Principles of Dose, Schedule, and Combination Therapy
Authors: Hait William N. , Eder Joseph P. 
Published: December 2019

Overview

The discovery and development of oncology drugs are complex and associated with a high failure rate. For example, the chance of a new drug that enters clinical trial has an approximately 10% chance of achieving regulatory approval and ultimately becoming available for patients. Determining the proper dose and schedule of a drug are arguably the two most important determinants of both safety and efficacy, the primary determinants of regulatory approval. Understanding how to best estimate the proper dose and schedule for the many types of therapeutic agents now widely available and in development is a critical skill for those in the drug discovery and development field. This area of expertise has been made more complex with the addition of biological agents such as monoclonal antibodies, alternative protein scaffolds, and vaccines to that of hormones and small molecule platforms. In this chapter, we review the basic principles that underlie the appropriate selection of dose and schedule, with a major focus on cytotoxic chemotherapy. In addition, we discuss the many variables that can underlie the dose–response relationship including characteristics of the tumor, the tumor microenvironment, the host including enzymes of drug metabolism, and mechanisms of drug clearance. Finally, we review the clinical trial designs that have been successfully used to properly select dose and schedule for oncology drugs.

The field of dose, schedule, and combination of chemotherapy agents has seen comparatively few developments in the past few years, as the focus of oncology progressively shifted from the so‐called traditional cytotoxic agents to target agents, and more recently to immunotherapy. Nevertheless, notably in the breast cancer field, dose dense chemotherapy regimens have come to the fore following the GIM‐2 trial.
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It would be valuable to cite this published study, the ovarian cancer study GOG–0252 and breast cancer PANTHER study, as well as the recently presented meta‐analysis of dose dense trial by the EBCTCG presented at SABCS 2017.
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) Furthermore, two additional strategies have risen in the recent decades—in the advanced setting, the use of maintenance chemotherapy with either the reduction of current regimens or switching for non‐cross‐resistant drugs.
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In the early setting, the combination of neoadjuvant therapy followed by postneoadjuvant therapy for select patients without adequate response at surgery,
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and citing the potential of precision medicine to contribute to dose and combination design, chiefly through the evolving field of pharmacogenomics as well tumor mutation panels that are currently being tested.
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The final segment, giving a panoramic view of an “integrated approach to cancer chemotherapy” should also mention the potential contributions of liquid biopsy strategies.
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Finally, the field of immunotherapy has grown exponentially. Though a specific chapter is likely dedicated to the topic of immunotherapy, the potential of chemotherapy + immunotherapy combinations, both concomitant and sequentially, with chemotherapy acting as a “booster” would be interesting.
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The TONIC trial presented during ESMO 2017 serves as a good example of the potential of this strategy.(

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