When Toxicity Counts: It's Time to Reappraise Non-Severe but Clinically Relevant Side Effects

Maurie Markman, MD
Published: Friday, Nov 02, 2012
Maurie Markman, MD

Maurie Markman, MD

As an increasing number of cancers are considered chronic diseases treatable with continuous (ie, maintenance) drug delivery, it is essential that our vocabulary describing the side effects experienced by our patients more appropriately reflects this new paradigm. Our concepts of measuring the toxic side effects associated with antineoplastic drug therapy were fashioned in an era where such treatment was generally relatively limited in duration ( <6 months), where serious and even life-threatening toxicities were the greatest concern (eg, grade 4 neutropenia, thrombocytopenia, mucositis), and where cytotoxic therapy was most commonly delivered by the intravenous route. In this earlier era, patients generally received a single che-motherapy regimen for metastatic cancer, or at most, perhaps two regimens. Survival for patients presenting with stage IV cancers, or where the tumor recurred after initial local therapy, was also quite limited, and in the majority of situations was less than one year or a maximum of two years in duration.

The standard drug development paradigm during this time included the conduct of one or more phase I trials designed specifically to define the maximally tolerated dose to be utilized in future phase II and phase III studies, and likely ultimately in clinical practice, assuming an acceptable degree of efficacy was subsequently documented. This approach was employed for both novel agents introduced into the clinic and unique combinations of routinely utilized antineoplastic drugs.

In many trials, the phase I dose and schedule deemed acceptable actually was frequently determined based solely on what could be reasonably well tolerated during a single treatment cycle, or at most, two cycles. This occurred principally because in typical phase I trials, objective responses were rarely observed and progression was often quite rapid. Further, chronic or prolonged use of the strategy was rarely, if ever, contemplated.

Finally, and most relevant to the specific point of this commentary, the dose-limiting toxicity in these regimens was in the vast majority of circumstances defined by the incidence of severe and relatively easily measurable side effects, such as two of three or three of six patients demonstrating grade 3 or 4 bone marrow suppression. This clinical trial paradigm was mandated regardless of whether the sponsor of a trial was a pharmaceutical company, an individual academic investigator, or a not-for-profit multi-institution cooperative group.

Table 1. Gastrointestinal Disorders, Adverse Event Criteria

Definition A disorder characterized by a queasy sensation and/or the urge to vomit
Grade 1 Loss of appetite without alteration in eating habits
Grade 2 Oral intake decreased without significant weight loss, dehydration, or malnutrition
Grade 3 Inadequate oral caloric or fluid intake; tube feeding, total parenteral nutrition, or hospitalization indicated

Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. National Cancer Institute website. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed September 27, 2012.

New Regimens Change Dynamic

But a new era is upon us. Oral antineoplastic drug administration is increasingly common, and it is not unusual for responding patients to remain on a treatment regimen for prolonged periods of time (eg, greater than one or even many years). Further, in several settings involving a number of tumor types, “maintenance therapy” following the attainment of a maximal response (complete, partial, or stable disease) is currently the standard of care, or at least commonly considered a reasonable approach in routine disease management.

In this scenario, it can be argued that lower-grade intermittent, or continuous and far less quantifiable, side effects may become extremely distressing and seriously impact an individual patient’s quality of life. Further, as a consequence of such outcomes, an individual patient might even abandon quite effective therapy.

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