Chemotherapy Dosing in the Setting of Liver Dysfunction
Chemotherapy Dosing in the Setting of Liver Dysfunction
The dosing of chemotherapy is,
at best, an imperfect science.
Long-standing convention has
us calculating body surface area to
two decimal places-a largely discredited
and unnecessary exercise-yet we
have so far failed to learn how to incorporate
potentially important variables
related to race, sex, and pharmacogenetics.
This review, "Chemotherapy
Dosing in the Setting of Liver Dysfunction,"
by Eklund et al highlights
another limitation in our understanding
of how to use chemotherapy: There is
little known about how to dose drugs inpatients with anything other than normal
As demonstrated in this thorough
review of the literature, what we know
about the dosing of chemotherapeutics
in patients with hepatic dysfunction
is minimal. The recommendations
that do exist are often a balance of
anecdote and extrapolation, even
when prospective studies designed
specifically to address the question
for a particular agent have been completed
and reported. Why is this area
of investigation-in a clinical setting
that often confronts oncologists-so
The Drug Development Process
As Eklund et al note, the drug development paradigm progresses from normal individuals and then through cancer patients with normal organ function, largely to avoid unanticipated toxicities or complications that may waylay an otherwise active agent.Once an agent shows promise and becomes available, it is moved into combination regimens in the search for additive or synergistic efficacy in a broad range of cancers. Only then, and when the drug appears active and approvable, might we step back to explore the chosen doses and the pharmacokinetics that can guide the agent's use in patients with liver or renal dysfunction. Indeed, to explore new agents in some circumstances, eg, patients with hepatocellular carcinoma, for example, such an analysis is mandatory (and the need for such work may, in conjunction with the perceived refractoriness of the disease, help to explain the paucity of agents being studied in hepatocellular carcinoma). By necessity, such studies to assess safety and dosing of agents in patients with organ impairment are time-consuming, complex in design,and open to interpretation because of their small sample size. Is the patient with extensive hepatic metastases from colon cancer comparable to a patient with cirrhosis of the liver from hepatitis C? Does an isolated elevation of bilirubin predict hepatic function, or are alkaline phosphatase and albumin better markers? Is the presence of Gilbert's syndrome and its prediction for irinotecan (Camptosar) toxicity equivalent to liver function abnormality of other etiologies? And how about the patient with entirely normal liver function tests with a thrombosed portal vein (not to mention the elderly patient with a normal creatinine compared to the young patient missing a kidney)? Each of these scenarios highlights the clinical uncertainties we face in quantifying organ dysfunction. Paclitaxel With Liver Dysfunction
And what does it take to complete such trials? An analysis of Cancer and Leukemia Group B (CALGB) 9264, one of the very first prospective studies designed to systematically address the dosing of a chemotherapeutic agent in patients with varying degrees of liver dysfunction, is informative. This study of 24-hour infusional paclitaxel explored its dosing in three cohorts of patients felt to represent degrees of liver dysfunction, defined prospectively as patients with isolated elevations of transaminases or those with moderate or extreme elevations of bilirubin. When CALGB 9264 was initiated, paclitaxel was not yet approved and itwas a hot commodity. Accrual to the early stages of the study was brisk, despite the rather low doses being tested and the restrictive eligibility criteria. As time went on, however, paclitaxel became commercially available; the preferred schedule became a 3-hour infusion, paclitaxel was used mostly in combination regimens, and patients willing to receive low doses of this wonder drug became scarce. Hence, the well-intentioned effort wound up closing prematurely, providing some data identifying the importance of hepatic metabolism of paclitaxel and its pharmacokinetics, but little guidance for the dosing of the agent in the real world. This analysis is not meant to be critical of the paclitaxel study, but to highlight the problems with addressing this clinical scenario. Other prospective studies of chemotherapy usage in patients with hepatic dysfunction referred to in this review, including those of gemcitabine (Gemzar), irinotecan,[ 4,5] and oxaliplatin (Eloxatin), were all well-designed and wellintentioned but the findings were of variable value. The study we design today will look markedly different from these earlier studies, based on lessons learned, yet the data we garner may still not be generalizable. Conclusions
All of this serves as a reminder of the limits of our drug development process. It is particularly daunting given the proliferation of new oral agents including substrates for p450, antibodies,and chemotherapeutics. If it is not hepatic dysfunction one is addressing, what of renal dysfunction? Or how about the metabolic changes of aging? These real-life patient management issues remain challenging research questions without answers. In the review by Eklund et al, the data, as it exists, are well-summarized. It is up to the clinician to apply it, as well as the art of oncology, when the individual patient is to be treated.
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3. Venook AP, Egorin MJ, Rosner GL, et al: Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 18:2780-2787, 2000.
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6. Doroshow J, Synold T, Gandara D, et al: Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: A preliminary report of the National Cancer Institute Organ Dysfunction Working Group. Semin Oncol 30:14-19, 2003.