Gastric cancer is the most frequent cancer in Korea and the second most common cancer worldwide 1 2 Surgical resection remains the primary curative treatment option with overall 5-year survival rates of 15% to 35% 3 . The survival rate for patients with gastric cancer has only slightly be improved in the last years by using technical advances in surgery and adjuvant chemotherapy 4 .

It is well known that surgical stress suppresses the immune system. Granulocyte function, numbers of natural killer (NK) cells and T-helper lymphocytes decrease after major surgery 5 6 . Furthermore, chemotherapeutics like 5-FU frequently (≥1:100, <1:10) cause immunosuppression (neutropenia, myelosupression) with increased risk of infection 7 and may have a negative impact on patients´quality of life 8 . Adjuvant 5-FU as monotherapy or in combination with other chemotherapies has been effective in gastric cancer patients UICC stage I-IV to reduce mortality 9 and is a standard therapy in patients with gastric cancer stage II-III 10 . Instead of 5-FU in Japan and Korea also the 5-FU prodrug doxifluridine (5-DFUR), which can be applied orally, is used 11 .

Aqueous mistletoe extracts (Viscum album L.) have been widely used in complementary cancer therapy for decades 12 . Mistletoe extracts as well as isolated mistletoe-lectins were shown to have immunomodulatory properties by enhancing the secretion of cytokines and the number and activity of immunological effector cells like NK-cells 13 14 and T-lymphocytes 15 . NK-cell activity can predict the prognosis of patients with gastric cancer 16 and NK-cells are reduced stage dependently in Korean gastric cancer patients 17 but there are not many studies on this issue. NK-cells were, therefore, chosen as an immunological parameter in this trial. Low Interleukin (IL)-2 is regarded as disadvantageous for sufficient T-cell response 18 and was, therefore, also included into the analysis.

Moreover, mistletoe extracts inhibited tumor cell proliferation and tumor growth in numerous in vitro studies and animal experiments 19 20 21 22 . The effects could be attributed to the specific components mistletoe lectin I–III. 22 23 . abnobaVISCUM® Q (aVQ) is one of the mistletoe preparations with the highest content of mistletoe lectins on the market 24 .

It has been shown in clinical trials, especially with breast or colorectal cancer patients, that QoL improved under mistletoe therapy 12 25 . In operated patients with gastric cancer during chemotherapy, mistletoe treatment has not yet been investigated 25 . We, therefore, conducted a randomized clinical trial to investigate the effect on quality of life, immunomodulation and safety of adjuvant subcutaneous mistletoe treatment on patients with gastric cancer receiving chemotherapy after operation.

A total of 32 patients with stage Ib/II gastric cancer, eligible for adjuvant oral doxifluridine treatment, were enrolled into this clinical trial. Three of the enrolled patients, one from the treatment group and two from the control group, were drop outs because they retrieved the informed consent.

No significant differences were observed in age, sex, height, weight, blood pressure, pulse rate, type of operation (total gastrectomy or distal gastrectomy) and pathologic classifications between the two groups (Table 1). In both groups, the number of male patients was significantly higher. There were 28 patients in stage Ib and only one patient in stage II.

Except 3 QoL parameters (pain, p = 0.038; eating restrictions, p = 0.037; hair loss, p = 0.023) and basophiles (p = 0.0315) baseline of QoL, immunological parameters, hematology and liver function tests were not different between the groups (Tables 2, 3, 4, 5).

*p<0.05, **p<0.01, SD: standard deviation.

SD: standard deviation; CD 16⁺/CD 56⁺ : lymphocytes with CD 16⁺/CD 56⁺ (NK-cells), CD 19⁺ : lymphocytes with CD 19⁺, TNF-α: tumor necrosis factor alpha, IL-2: interleukin-2.

IL-2: interleukin-2.

+AST: aspartate aminotransferase; ^†ALT: alanine aminotransferase; ‡ ALK: alkaline phosphatase; *p<0.05 **p<0.01.

Repeated analysis of variance (ANOVA) of the quality of life scales QLQ-C30 and QLQ-STO22 revealed a strong improvement of the “Global Health Status” (p = 0.0098) in the intervention group (Table 2). The Global Health Status is a sum parameter of 2 questions of the QLQ-C30 questionnaire with a broader range (range = 6) than the other 28 questions (range = 3), which allows a more precise judgment of the patients situation regarding the overall health and quality of life status. All other function and symptom scales of the QLQ-C30 and the stomach cancer module QLQ-STO22 did not show a significant effect of the intervention. The analysis of variance for the hematologic variables showed significantly higher WBC counts (p = 0.0101) and eosinophil counts (p = 0.0036) in the intervention group. For the immunologic variables repeated measured ANOVA detected no significant differences in CD16⁺/CD56⁺ and CD 19⁺ lymphocytes, TNF-alpha and IL-2 between control group and intervention group (Table 3). Anyhow, the IL-2 mean values are considerably higher in the treatment group (Table 4) with an extreme coefficient of variation. Applying the non-parametric rank sum test for the IL-2 values a significant difference results (F = 4.4794; p = 0.0433). Also the IL-2 median at visit 3, but not at the other visits, was significantly higher in the intervention group compared to the control group (Table 4, p=0.034, two sided Mann-Withney U-test).

Mean alkaline phosphatase (ALK) values were higher in the in the treatment group (visit 2, 3, 4, Table 5). Anyhow, a significant influence of the mistletoe treatment on the ALK values could not be confirmed by ANOVA (F = 2.6545, p = 0.1145). Increase of ALK is a known side-effect of doxifluridine therapy.

The number of adverse events was similar in the control group (n = 96) and the treatment group (n = 92). Except 2 serious adverse events (SAE’s), 1 case of post-operative bleeding and 1 case of an acute infection, both in the treatment group and 1 AE with severe degree (itching at injection site, treatment group) all AE´s were mild or moderate. The SAE’s were judged as not related to the study medication. In the treatment group 26 of the 92 adverse events had at least a possible relationship to the mistletoe treatment. 80% (21 cases) of them were related to reactions at the injection site like local pain, itching, rash or urticaria. The others were 1 case of chest pain, 1 case of myalgia, 1 case of dizziness and 1 case of diarrhea. In the control group 20 cases of diarrhea (21% of the 96 cases) were recorded. The difference in diarrhea (6.7% in the treatment group, 50% in the control group, p = 0.014) was statistically significant. All recorded cases of diarrhea had a mild degree but in 3 patients of the control group the symptoms persisted until the end of the study.

While the effect of treatment with mistletoe preparations on survival of cancer patients is still unclear because adequate studies are lacking, there is an increasing number of studies showing beneficial effects regarding QoL 12 25 . Our controlled, randomized pilot study is in line with these findings, showing that also in patients with gastric cancer during adjuvant oral chemotherapy treatment with a mistletoe extract significantly improved the global health status (p<0.01). Interestingly, except the lower frequency of diarrhea, no specific improvement during mistletoe treatment occurred (Table 2). Possible mechanisms how mistletoe treatment could improve the global health status include immunological effects and elevating body temperature 27 , because immunological disturbances and an altered circadian rhythm are factors that may contribute to reduced QoL in cancer patients 28 .

White blood cell count and eosinophils increased in the treatment group compared to the control group. These effects have been reported in other studies evaluating immunological effects of mistletoe preparations and mistletoe lectins in healthy probands and are most likely related to a stimulation of GM-CSF, IL-5 and IFN-gamma by mistletoe lectin 15 29 . The increase in eosinophils and WBC might therefore also in our study with cancer patients be related to a stimulation of IL-5 and/or GM-CSF Apart from WBC and eosinophils there were no significant differences in immune parameters between the groups.

IL-2 function seems to contribute considerably to the operation-induced immunosuppression in gastric cancer patients 30 and preoperative treatment with IL-2 had been promising 31 32 . Applying a non-parametric statistical method (rank transformation) the IL-2 values significantly increased in the group of gastric cancer patients receiving mistletoe treatment. This can, however, be explained by outliers. Peak levels were measured 7 times only in the treatment group and not in the control group. Analysis of medians showed significantly higher values at visit 3 in the intervention group. Anyhow, the IL-2 increase might have been missed in ANOVA analysis due to the low number of patients or might have been compromised by the concurrent chemotherapy. To distinguish this effect certainly a much larger number of patients would be necessary. Nevertheless it can be assumed that the increased WBC and eosinophil count and possibly also the strong IL-2 increase in individual patients are a result of the immunomodulatory effect of the mistletoe extract.

The compliance regarding administration of the mistletoe extract was good. There was no drop-out related to the investigated medication. The tolerability and safety of the medication were also good. Mistletoe treatment related local reactions at the injection site did not lead to a discontinuation of treatment. With the exception of local reactions, there were no significant differences concerning number of adverse events or laboratory parameters between the intervention group and the control group. Moreover, in the intervention group, diarrhea was less frequently reported than in the control group (7% versus 50%, p=0.014). Reduced diarrhea has also been reported in a non-interventional trial when abnobaVISCUM was given in parallel to adjuvant chemotherapy in breast cancer patients 33 . Mucosal injury is a relevant side effect of modern antineoplastic therapies caused by cytotoxicity, apoptosis induction and anti-angiogenesis 34 and is typical for FU-based chemotherapies 35 . The beneficial effect of the mistletoe therapy on diarrhea could possibly be explained by its immunomodulating properties which might have inhibited apoptosis in the normal gut mucosa. This needs, however, further investigations.

In this pilot trial the mistletoe extract was safe, improved the global health status and reduced the rate of diarrhea in gastric cancer patients receiving adjuvant oral chemotherapy.

JE is working for Abnoba company which produces the mistletoe product used in this trial. RH obtained compensation from Abnoba company for scientific projects but not in relation to this study. The study was performed investigator initiated and financed from Abnoba GmbH and Abnoba Korea co. Ltd.

KCK and JHY conducted and coordinated the study and significantly contributed to the study protocol. BSK was the principle investigator of the study and wrote the study protocol. JE monitored the data and checked the analyses. RH reviewed the data and prepared the manuscript. All authors have read and approved the final manuscript.