When used as first-line treatment for advanced ovarian cancer in phase III trials, single-agent carboplatin has produced clinical complete response rates comparable with or exceeding those of ...single-agent cisplatin. Phase I/II trials of combination chemotherapy have yielded overall objective response rates of 44% to 75% when carboplatin was combined with either cyclophosphamide or chlorambucil. In randomized phase III trials of carboplatin combination chemotherapy, response rates similar to those of cisplatin combinations have been achieved but with greatly reduced toxicities. The data from these phase I, II, and III trials show that carboplatin is as active as cisplatin in patients with advanced ovarian cancer and is associated with a significantly lower incidence and is associated with a significantly lower incidence of emesis, ototoxicity, peripheral neuropathy, and renal dysfunction. Thus, carboplatin should be considered the platinum compound of choice in the firstline treatment of advanced ovarian cancer.
The discovery and development of new anticancer drugs is a complex and largely empirical process. New compounds can be discovered by screening, modification of existing compounds, rational drug ...design, and serendipitous basic research observations. Selection of compounds for clinical trials depends on assays of uncertain predictive value. In the pharmaceutical industry, priorities for development of potentially active entities are set and available resources allocated based on the availability and cost of supplies, patent status, potential spectrum of activity, ability to meet regulatory requirements, and market assessments. Competition for resources also occurs from noncancer drugs, eg, cardiovascular agents. Clinical development (testing and approval for commercial distribution) requires close attention to the requirements of national regulatory agencies such as the United States Food and Drug Administration. The arbitrary nature by which compounds with antitumor potential are chosen for development means that some that would be useful never reach clinical trial and others are never made generally available. This article reviews the decision making process in the pharmaceutical industry by which compounds are identified and selected for clinical trial, the regulations in the United States that govern such trials, and what is required to have the drug approved for commercial distribution.
Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of ...hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.
We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol ...(paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.
Recent therapeutic and technological advances have profoundly modified the parameters of new drug testing in ovarian cancer. The potential of compounds tested today in this disease therefore needs to ...be assessed according to this changing reality. Previous treatment with or without cisplatin is the criterion we have applied in our review of the single agent clinical data. Results obtained with older compounds have also been, when possible, reassessed in order to facilitate a comparative interpretation of recent trials. A brief overview of the most recently developed laboratory screening models has been conducted in order to stress their close relationship and their crucial role in future new drug development.
