Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer

Abstract

Purpose: Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration.

Materials and methods: This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL.

Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4.

Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted.

Significance: Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME's effect on survival and chemotherapy tolerability.

FIGURE 1

Best objective response. NSCLC: non–small cell lung cancer; PD: progressive disease; SD: stable disease. Note: Waterfall plot of patients treated with Helixor-M and had follow-up scans after baseline to evaluate tumor response (N = 17). Their best tumor response is shown as the percentage change from baseline in the longest diameter of the target lesion. The numbers in parentheses are the number of prior systemic therapies (including targeted therapy, hormonal therapy, immunotherapy, or chemotherapy), the number of prior radiation treatments, and the number of surgeries.

FIGURE 2

Time to stable disease, progressive disease, and death. NSCLC: non–small cell lung cancer; PD: progressive disease; SD: stable disease. Note: Time to stable disease, progression, and death of all patients treated with Helixor-M (N = 21). The treatment duration is shown as the length of bars. The numbers in the parentheses are the number of prior systemic therapies (including targeted therapy, hormonal therapy, immunotherapy, or chemotherapy), the number of prior radiation treatments, and the number of surgeries. The time to death should be interpreted with caution, as patients received different subsequent treatments.

FIGURE 3

Chemokines, cytokines, and growth factors in patients showing stable disease. Note: Serum cytokine/chemokine/growth factor profiling. A, Superimposed scatter plot showing levels of cytokines, chemokines, and growth factors in patients JHU-008, JHU-011, and JHU-012 at week 4. Analytes showing greater changes (up or down) as compared with baseline are labeled in the plot and were selected for multi-timepoint analysis. B, Line graph showing levels (pg/mL) of CXCL10, CXCL9, and GCSF in serum samples of patients JHU-008 and JHU-012. C, Heatmap showing serum levels (pg/mL) of selected analytes from scatter plot for patient JHU-011. D, Superimposed scatter plot showing median levels of cytokines, chemokines, and growth factors in patients group showing either progressive or stable disease. Slope of the line indicate if a particular analyte was higher or lower in the stable disease group as compared with patients with progressive disease. Factors that show up or downregulation in the stable disease group are labeled in the plot. IL3 was removed from the temporal analysis because it was under the lower detection limit in all the subjects. IFNα2 was also removed from the investigation because it was either not detectable or unchanged compared with baseline levels.