Омела белая Viscum album Mistletoe

4. Discussion

We observed 30% grade 3 neutropenia and 10% grade 3 thrombocytopenia, while single agent gemcitabine testing has resulted in 19% grade 3 nonfebrile neutropenia and 4% grade 3 thrombocytopenia [44]. Thirty-seven percent of patients experienced nonneutropenic fever, while single agent gemcitabine was associated with 41% fever. There was no documented incidence of febrile neutropenia for the combination regimen. Flu-like symptoms occurred in 18% of patients.

The hematologic toxicity profile of the mistletoe/gemcitabine combination and febrile reactions in this study were similar to single agent gemcitabine [44]. The addition of mistletoe did not exacerbate hematologic gemcitabine toxicity. Interestingly, there was a trend (P = 0.06) towards increased ANC nadir during the first 3 weeks of initiation of mistletoe and of ANC maximum during the first 6 weeks as a function of mistletoe dose (P = 0.034). Others have claimed that mistletoe may boost chemotherapy tolerance, but published data on dosing and mistletoe schedule are lacking, while these were collected in detail in this study.

Flu-like symptoms may be more common when mistletoe is added to gemcitabine. We observed febrile and flu-like reactions attributable to mistletoe across the entire mistletoe dosing spectrum that did not seem to be dose dependent.

The addition of mistletoe did not affect the pharmacokinetics of gemcitabine at any of the mistletoe dose levels tested, suggesting that mistletoe can be added to gemcitabine without concern about adversely affecting gemcitabine's pharmacokinetic profile. The MTD for the gemcitabine/mistletoe combination in this study was gemcitabine 1380 mg/m² given weekly on day one and eight of a three-week cycle with mistletoe 250 mg s.c. daily. As per the manufacturer recommendations, gemcitabine is commonly dosed at 1000 mg i.v. weekly for three weeks on a 28-day cycle. In our study a higher dose was tolerated.

Stimulatory effects of mistletoe on neutrophils and lymphocytes have been reported in vitro as well as in patients. We observed a mistletoe dose-dependent trend towards increased absolute neutrophil count ANC nadir during cycle 1 and ANC maximum during cycle 2. None of the study patients developed febrile neutropenia even at the highest gemcitabine dose of 1650 mg/m². As this study employed a dose escalation scheme in a diverse group of patients with advanced cancer, many of whom were heavily pretreated, this observation would have to be verified and confirmed in a setting of increased homogeneity of patient population and treatment regimen with a larger sample size.

There is a sizable body of literature on the effects of mistletoe on cytokine production [21]. We selected testing for IL-6, IL-12, IFN gamma, and TNF alpha based on their previously described role in tumor development and proliferation as well as existing publications of possible effects of mistletoe on the production of these cytokines. The production of these cytokines in patients with cancer however has not been studied in detail when chemotherapy was combined with mistletoe. We did not detect any consistent pattern of increased or decreased production of any of the cytokines tested.

Mistletoe lectin (ML)-3 antibody formation of the IgG type was detected in all patients by cycle 3 of therapy or 9 weeks and thus was independent of the actual mistletoe dose administered. The physiologic effect of the formation of ML antibodies is not well understood. While we did not compare participants' injections site reactions to this immunological data, we did observe injection site reactions early in treatment of all study participants. Others have reported local reactions in 87% [31]. In most studies, mistletoe is injected three times per week, while our patients injected mistletoe daily. It is thus not surprising that our study would find a higher rate of local injection site reactions. Skin reactions decreased over the course of therapy. This phenomenon may have resulted from the increasing formation of ML antibodies over time mitigating the mistletoe related injection site reactions. Febrile reactions occurred in more than one-third of the patients. It is not clear from our data that there was any relationship between the appearance of ML antibodies and febrile reactions or other toxicities. The study was not designed to yield reliable data on clinical response to the study regimen. Therefore, we are unable to determine associations between clinical response and the formation of ML antibodies or febrile reactions. Future studies may add the understanding of the physiological reactions to mistletoe therapy by connecting immunological data to changes in symptom presentation.

The finding of a partial response rate of 6% is comparable to what would be expected from single agent gemcitabine in this population of patients with advanced, mostly heavily pretreated carcinomas. The median survival from study enrollment of about 200 days is within the range of what would be expected from single agent gemcitabine. Compliance with the mistletoe regimen was high, and no episode of febrile neutropenia was observed in any of the 44 patients. The lack of episodes of febrile neutropenia in a set of heavily pretreated patients of whom almost 50% received gemcitabine doses of 1100 mg/m² or higher is noteworthy, but would have to be confirmed in a larger, more homogenous cancer population.

The above results should be interpreted in light of several study limitations. First, the study sample included 4 different types of solid tumors, each of which may respond differently to GEM or mistletoe/GEM therapy. As such, the results presented herein may not extend to more homogenous groups of cancer patients. Second, the overall sample size was small (n = 44). As a result, the study may have been underpowered to detect significant trends for the study outcomes. Despite the majority of study outcomes remaining descriptive in nature, the statistical tests applied (e.g., survival analyses and Jonckheere-Terpstra trend test) should be interpreted in light of the small sample sizes used in each respective test. The overall small sample size precluded subgroup analyses (e.g., treatment naïve participants' response), which may be a worthwhile area for future studies to pursue. Finally, the study was not designed to examine the effectiveness of a mistletoe/GEM combination. Future work should apply double blind, randomized controlled study designs to examine.

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