Targeting inflammation in cancer-related-fatigue: a rationale for mistletoe therapy as supportive care in colorectal cancer patients.

BACKGROUND: Cancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up to several years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue during treatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancer therapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supported by a pharmaceutical mistletoe preparation (Iscador(®)Qu) (181patients). We compared the outcome to a parallel control group (143 patients), which did not receive this supportive care treatment. METHODS: The medical records of 324 patients with non-metastasized colorectal cancer (UICC stage I-III), which were obtained from hospitals and resident physicians, were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoe interventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period the patients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians. RESULTS: At the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportive care group and 86/143 (60.1%) in the chemo- or radio-chemotherapy group without supportive mistletoe medication. Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medication compared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p < 0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14 confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospital versus office-based treatment and the co-morbidity/inflammation represent independent but important determinants for fatigue levels. CONCLUSION: The clinically used mistletoe medication (Iscador(®)Qu) is the first candidate to be included in a supportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF without discernable toxicities.

Systematic evaluation of the clinical effects of supportive mistletoe treatment within chemo- and/or radiotherapy protocols and long-term mistletoe application in nonmetastatic colorectal carcinoma: multicenter, controlled, observational cohort study.

In Europe, patients with colorectal carcinoma (CRC) frequently receive mistletoe extracts to improve quality of life and survival. This study was designed to evaluate supportive treatment with mistletoe extract Iscador (ISC) in nonmetastatic CRC patients under routine clinical conditions and to create well-founded hypotheses for future prospective clinical studies. The design of a multicenter, controlled, retrospective, observational cohort study with parallel groups met the Good Epidemiological Practice rules. Anonymous unselected standardized data from eligible patients with surgically treated stage I-III CRC and adjuvant therapy (AT) or conventional aftercare were included. End points were adjuvant therapy-related adverse reactions (AT-ADRs), symptoms, and disease-free survival (DFS). The results were adjusted for confounder effects. Eight hundred four (429 ISC vs 375 control) CRC patients from 26 centers were observed for a median of 58 versus 51 months; the median ISC therapy lasted 52 months. ISC patients showed fewer AT-ADRs (19% vs 48%, p < .001) and fewer persisting symptoms (p < .001). The DFS hazard ratio of 0.60 (p = .013) suggests a survival benefit in ISC patients versus controls. ISC was well tolerated without life-threatening ADRs, drug interactions, or tumor enhancement. These results suggest a beneficial effect of supportive care ISC therapy within AT protocols and long-term ISC treatment in stage I-III CRC patients, particularly improvement in AT-ADRs and symptoms and possible extension of DFS.

Safety and efficacy of the long-term adjuvant treatment of primary intermediate- to high-risk malignant melanoma (UICC/AJCC stage II and III) with a standardized fermented European mistletoe (Viscum album L.) extract. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland.

BACKGROUND: Mistletoe therapy is the most frequently used complementary treatment in cancer patients in Germany and Switzerland. However, its safety and efficacy were controversially discussed, also in case of malignant melanoma (MM). OBJECTIVES: The present study should evaluate the therapeutic safety and efficacy of a long-term therapy with a standardized fermented European mistletoe (Viscum album L.) extract Iscador (FME) during post-surgical aftercare of primary intermediate to high-risk MM (UICC/AJCC stage II-III) patients and compare it with an untreated parallel control group from the same cohort. METHODS: The study was designed as a multicenter, comparative, retrolective, epidemiological cohort study with parallel groups, carried out according to the guidelines of Good Epidemiological Practice (GEP). All patients suffered from surgically treated and histopathologically confirmed primary MM in UICC/AJCC stage II-III without distant metastases. In the study group, FME was administered subcutaneously 2-3 times weekly for at least three months, while the untreated control group was merely observed ("watchful waiting"). In both groups some patients also received radio-, chemo-, and/or immunotherapy. The patients were followed until the last visit or until death. Unselected, chronologically ordered, and standardized anonymous data from medical records that satisfied the predefined eligibility criteria were included for the "per protocol" analysis. Safety was assessed by the number of patients with FME-associated adverse drug reactions (ADRs) and by the search for tumor enhancement. The primary endpoint of efficacy was the adjusted tumor-related survival. Secondary end-points were the overall-, the disease-free- and the brain metastasis-free survival. The survival results were analyzed after adjustment for baseline imbalances, treatment regimens and other potential confounders by the Cox proportional hazard regression method. RESULTS: 686 eligible patients (329 FME vs. 357 controls) from 35 centers were observed for a median aftercare of 81 vs. 52 months. The median FME therapy duration was 30 months. At baseline, both groups were comparable concerning demography, tumor history and risk factors for progression. Additional adjuvant chemotherapy was more frequent in the study group, while immunotherapy was more frequent in the control group. Eleven patients (3.3 %) developed systemic ADRs attributed to the FME-treatment, and 42 patients (12.8 %) developed local ADRs, with mild to intermediate (WHO/CTC grade 1-2) ADR severity and spontaneous resolution in most cases. In six patients the ADRs resulted in therapy termination. Life-threatening ADRs, ADR-related mortality or tumor enhancement were not observed. On the contrary, the incidence rate of lung metastases and the adjusted hazard ratio for brain metastases were significantly lower in the FME group. In the course of the study and during aftercare a total of 212 (30.9 %) patients relapsed or progressed, and 107 (15.6 %) died. A significantly longer tumor-related survival was found in the FME group when compared with the untreated controls (unadjusted tumor-related mortality rate 8.9 % vs. 10.7 %, Kaplan-Meier estimate, Log-rank test, p = 0.017), which was confirmed after adjusting for potential confounders by the tumor-related mortality hazard ratio estimate HR (95 % confidence intervals) = 0.41 (0.23-0.71), p = 0.002. The adjusted HR results of the overall survival, disease-free survival, and the brain metastases-free survival were also significantly superior in the FME group. CONCLUSION: The long-term FME treatment in patients with primary intermediate to high-risk MM appears safe. Tumor enhancement was not observed. When compared with an untreated parallel control group from the same cohort, the results of the FME treatment suggested a significant survival benefit in primary stage II-III MM patients. These results on survival warrant reconfirmation in a prospective randomized clinical trial with optimized study design and treatment conditions.

[Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland]. / Wirksamkeit und Sicherheit der komplementären Langzeitbehandlung mit einem standardisierten Extrakt aus Europäischer Mistel (Viscum album L.) zusätzlich zur konventionellen adjuvanten onkologischen Therapie bei primäirem, nicht metastasiertem Mammakarzinom. Ergebnisse einer multizentrischen, komparativen, epidemiologischen Kohortenstudie in Deutschland und der Schweiz.

OBJECTIVES: The purpose of the study was to evaluate the therapeutic efficacy and safety of long-term complementary therapy in primary, non-metastatic mammary carcinoma patients in UICC stage I-III with a standardized European mistletoe extract (Viscum album L., Iscador, "mistletoe extract") given in addition to conventional adjuvant oncologic therapy (i.e. chemo-, radio-, and hormonal therapy; "conventional therapy"). METHODS: The multicenter, comparative, retrolective, pharmaco-epidemiological cohort study with parallel groups design and randomly selected centers was carried out according to Good Epidemiological Practice (GEP) rules. The test group patients received subcutaneous mistletoe extract injections for at least three months in addition to the conventional therapy, while the control group was treated with conventional therapy only. The patients were followed up for at least three years or until death. The primary endpoint for efficacy was the overall incidence of adverse drug reactions (ADRs) attributed to the conventional therapy. Secondary endpoints were symptoms associated with disease and treatment, as well as the survival. All end-points were adjusted to baseline imbalance, therapy regimen and other confounders by the logistic regression or the Cox proportional hazard regression. Safety was assessed by the number of patients with ADRs attributed to the mistletoe extract treatment, the ADR severity and the evaluation of a possible tumor enhancement. RESULTS: 1442 patients (710 tests and 732 controls) were eligible for the "per protocol" analysis of efficacy and safety. At baseline, the mistletoe extract group had a more advanced disease and worse prognostic factors profile. After a median follow up of 67 vs. 61 months, and a median mistletoe extract therapy duration of 52 months, significantly fewer test group patients (16.3%) than control patients (54.1%) developed one or more ADRs attributed to the conventional therapy (adjusted odds ratio (95% confidence interval, CI): OR = 0.47 (0.32-0.67), p < 0.001). In the mistletoe extract group, several symptoms more frequently disappeared, and the overall estimated survival was significantly longer (adjusted mortality hazard ratio (95% CI): HR = 0.46 (0.22-0.96), p = 0.038). Systemic ADRs attributed to the mistletoe extract treatment developed 0.8%, and local ADRs 17.3% of the patients. The ADR severity was mild to intermediate (WHO/CTC grade 1-2). Severe mistletoe extract therapy-related ADRs or tumor enhancement were not observed. CONCLUSIONS: The results of the present study confirmed the safety of the complementary therapy of patients with primary, non-metastatic mammary carcinoma with a standardized mistletoe extract and showed considerably fewer ADRs attributed to concurrent conventional therapy, as well as reduced disease and treatment-associated symptoms, and suggested a prolonged overall survival in the mistletoe extract group as compared with controls.