regarding survival remain and validity of evidence is moderate at best. An independent, GCP-conform trial with sufficient power would be desirable to further evaluate potential survival benefit.

Regarding tumour behaviour, evidence from RCTs is scanty; most benefits were shown in non-randomized studies. In single-arm studies of patients with no concomitant conventional cancer treatment, high-dose or local application of whole VAE led to substantial remission of tumour or malignant effusion. This was also observed in animal studies: local application resulted in tumour-growth inhibition and increased survival. However, this application and dosage is not standard and cannot be recommended widely due to potential risks of high dose or local application. With ordinary VAE application, schedule and dosage, spectacular tumour remissions tend to be the exception [20,36]. No tumour remission was observed after application of rMLs. Remission in CIN cannot be distinguished from spontaneous remission rates, which are frequent in this indication.

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 [49-51,53], patients were excluded before baseline assessment. Here the patients were provisionally enrolled into the matching and pairwise randomization procedure; subsequently they were asked for informed consent, and were excluded from the study if they declined, together with their matched twin. Even though the risk of bias with this procedure is small, as the complete randomization unit (patient pair) is excluded, the preferred conservative quality assessment in this review assessed these studies as not having excluded a drop-out bias. Of the remaining 5 trials, one had protocol violations in about 20% of patients as discussed above [62], and one trial used an aggressive chemotherapy that inevitably had to be halted in several patients [63]. Three trials did not report details.

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 [70,146]. It is therefore indispensable to conduct careful adjustment of baseline imbalances or matching [147-149]. This has been done to a varying degree in most studies except in one without any adjustment [64], and in another which only adjusted for the main outcome parameter but not for the other reported results [69]. Without any adjustment, no conclusions can be drawn regarding the applied treatment. When conducted and analysed carefully, non-RCTs can provide valuable information regarding external validity and effectiveness, as they can investigate treatment effectiveness under routine conditions without distortion by the artificial and selective conditions of an RCT's experimental situation [150].

In preclinical studies, VAE show substantial cytotoxic effects in cells originating from breast and gynaecological cancer, and display tumour-growth inhibition in animal studies. Cytotoxicity, especially of the MLs (which bind on human breast cancer cells [151]), may be the cause of tumour reduction after local, intratumoural application of VAE. If systemically applied, the cytotoxicity of the MLs is of less relevance, as it is inhibited by serum glycoproteins [152] and by anti-ML antibodies [153] which are produced after a few weeks of VAE application. Therapeutic effects of the MLs were inconsistent and not very impressive in the reviewed experiments. However, in other tumour types, MLs have also shown substantial growth-inhibiting effects (e.g. [154-157]). Interestingly, in two experiments, the application of VAE-activated macrophages in mice not directly treated with VAE also showed tumour-growth inhibiting effects, while the application of non-activated macrophages had no effects [121]. Similarly in melanoma, the application of VAE-activated splenocytes inhibited metastasis [158,159].

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