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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 organ function. 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 poorly developed? 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[1] 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,[2] 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),[3] irinotecan,[ 4,5] and oxaliplatin (Eloxatin),[6] 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.

Disclosures

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Innocenti F, Undevia SD, Iyer L, et al: Genetic variants in the UDP-glucuronosyltransferase IAI gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 20:1382-1388, 2004.
2. Venook AP, Egorin MJ, Rosner GL, et al: Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 16:1811-1819, 1998.
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.
4. Venook AP, Klein CE, Fleming G, et al: A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863. Ann Oncol 14:1783-1790, 2003.
5. Raymond E, Boige V, Faivre S, et al: Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 20:4303-4312, 2002.
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.
 
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