An Algorithm to Define the Optimum Biological Dose of Metronomic Chemotherapy

Open access

Summary

The best effective dose of a chemotherapy is defined using the maximum tolerated dose (MTD) of toxicity. It is possible that the toxicity of a dose may increase when the dose-response curve is not monotonic. In the case of metronomic chemotherapy (MC) a 1/10th level of MC dose is considered as a targeted dose of therapy and is safer in terms of toxicity levels. The objective of this study is to develop an algorithm based on the dose response model of MC to evaluate the best effective dose based on the molecular target agent. The molecular target agent is defined as the optimal biological dose achieved by the best effective dose, as the lowest dose with the highest rate of safety and efficacy. The first proposed design is parametric and assumes a logistic dose-efficacy curve for dose determination, and the second design uses quadratic regression to identify the optimal biological dose. We conducted extensive simulation studies to investigate the operating characteristics of the proposed designs. Simulation studies provide a possible way to decide on the best effective dose of MC to be considered in further phases through the finding of the optimal biological dose. The proposed design is assumed, with the threshold value of optimum biological dose (OBD), to detect the best dose of MC. This consistent design with specific dose response models can be recommended for practice.

Bhattacharjee A., Patil V.M. (2016): Time-Dependent Area under the ROC Curve for Optimum Biological Dose Detection. Turkiye Klinikleri J Biostat 8: 103-109.

Bhattacharjee A., Patil V.M. (2017): Determining an Optimum Biological Dose of a Metronomic chemotherapy. Journal of Data Science 15(1):77-94.

Briasoulis E., Pappas P., Puozzo C., Tolis C., Fountzilas G., Dafni U. (2009): Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 15: 6454-6461.

Cheung Y.K., Chappell R. (2000): Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 56: 1177-1182.

DeVita V.T. Jr., Chu E. (2008): A history of cancer chemotherapy. Cancer Res 68: 8643-8653.

Golfinopoulos V., Salanti G., Pavlidis N., Ioannidis J.P.A. (2007): Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol 8: 898-911.

Hanahan D., Bergers G., Bergsland E. (2000): Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105: 1045-1047.

Hobson B., Denekamp J. (1984): Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br J Cancer 49: 405-413.

Ilie M., Long E., Hofman V., Selva E., Bonnetaud C., Boyer J.(2014): Clinical value of circulating endothelial cells and of soluble CD146 levels in patients undergoing surgery for non-small cell lung cancer. Br J Cancer 110: 1236-1243.

Kerbel R.S., Kamen B.A. (2004): The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4: 423-436.

Kerbel R.S., Klement G., Pritchard K.I., Kamen B. (2002): Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic. Ann Oncol 13: 12-15.

Kumar R., Jose J., Vishwakarma G.K., Bhattacharjee A. (2017): Alternative of clinical end point selection for metronomic studies. IJS Short Reports. Medknow Publications and Media Pvt. Ltd 2: 50.

Marmé D., Fusenig N. (2007): Tumor Angiogenesis: Basic Mechanisms and Cancer Therapy. Springer Science & Business Media.

Pantziarka P., Hutchinson L., André N., Benzekry S., Bertolini F., Bhattacharjee A. (2016): Next generation metronomic chemotherapy - Report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6- 8 May 2016, Mumbai. Ecancermedicalscience 10: 689.

Patil V.M., Noronha V., Joshi A., Muddu V.K., Dhumal S., Bhosale B.(2015): A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol. Elsevier 51: 279-286.

Saltz L.B. (2008): Progress in cancer care: the hope, the hype, and the gap between reality and perception. J Clin Oncol 26: 5020-5021.

Scharovsky O.G., Mainetti L.E., Rozados VR. (2009): Metronomic chemotherapy: changing the paradigm that more is better. Curr Oncol. 16: 7-15.

Schmid P., Schippinger W., Nitsch T., Huebner G., Heilmann V., Schultze W.(2005): Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol 23: 432-440.

Skipper H.E., Schabel F.M. Jr, Mellett L.B., Montgomery J.A., Wilkoff L.J., Lloyd H.H. (1970): Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemother Rep 54: 431-450.

Vacca A., Iurlaro M., Ribatti D., Minischetti M., Nico B., Ria R.(1999): Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 94: 4143-4155.

Biometrical Letters

The Journal of Polish Biometric Society

Journal Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 317 317 33
PDF Downloads 120 120 13