NCCAM/NCI phase 1 study of mistletoe extract and Gemcitabine in patients with advanced solid tumors

Abstract

properly cited.Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m 2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study

“…Therefore, while i.v. application can rapidly reach a high C max⁡ , thereby increasing the risk of systemic, hypersensitivity type reactions (pruritus, urticaria), s.c. application is more likely to induce a local inflammatory response accompanied by cytokine activation of a febrile response [ 25 , 43 ]. Furthermore, i.v.…”

“…applications of high dose mistletoe were temperature related (mild to moderate pyrexia) or skin related (generalised exanthema and pruritus) [ 48 ]. In contrast, s.c. applications are associated with frequent injection site reactions, along with pyrexia [ 25 ]. A retrospective study focusing on therapy with high doses of mistletoe found i.v.…”

“…application of anthroposophic mistletoe preparations is still classified as “off-label” use. While s.c. mistletoe therapy has proven to be well-tolerated [ 23 – 25 ], i.v. mistletoe therapy often involves much higher doses, and limited research has been conducted regarding the safety of this application [ 19 , 20 ].…”

Efficacy of mistletoe extract as a complement to standard treatment in advanced pancreatic cancer: study protocol for a multi-centre, parallel group, double-blind, randomised controlled clinical trial (MISTRAL)

“…In addition, patients reported substantially better HRQoL and tended to gain weight when treated with ME compared to the control group [35]. Two phase I/II trials and some retrospective studies also reported favourable outcomes regarding safety and efficacy of ME in patients with pancreatic cancer [40][41][42]. Tumour remission under ME is rare but has been reported in some small studies and case reports, mostly applying high dose ME directly at the tumour site [31,[43][44][45][46].…”

“…However, in rare cases, a generalised allergic reaction may occur [23,24,47,48]. Unwanted and/or clinically significant interactions with ME and established chemotherapeutic drugs have not been observed [23,40,[49][50][51][52].…”