A Call to Action: Determining Optimal Dose, Schedule, and Appropriate Modifications for Antineoplastic Pharmaceutical Agents

Maurie Markman, MD

If asked to do so, it would be easy to provide a list of clinical issues in critical need of increased attention by the oncology community. However, within that list, it would be difficult to suggest any single item is of greater importance than the need to revisit our basic concepts of how we define optimal doses and schedules, as well as appropriate modification schema for antineoplastic agents, with acknowledgment of the essential balance between efficacy and toxicity for this broad class of drugs.

In the earliest days of the modern chemotherapeutic era, the dose- and schedule-related questions were simply defined, subsequently relatively easily addressed, and the most relevant toxicity metrics (eg, hematologic blood counts, renal and hepatic function tests) were not difficult to obtain. A standard toxicity scale (grades 1-4) routinely employed in clinical cancer investigative efforts for multiple possible adverse effects (AEs) added to the convenience of establishing an accepted language among investigators for the negative effects of the therapy. Even the less common, but potentially more devastating effect of anthracyclines on the heart could be monitored and quantified by routine noninvasive examination of cardiac function tests.

Measures of efficacy were also straightforward and included the objective response rate (in phase 2 and 3 trials) and survival outcomes (progression-free and overall) in randomized controlled studies (or far less convincingly, experimental data compared with contemporaneous or historical controls).

In this era, the strategy was to administer treatment (in most settings intravenously and intermittently) at the maximum tolerated dose (MTD), as determined through careful examination of the toxicity severity metrics. The severity of AEs in each treatment cycle, the observed time to recovery of normal hematopoietic function, and other pathophysiologic events were considered in the definition of MTD.

Rather arbitrary dose modification schemas (eg, initial 25% dose reduction) were routinely employed in the face of excessive AEs or delayed recovery of the measured toxicity parameters. This strategy was usually deemed successful in this era of intermittent systemic cytotoxic therapy, which generally did not exceed between 4 and 6 months in total duration, most often due to rather rapid evidence of disease progression or lack of evidence of a clinically meaningful response in the presence of unacceptable toxicity.

What has been outlined above is a relatively simple, standardized process that was fairly easily monitored with routine laboratory testing. Further, because it was not realistically possible to safely administer even higher drug doses without some form of bone marrow support, one could confidently argue that an alternative dosing strategy would be unable to produce a superior effect on the growing cancer.

Where does one begin to fix this state of affairs?

First and perhaps the most relevant comment is the decision to focus on the MTD assumes this is the optimal dose for achieving the desired anticancer effect. What if treatment delivered at 80% or even 50% of the declared MTD of an individual drug or combination chemotherapy produced an equivalent degree of tumor shrinkage while reducing the risk of serious or even only moderately bothersome AEs? What if it also permitted a particular regimen to be administered over a more extended period, possibly prolonging the favorable effects of the therapeutic regimen?

Second, lower doses of an effective antineoplastic would likely result in reduced costs to hospitals, oncology practices, and, most importantly, individual patients. This point is increasingly relevant in an era of simply staggering financial implications of this form of therapy, including the effect of drug wastage.¹

Finally, the management of cancer has rather dramatically changed over the past several decades, in the types of agents administered (small molecule targeted and immunotherapeutic agents), anticipated AEs (bone marrow suppression/emesis not necessarily the most severe toxicity), duration of treatment (increasingly common to employ an extended maintenance approach), and in method of delivery (continuous oral vs intermittent intravenous).

Further, as advanced cancers are increasingly recognized to be serious but more chronic conditions resulting from the delivery of multiple sequential effective therapeutic strategies, and where survival today may be measured in years rather than months, the cumulative influence of AEs on normal organ function and a patient’s quality of life over this extended period must be considered.

Therefore, a continued focus on dose and schedule that ignores this reality and fails to consider the well-recognized fact that research subjects unfortunately rarely reflect noninvestigative cancer patient demographics (eg, age, presence of relevant comorbidities, medications commonly employed in older individuals) would appear to be a serious error.

Consider for a moment the required decision-making process of a busy community oncologist (most patients with cancer in the US receive their care at oncology practices) seeing for the first time a 75-year-old individual with newly diagnosed metastatic cancer. Their performance status is adequate for systemic therapy, and the patient desires to at least initially pursue an aggressive approach to disease control. Further, the individual is objectively overweight, was until 5 years ago a moderately heavy smoker, has a long history of well-controlled but medication-dependent diabetes and hypertension, and also experienced a mild cerebrovascular event (all signs now resolved) 8 months prior to the diagnosis of malignancy. Today, there is nothing about this brief medical history that is strikingly unusual for patients with advanced cancer in the United States.

Multiple questions regarding the optimal care of this individual can be asked. For example, should concern for the risk of toxicity lead the oncologist to initiate drug therapy at a reduced dose? Will this compromise the treatment’s efficacy? If a dose reduction is required due to observed AEs after the first cycle, should a standard modification paradigm be employed, or should a greater change be instituted due to heightened concerns in this older individual with comorbidities?

The broader question to be addressed is whether as a society we can do a better job defining the optimal use of antineoplastic regimens (single-agent and combination strategies). This includes the following critical items:

• The recognition by the pharmaceutical industry, relevant governmental agencies, and the cancer research community that participants in antineoplastic drug trials designed for regulatory approval simply do not appropriately represent the population of individuals treated in the noninvestigative setting, which seriously impairs the ability to adequately define potential toxicities and their appropriate amelioration.
• The continued focus on determining the MTD as a strategy for drug approval does not necessarily define the most appropriate method for optimal drug administration. Fortunately, there is evidence that the FDA is increasingly aware of this conundrum and taking action to improve the situation.² But greater efforts in this arena are clearly needed.

References

1. Shah VS, Irvine C, McWilliams RR, et al. Reducing cancer drug cost: 3-year analysis of automated dose rounding in electronic health records. J Oncol Pract. Published online August 5, 2024. doi:10.1200/ OP.23.00688
2. Shah M, Rahman A, Theoret MR, Pazdur R. The drug-dosing conundrum in oncology – when less is more. N Engl J Med. 2021;385(16):1445-1447. doi:10.1056/NEJMp2109826