Metronomic Vinorelbine
Metronomic Vinorelbine
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Metronomic chemotherapy implies the use of a lower-dose agent over protracted periods of time. In the current phase I trial, vinorelbine was administered orally, three times weekly to 62 patients at various escalating doses, and it was determined that 50 mg/dose was optimal. In general, toxicity was not apparent until higher doses were reached. Of the 62 patients, eight patients had measurable responses, 32 had stable disease for six months or more, and three patients have remained on the drug for over three years. Thus, metronomic administration of oral vinorelbine is feasible, safe, and effective for some patients. Additional investigation is warranted.
Source: Briasoulis E, et al. Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res. 2009;15:6454-6461.
As an alternative to standard chemotherapy approaches that involves maximum tolerated doses of drugs administered in cycles, metronomic chemotherapy (MC) is a novel dosing strategy that refers to dense, non-break administration of sub-toxic doses of chemotherapy over protracted periods of time, even years, with the aim to primarily target tumor angiogenesis.1-3 This, based upon the high turnover rate and remarkable sensitivity of endothelial cells to cytotoxic agents to which they are directly exposed.4
Briasoulis et al from two academic medical centers in Greece present the results of a phase I trial that aimed to determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine, as well as obtain preliminary data on biomarkers and efficacy in patients with advanced cancer.
Successive cohorts of patients received escalated doses of oral vinorelbine, given thrice a week (M-W-F), until disease progression, unacceptable toxicity, or consent withdrawal. Unacceptable toxicity was defined as any grade 4 toxicity, or grade 2 or 3 toxicity that required longer than a two-week break during the first two months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins.
Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for a median of 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response was documented in eight cases and 32% of patients experienced disease stability for a minimum of six months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over three years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found to be predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL.
Commentary
Metronomic chemotherapy moved fast from a theoretical construct to clinical investigation on the basis of impressive preclinical data.1-3 However, the early clinical research was empirical in that it was not designed to define optimal dose or schedule or provide additional evidence for a mechanism of action distinct from the standard larger dose, cyclic chemotherapy.5,6 Thus, the current trial was designed to define certain of these key elements to support the concept of metronomic chemotherapy. It was designed to define the recommended dose of an agent that could be readily administered in a sustained (i.e., without break) non-toxic fashion. Vinorelbine seemed like a natural choice because of its anti-microtubule activity for which endothelial cells are known to be sensitive7 and because of its oral formulation. The drug was known to have reasonably good bioavailability after oral administration (40%), and linear pharmacokinetics.8,9
The current trial represents an outstanding example of translational research. Based upon a well conceived basic concept and supported by robust preclinical data, Briasoulis et al conducted a phase I trial that addressed the key issues for this concept of metronomic chemotherapy to move forward. They established a dose and schedule that was well tolerated, readily administered (oral), more than marginally effective, and safe. Furthermore, they provided supportive pharmacokinetic data and additional clues on mechanism of action by focused biomarker studies.
The results of this trial were quite impressive. Nearly one-third of enrolled patients had stable disease for six months and three patients have been on sustained treatment for over three years. It is notable that these three patients had highly vascular tumors (renal cell, Kaposi's and thyroid cancer), suggesting that such diseases may be the logical phase II targets. Furthermore, toxicity was minimal, especially considering prior treatments and/or advanced stage of disease in the enrolled patients. Taken together with the pharmacokinetic and biomarker data, the findings suggest that metronomic chemotherapy with oral vinorelbine is a novel therapeutic approach worthy of expanded clinical investigation.
References
1. Hanahan D, et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045-1047.
2. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4: 423-436.
3. Kerbel RS, et al. Continuous low-dose anti-angiogenic/ metronomic chemotherapy: From the research laboratory into the oncology clinic. Ann Oncol. 2002;13:12-15.
4. Hobson B, Denekamp J. Endothelial proliferation in tumours and normal tissues: Continuous labelling studies. Br J Cancer. 1984;49:405-413.
5. Colleoni M, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: Antitumor activity and biological effects. Ann Oncol. 2006;17:232-238.
6. Dellapasqua S, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol. 2008;26:4899-4905.
7. Vacca A, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood. 1999;94:4143-4155.
8. Marty M, et al. Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors. Ann Oncol. 2001;12:1643-1649.
9. Puozzo C, Gridelli C. Non-small-cell lung cancer in elderly patients: Influence of age on vinorelbine oral pharmacokinetics. Clin Lung Cancer. 2004;5:237-242.
Metronomic chemotherapy implies the use of a lower-dose agent over protracted periods of time. In the current phase I trial, vinorelbine was administered orally, three times weekly to 62 patients at various escalating doses, and it was determined that 50 mg/dose was optimal.Subscribe Now for Access
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