[Cancer therapy--economic aspects].
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Cost-Benefit Analysis↗
Biomedical subjects
M Rozencweig
Publications and source records attributed to M Rozencweig.
Relation between plasma concentrations of didanosine and markers of antiviral efficacy in adults with AIDS or AIDS-related complex.
The relation between the average steady-state plasma concentration (Cpss) of didanosine and selected measures of efficacy, such as CD4 cell count, p24 antigenemia, and weight gain, was evaluated in patients participating in a phase 1 safety and pharmacokinetics study. All patients were diagnosed as having AIDS or severe AIDS-related complex. These individuals first received intravenous didanosine for 2 weeks at doses of 0.8-33 mg/(kg.d) and then took the drug orally at twice the intravenous dose. Cpss values were calculated on the basis of apparent oral clearance after 4 weeks of oral administration and average daily dose over the first 12 weeks of the study. These data were available for 61 patients enrolled at three clinical sites. High values for Cpss were strongly correlated with an increase in CD4 count (P = .006), a decrease in serum levels of p24 antigen (P = .006), and weight gain (P = .0001) at week 12. Logistic regression analysis was used to assess the influence of Cpss on response (as judged by the three criteria just mentioned) after adjustment for other potential factors related to infection with human immunodeficiency virus. The baseline CD4 cell count and the status with regard to prior zidovudine therapy were related to the CD4 response. However, the odds that a response would include all three parameters were nearly twice as high when the Cpss value increased by twofold.(ABSTRACT TRUNCATED AT 250 WORDS)
AIDS-Related Complex↗
Longitudinal analysis of responses to oral didanosine therapy following zidovudine therapy in advanced infection with human immunodeficiency virus.
The effect on immunologic and virological parameters of up to 24 weeks of therapy with didanosine at daily oral doses of < or = 12.5 mg/(kg.d) was studied retrospectively in 69 patients with advanced disease due to human immunodeficiency virus--i.e., AIDS or advanced AIDS-related complex--who had previously been treated with zidovudine. Patients entered the study with a low CD4 cell count (median, 39/microL) and with evidence of an ongoing depression of bone marrow function. Didanosine therapy was associated with a significant increase in CD4 counts and a prolonged decrease in serum levels of p24 antigen relative to baseline. These changes were more pronounced in the population with baseline CD4 counts of > or = 100/microL. A beneficial effect of didanosine therapy on hematologic parameters was observed in these patients, with increases during therapy of hemoglobin levels as well as white blood cell, granulocyte, and platelet counts. These responses were maximal at weeks 16-20. Further investigations are needed to establish the clinical correlates of these observations.
Administration, Oral↗
Overview of Taxol safety.
The safety profile of Taxol administered intravenously as a single agent has been established based on the experience of 655 patients. Of these patients, 253 were treated in nine phase I studies, and 402 were treated in eight disease-oriented phase II studies. Myelosuppression, specifically neutropenia, was the dose-limiting toxicity in all studies conducted in patients with solid tumors. Neutropenia was schedule dependent and was less severe when Taxol was administered via a 3-hour infusion. Severe hypersensitivity reactions were controlled in the phase II program with a premedication regimen consisting of dexamethasone, an antihistamine, and an H2 blocker. Cardiovascular toxicities were minimal and do not indicate constant electrocardiographic monitoring during Taxol infusions. Peripheral neuropathy was usually mild to moderate and dose related; however, it rarely caused treatment discontinuation. Additional adverse events associated with Taxol include arthralgia/myalgia, mucositis, nausea and vomiting, and alopecia.
Bone Marrow↗
Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease.
Myelosuppression is associated with human immunodeficiency virus (HIV) infection and may also be produced by agents used for the treatment of the disease or the treatment of its complications. Didanosine (ddl; 2',3'-dideoxyinosine) is a newer purine nucleoside that has recently become available for therapy for HIV infection. The effects of didanosine on peripheral blood counts have been retrospectively evaluated in the first 170 patients treated with this new agent in four phase I trials. Patients treated with didanosine showed statistically significant improvements in hemoglobin levels, white cell counts, and granulocyte and platelet numbers as compared with baseline values. These changes were seen with or without prior therapy with zidovudine, were somewhat more pronounced at higher doses of didanosine, and persisted for up to 1 year. Reported adverse events included peripheral neuropathy, diarrhea, and most notably, pancreatitis. It is concluded that, while some toxic side effects occur, didanosine therapy in HIV infection is associated with an amelioration of HIV-induced myelosuppression.
AIDS-Related Complex↗
Drug discovery and development in the pharmaceutical industry.
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.
Animals↗
Phase II study of tallysomycin S10b in patients with advanced head and neck cancer.
Twenty patients with advanced head and neck tumors were entered in a phase II trial of tallysomycin S10b given intravenously at weekly doses of 2.5 mg/m2. All patients had received prior chemotherapy +/- radiotherapy. Sixteen patients were evaluable for response. Two had stable disease for 15 and 22 weeks respectively. None exhibited tumor shrinkage. Non-hematologic toxicities primarily consisted of gastrointestinal intolerance. Mild fever was noted in about half of the patients and increase in serum creatinine was observed in four. Other side effects consisted of decrease in pulmonary diffusion capacity and skin changes. In conclusion, tallysomycin S10b has no activity in previously treated head and neck cancer patients and has a toxicity spectrum similar to that of bleomycin.
Aged↗
Comparative effect of cisplatin, spiroplatin, carboplatin and iproplatin in a human tumor clonogenic assay.
A modified double-layer Hamburger and Salmon cloning assay was used to test cisplatin and its analogs (spiroplatin, carboplatin and iproplatin) on fresh tumor samples from 63 patients with a variety of non-hematological malignancies. Among them were 18 breast cancers, 17 ovarian cancers and 7 of unknown primaries. Half the patients received prior chemotherapy. Cisplatin regimens were given in 16 cases. When possible, cells were exposed for 1 h to each drug in concentrations of 0.1 microgram/ml and 1.0 microgram/ml for cisplatin and spiroplatin, 1.0 microgram/ml and 10 micrograms/ml for carboplatin and iproplatin. A greater than or equal to 50% cell kill with at least one drug was found in 20 samples including 8 ovarian cancers, 3 breast cancers and 1 unknown primary. A greater than or equal to 70% cell kill was seen in 2 samples with cisplatin, 3 with spiroplatin and carboplatin, and 6 with iproplatin. There was only partial cross-resistance between cisplatin and its analogs. Among 57 paired comparisons of cisplatin with spiroplatin, 2 showed drug sensitivity to cisplatin alone, 6 to spiroplatin alone, and 6 to both. The same sort of observation was made with carboplatin. The lack of cross-resistance between cisplatin and iproplatin was particularly striking: among 53 pairs, 6 were sensitive to cisplatin alone, 8 to iproplatin alone, and 2 to both. About 20% of the samples that were resistant to cisplatin were sensitive to iproplatin. Our data show hints of activity in breast and ovarian cancers with all analogs and suggest that they will achieve clinical antitumor activity similar to that they will achieve clinical antitumor activity similar to that of cisplatin. The in vitro evidence of incomplete cross-resistance between cisplatin and its analogs should be investigated further.
Carboplatin↗
Phase II study of tallysomycin S10b in patients with advanced colorectal cancer.
A total of 16 patients with histologically confirmed colorectal cancer were entered into this phase II trial, designed to evaluate the efficacy and safety of tallysomycin S10b. The compound was given i.v. weekly at a dose of 2.5 mg/m2 by push injection. Pulmonary toxicity was the most significant side effect; it was observed in three patients and required treatment discontinuation in one. Skin lesions occurred in three patients. Other side effects were mild and their relationship to drug administration was ill-defined. No responses were observed in this group of patients, most of whom had received prior therapy.
Adenocarcinoma↗
Overview of hormonal therapy in advanced breast cancer.
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.
Breast Neoplasms↗
Resistance to platinum compounds: mechanisms and beyond.
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Animals↗
Megestrol acetate: clinical experience.
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Acquired Immunodeficiency Syndrome↗
Combination of cisplatin, vindesine, and dacarbazine in advanced malignant melanoma. A Phase II Study of the EORTC Malignant Melanoma Cooperative Group.
A Phase II study combining cisplatin, vindesine, and dacarbazine was performed on patients with disseminated malignant melanoma by the European Organization for Research and Treatment of Cancer (EORTC) Malignant Melanoma Cooperative Group (MMCG). The treatment consisted of intravenous administrations of dacarbazine 450 mg/m2, vindesine 3 mg/m2, and cisplatin 50 mg/m2 on day 1 and 8 of each course. Courses were repeated every 4 weeks. Treatment was discontinued in case of progression after two courses, otherwise continued until progression or for a minimum of six courses. One hundred five patients entered the trial with 92 patients being evaluable. The response rate calculated after clearance by the Extramural Review Committee shows four complete and 18 partial responses, i.e., 24%, with a median remission duration of 23 weeks. Toxicity and subjective tolerance to this regimen were moderate, requiring 140 modifications of 642 administrations (22%). Main toxicities were nausea and vomiting (95%), leucopenia (70%), alopecia (56%), peripheral neuropathy (32%), and nephrotoxicity (17%). The discussion emphasizes some particular points of interest in the management of advanced malignant melanoma.
Actuarial Analysis↗
Activity of a new antiemetic agent: alizapride. A randomized double-blind crossover controlled trial.
Alizapride is a methoxy-2-benzamide derivative three times more potent than its parent compound, metoclopramide, as an antagonist of apomorphine-induced emesis in dogs. The antiemetic activity of alizapride plus dexamethasone (DXM) was compared with that of placebo plus DXM in a randomized, double-blind, crossover study in cancer patients receiving cisplatin (DDP). Alizapride, given at the maximally tolerated dose of 4 mg/kg x 5, or placebo was given in a sequence determined by randomization during two successive, identical courses of antitumor chemotherapy. The antiemetic treatment was given 30 min before and 1.5, 3.5, 5.5, and 7.5 h after starting. DXM, in a dose of 12 mg, was given IV with the first administration of alizapride or placebo. A total of 39 patients completed the two courses of chemotherapy. The severity of gastrointestinal symptoms was influenced by previous treatment but not by the treatment sequence. Although our overall results suggest that alizapride does not add to the activity of DXM against DDP-induced amesis, a statistically significant difference favoring alizapride plus DXM was found among patients with the lowest gastrointestinal tolerance to DDP: women, patients under 50 years of age, and patients pretreated with chemotherapy including DDP and non-DDP agents. Side effects consisted of orthostatic hypotension, which was symptomatic in two patients, and a single occurrence of severe extrapyramidal syndrome. We conclude that alizapride is more active than placebo when combined with DXM for DDP-induced emesis in patients at high risk of severe nausea and vomiting. The severity of the side effects in this study indicates that a dose reduction of alizapride might be appropriate for further studies.
Adolescent↗
Comparative effect of cisplatin, spiroplatin, carboplatin, iproplatin and JM40 in a human myeloid clonogenic assay.
The relative toxicities of cisplatin and its analogs, spiroplatin, carboplatin, iproplatin and JM40, were tested against normal human progenitor myeloid cells (CFU-GM) in a clonogenic assay. Cells obtained from five bone marrows were incubated for 60 min with various drug concentrations and plated. The mean inhibitory concentrations for 50% of the bone marrow colonies (IC50) were 15.6 micrograms/ml for cisplatin, 0.4 micrograms/ml for spiroplatin, 56.3 micrograms/ml for carboplatin, 36.3 micrograms/ml for iproplatin and 179.5 micrograms/ml for JM40. Ratios of the IC50s of the analogs with cisplatin as reference drug closely followed the corresponding ratios of the clinical maximum tolerated doses. This correlation between the CFU-GM assay results and the clinical myelotoxicity suggests that the assay is adequate for predicting myelotoxicity in vitro and selecting in vitro drug concentrations for the human tumor clonogenic assay.
Antineoplastic Agents↗
Carboplatin: current status and future prospects.
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Antineoplastic Agents↗
The EORTC Clonogenic Assay Screening Study Group (CASSG) program.
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Cisplatin↗
Sensitivity of normal human bone marrow myeloid progenitor cells to anthracycline, cisplatin, anthracene and flavone acetic acid derivatives, and its relevance for the prediction of human plasma concentrations of anticancer drugs.
Many in vitro investigations with anticancer agents are performed at concentrations equal to the peak concentrations or fractions of the peak concentrations achieved in human plasma after administration of these agents. In an effort to develop an in vitro test capable of predicting these peak plasma concentrations prior to the completion of pharmacokinetic studies, the effect of several classes of anticancer agents against normal human bone marrow myeloid progenitor cells (CFU-GM) was studied. The investigated agents included anthracycline antibiotics, cisplatin and its analogs, anthracene derivatives and two flavone acetic acid derivatives. The CFU-GM were exposed to these agents for 30-60 min. An exponential relationship between drug concentration and CFU-GM growth was observed for all compounds with the exception of the flavone acetic acid derivatives which were inactive. For the latter two compounds, an inhibition of CFU-GM growth was observed after continuous exposure. When compared to the plasma concentrations after parenteral administration of these agents, there was a very good agreement between 1/10 of the peak plasma concentration and the concentration inducing a 90% inhibition of the CFU-GM growth for the anthracycline antibiotics and anthracene derivatives. In contrast, for cisplatin and its analogs, there was a better agreement between 1/10 of the peak plasma concentration and the concentration inducing a 10% inhibition of CFU-GM growth. The combination of concentrations inducing inhibitions of 10 and 90% of the CFU-GM growth provides a range of concentrations that predict reasonably well the peak plasma concentrations of several anticancer agents and that could be used as guides for other in vitro investigations.
Anthracenes↗