Principles of Dose, Schedule, and Combination Therapy
Authors: Eder Joseph P. , Hafez Navid 
Published: October 2022

Overview

The role of dose and schedule have always and continue to play a critical role in clinical cancer drug treatment. Dose is a significant determinant of the antitumor activity and toxicology for the established cytotoxic chemotherapeutic agents and newly developed targeted agents. The relationship for dose, or more correctly exposure, is quite consistent for the effect on normal tissues, most clearly seen in the deoxyribonucleic acid (DNA) damaging agents and mitotic tubule inhibitors. The effect of dose for biologically therapeutic agents such as the interferons, interleukins, monoclonal antibodies, hormones, and for molecularly targeted tyrosine kinase inhibitors is complicated, and there is not the same unequivocal evidence for a dose–response effect with these agents. Contemporary targeted agents have a much more specific relationship to the extent of target interaction. The schedule of drug administration may be important to the therapeutic index independent of dose. Cytokinetic studies related to drug schedule have led to the improved use of agents such as cytosine arabinoside (cytarabine, ara‐C) in both experimental and clinical leukemia. Most of the molecularly targeted agents, whether small molecules or monoclonal antibodies, are dosed to provide a continuous effect, which markedly changes the clinical toxicity profile but has come for reconsideration as a general approach.

The intrinsic tumor cell sensitivity, the tumor burden, and the presence of resistance determine the outcome of therapy as much as exposure, which does correlate well with host factors and toxicity, particularly the pharmacokinetics of drug clearance and kinetics of sensitive host cell targets. Bone marrow transplantation and hematopoietic growth factors have permitted the use of increased doses of alkylating agents to improve results and increase cures in several settings.

For most chemotherapeutic agents that directly or indirectly target DNA or the mitotic spindle used alone or in combination, intermittent courses (e.g., four 5‐day courses every 3–4 weeks) are generally superior to other schedules such as continuous dosing to permit normal tissue recovery and maximize dose. Cytarabine in acute myeloid leukemia (AML) and 5‐fluorouracil (5‐FU) in gastrointestinal (GI) cancers are notable exceptions, driven in short by the extremely rapid plasma clearance due to metabolism.

Continuous oral administration of many new targeted therapies, particularly kinase inhibitors is the current clinical schedule for reasons related to the mechanism of action. The continued suppression of proliferative growth factor signals and interruption of survival pathway signals in tumor cells or the repair of DNA appears necessary in the clinic and in preclinical models. This is the case for the poly (ADP‐ribose) polymerase (PARP) inhibitor rucaparib. Monoclonal antibodies produced with contemporary means, whether alone or as a drug antibody conjugate, have predictable clearance/half‐lives equivalent to native immunoglobulin G (IgG) proteins (half‐life 21–23 days).

The most compelling rationale for combination chemotherapy is tumor cell heterogeneity and its implication for drug resistance, and the success of combination chemotherapy in the clinic. In practical clinical terms, the selection of specific combinations in particular types of cancer depends on the individual activity of the agents in the target cancer type and the absence of overlapping toxicities. The agents with the highest single‐agent activity are preferred, particularly agents that produce complete responses (if any such agents exist), with different mechanisms of action to address the theoretical heterogeneity issue.

The vast majority of cancers are treated successfully only with combinations of agents chosen for the highest possible individual activity against a specific type of cancer. Empiricism was an essential component in the development of contemporary cancer therapy, but rational drug discovery, analog development, preclinical modeling, precise pathologic diagnosis, careful staging of disease, and clinical trial design are the foundation for the measure of success known today. The breakthroughs in molecular biology have presented the oncologist with enormous opportunities and challenges. Based on these breakthroughs, a molecular diagnosis will be able not only to determine where and how cancer originates but also the processes that are essential to its survival.