Commentary (Pazdur): New Anticancer Agents in Clinical Development
Commentary (Pazdur): New Anticancer Agents in Clinical Development
The article by Eckardt et al reviews numerous anticancer drugs presently undergoing clinical development in the United States. These drugs have an array of biochemical targets. Some agents, such as the camptothecin analogs, represent a novel class of antineoplastic drugs. Other drugs, such as docetaxel (Taxotere), are analogs of currently available drugs (paclitaxel [Taxol]) [1,2]. Still other agents, such as thymidylate synthase (TS) inhibitors (eg, ZD1694 [Tomudex], AG-331, and LY231514) and 5-ethynyluracil, a uracil reductase inhibitor, have been designed prospectively to inhibit specific enzymatic pathways [3-5]. Some agents discussed have preliminary activity in refractory diseases, such as that of irinotecan (CPT-11) in fluorouracil-refractory colon carcinoma and that of docetaxel in cisplatin (Platinol)-refractory non-small-cell lung carcinoma, or show activity in diseases for which standard therapies are less than optimal.
Eckardt et al conclude by stating that "the possibility of improvement in the treatment of patients with advanced and refractory malignancies exists," but in fact, the focus should be on critical analysis of the end points used to determine "progress." Although a new agent that offered an improvement in median survival would obviously merit widespread acceptance, such a "home run" is, unfortunately, uncommonly observed in single-agent drug development.
Response Rate Should Not Be the Final, Sole End Point
As noted in the article by Eckardt et al, medical oncologists frequently evaluate drugs initially by describing the response rate obtained in phase II or III clinical trials. Experience has demonstrated, however, that response rates for a specific therapy may vary widely, as illustrated by clinical trials examining the modulation of fluorouracil by recombinant interferon-alfa in patients with advanced colorectal carcinoma [6,7]. The reasons for such variation, when uniform response and eligibility criteria are established, are unclear, but perhaps reflect the trial's sample size, location (single institution vs multicenter), and adherence to protocol guidelines.
Although it provides a preliminary indication of activity, the response rate of an agent is, nevertheless, a surrogate end point representing an artificial construct of the academic discipline of medical oncology. It should not be used as the sole, final end point of drug development or drug approval or, most important, as the rationale for prescribing a new chemotherapeutic drug. In the absence of an agent's significant impact on survival, the clinical end point of drug development should be oriented toward the relief of disease-related symptoms or improvement in the patient's quality of life.
Unfortunately, few phase II or III trials have prospectively analyzed the impact of therapy on symptom relief. Although much of the chemotherapy administered in this country is allegedly palliative, there is no consensus among investigators as to which specific disease-related symptoms should be examined prospectively. Moreover, clinical trials frequently limit the entry of symptomatic patients by restricting the performance status of eligible patients, and thereby potentially create patient populations that may not reflect those usually encountered in clinical practice.
Recent clinical trials, especially pivotal drug approval trials, have had accompanying quality-of-life studies to assess the effect of a therapy on the patient's quality of life. These patient self-administered assessment tools examine physical, emotional, social, and financial concerns. Previous assessments of performance status and toxicity were made by physicians or other medical personnel, and attempted to characterize single dimensions of a patient's life. Although our ability to assess a patient's quality of life is evolving, it is hoped that continued interest will ensure better quality-of-life instruments that are applicable in the drug approval process.
Many toxic effects of drugs are difficult to quantitate, as our conventional toxicity criteria do not adequately measure chronic cumulative toxic effects or subtle effects that may disrupt the patient's sense of well-being. An example of such an effect is the fluid retention syndrome observed with docetaxel. This syndrome, which may be ameliorated by the use of corticosteroid premedication, is characterized by peripheral edema, pleural effusions, ascites, and weight gain. Although docetaxel has significant activity in metastatic breast and non-small-cell lung carcinoma, including anthracycline-refractory breast cancer and platinum-treated non-small-cell lung cancers, any therapeutic gains must be weighed against the drug's acute and chronic toxic effects [2,3].
A Recent Attempt to Delineate Clinical Benefit End Points
An example of an attempt to delineate clinical benefit end points is the FDA Oncologic Drugs Advisory Committee's recent recommendation for the marketing of gemcitabine (Gemzar) for advanced or metastatic pancreatic carcinoma. In addition to assessing conventional end points of response rates, median survival, and 6-month and 1-year survival data, a randomized clinical trial quantitatively examined the impact of gemcitabine on the patient's level of pain, need for pain medication, ability to perform daily activities, and weight change, and compared these end points to those in patients treated with fluorouracil. These data were especially useful in pancreatic carcinoma--a clinical setting in which improvement in symptomatic disease is difficult to assess by conventional response criteria that measure a change in tumor size.
With an increasing emphasis on cost-effective delivery of oncologic therapies, pharmacoeconomic analyses also have been incorporated into recent drug development strategies. These complicated analyses examine not only a drug's direct cost and administration expenses but also the total economic impact of a therapy, including expenditures for treatment of therapy-related toxic effects and supportive-care measures, transportation to clinics and hospitals, and lost wages of patients and patient caregivers.
Some New Therapies Provide Distinct Advantages
Although we have only preliminary data on the activities of most drugs described in the review by Eckardt and associates, some new agents may have biologic activity that is similar to that of current standard therapies. For example, Tomudex and uracil-ftorafur (UFT) plus oral leucovorin-drugs being developed for the treatment of advanced colorectal carcinoma-have activity in phase II trials (as assessed by response rates) that is not substantially different from that of intravenous fluoruracil plus leucovorin regimens [4,7,8]. Nevertheless, these newer treatments may have advantages that warrant their further development.
Tomudex, for example, administered as a single 15-minute infusion every 21 days, is more convenient than commonly used schedules of fluorouracil plus leucovorin, which usually require that patients be treated for 5 consecutive days or weekly. In addition, Tomudex may be useful in patients in whom fluorouracil therapy is difficult or imprudent to deliver (eg, patients with dihydropyrimidine dehydrogenase deficiency, in whom fluorouracil toxicity may be life-threatening, or patients who have developed unacceptable cardiac, neurologic, or severe dermatologic toxic effects of fluorouracil).
Similarly, the availability of a totally oral treatment regimen represented by UFT combined with oral leucovorin would represent a convenient, potentially cost-effective therapy, especially in the possible absence of serious neutropenia and mucositis. Other oral treatments being developed for advanced colorectal carcinoma also attempting to capitalize on the ease of such administration include capecitabine, doxifluridine, and oral fluorouracil combined with 5-ethynyluracil [5,9]. These treatments could provide the theoretical advantages of protracted exposure to fluorinated pyrimidines without the use of an expensive pump and the indwelling intravenous catheters requisite for protracted intravenous infusions of fluorouracil.
Definition of a "Successful" Drug Under Increased Scrutiny
The article by Eckardt and colleagues describes an array of potentially successful new drugs with novel and interesting mechanisms of action. However, the definition of what constitutes a "successful" drug will be increasingly scrutinized by the medical oncology community, third-party payors, and patients who demand greater participation in treatment decisions. Surrogate end points, such as response rates, time to treatment failure, and time to disease progression-which provide medical oncologists with the initial glimmer of an agent's activity--must be correlated with clinical end points that are ultimately important to patients--improvement in survival, reduction in drug toxicity, symptom relief, and enhanced sense of well-being. Even in the absence of significant gains in survival, laudable goals of drug development are therapies that are cost-effective, have reduced toxic effects, enhance the patient's quality of life, and are ultimately user friendly.
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