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Biomedical subjects

G R Petroni

Publications and source records attributed to G R Petroni.

12 recordsLinked to original sources

Designs for phase II trials allowing for a trade-off between response and toxicity.

In this paper we propose methods for designing phase II trials that allow for a trade-off between treatment safety and antitumor activity, where safety and antitumor activity are measured as binary endpoints. The designs can be carried out either in a single stage or can be conducted in two stages, with an interim analysis to assess whether the treatment appears sufficiently safe and effective to warrant continuing. The emphasis is on the derivation of stopping rules for phase II trials that require the enrollment of a small number of patients and are based on enumerating the exact distribution of the proposed test statistic. We illustrate the methods with a recent study that required the use of a group sequential design to monitor antitumor activity and toxicity.

Antineoplastic Agents

Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin's disease in relapse following MOPP. Cancer and Leukemia Group B.

PURPOSE: To evaluate the activity and toxicity of combined etoposide, vinblastine, and doxorubicin (EVA) in advanced Hodgkin's disease (HD) in relapse from or refractory to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). PATIENTS AND METHODS: Eligible patients were more than 15 years of age and had received only one prior course of MOPP and were in relapse with measurable disease. The EVA regimen (etoposide 100 mg/m2 intravenously [IV] on days 1, 2, and 3; vinblastine 6 mg/m2 IV on day 1; and doxorubicin 50 mg/m2 IV on day 1) was administered every 28 days for a minimum of four and a maximum of six cycles. Patients were restaged at 3 and 6 months. RESULTS: Forty-five eligible patients were treated, with an overall response rate of 73%. There were 40% complete responses (CRs) and 33% partial responses (PRs). The median follow-up time in 42 months. The median time to treatment failure (TTF) is 10 months, with 31% continuing progression-free. Eighteen patients achieved a second CR, with only seven recurrences in that group. Failure-free survival and overall survival were significantly better in patients whose first MOPP-induced remission was longer than 12 months and who were free of B symptoms at relapse. Toxicity was primarily myelosuppression, which resulted in two toxic deaths. Pulmonary toxicity was not observed. CONCLUSION: EVA is an effective second-line regimen for the treatment of HD in relapse following MOPP chemotherapy.

Adolescent

Bivariate sequential designs for phase II trials.

In this paper we propose methods for designing group sequential phase II trials with two dependent binary endpoints. The emphasis is on the derivation of stopping rules for phase II trials which require the enrollment of a small number of patients. The methods are based on enumerating the exact distribution for the binary endpoints. We illustrate the methods with a recent study which required the use of group sequential design to monitor antitumor activity and toxicity.

Antineoplastic Agents

A two-sample test for stochastic ordering with interval-censored data.

A new class of asymptotically nonparametric two-sample approximate tests for discrete interval-censored data is proposed. This class extends the family developed by Pepe and Fleming (1989, Biometrics 45, 497-507) for right-censored data and is based on an integrated weighted difference in survival function estimates. The tests are sensitive to the alternative of stochastic ordering and use Turnbull's (1976, Journal of the Royal Statistical Society, Series B 38, 290-295) estimator of the survival function. The choice of appropriate weight functions is investigated. Simulation results indicate that for interval-censored data the new procedure, with an appropriate weight function, can be more powerful than an omnibus likelihood ratio test and Mantel's (1967, Biometrics, 23, 65-78) test under a broad range of stochastically ordered alternatives. For small sample sizes (n = 50), with moderate censoring (47% and 70%), the size of the test is close to the nominal size.

Biometry

Changing patterns of hospital use for patients with musculoskeletal disease in Michigan, 1980 to 1987.

Over the past 10 years there have been dramatic changes in health care financing in the United States, such as Medicare's Prospective Payment System for hospitalized Medicare beneficiaries, and in health services delivery, such as the growth in health maintenance organizations and other forms of managed care. These changes have occurred largely in response to payors' concerns about the rising cost of health care. A study of such changes in financing and delivery, and how specific groups of patients are affected is necessary so that the effects of these changes on patients' health can be determined. We examined the hospitalization rates for patients with musculoskeletal diseases in Michigan from 1980 through 1987. During this period, the overall age-adjusted hospitalization rates decreased 7.0% per year (p = 0.001). The decrease occurred less for surgical discharges (6.0% per year) than for medical discharges (8.6% per year) (p < 0.001). While these overall trends are of interest, they obscure disease-specific trends that vary significantly from both the overall, and the medical and surgical trends. For example, while surgical discharges, in general declined, procedures related to major joint and limb reattachment (DRG #209) increased at a rate of 6.3% per year. And while medical discharges in general decreased over this period, discharges for osteomyelitis increased 5.4% per year. The patterns of disease-specific trends offers insight into the possible causes for these changes. Finally, it is important to understand the epidemiology of hospital use to evaluate the effects of new medical care delivery and payment systems on the care of subsets of patients.

Age Factors

Empirical evaluation of statistical models for counts or rates.

We consider methods for selecting the joint specification of the mean and variance functions in statistical models for rates or counts. Based on analyses of diagnosis-specific hospital discharge rates in Michigan, we show that a Poisson model with an extra variance component for the systematic variation is superior to several other probability models with regard to specification of the error structure. Further, the deviance residual appears superior to the Pearson residual. The proper specification of such variation is crucial for many types of analyses, such as identification of outliers and regression analyses designed to explain the systematic component of the variation.

Analysis of Variance

Small area analysis of hospital discharges for musculoskeletal diseases in Michigan: the influence of socioeconomic factors.

PURPOSE: The rise in health care costs has occasioned a number of initiatives in an attempt to reduce the rate of increase. Despite the growth of health maintenance organizations and preferred provider organizations and the introduction of Medicare's prospective payment system, health care costs have continued to increase. Coincident with these efforts, a number of researchers have shown that there exists wide variation in age-adjusted hospital discharge rates, which translate into significant variation in per capita expenditures. Much of the focus on the reasons for hospital admission variability has been on physician practice variation. If most of the variation in hospital discharge rates is due to physician practice style, then payment systems can be developed (e.g., capitation) that limit physician practice variation without harming patients. We examined socioeconomic factors in Michigan communities to assess their association with hospital discharge rates for patients with musculoskeletal diseases. PATIENTS AND METHODS: Data on hospital discharges from 1980 and 1987 were taken from the Michigan Inpatient Data Base. All admissions from the major diagnostic category 8, diagnosis-related group (DRG) 209-256 were included. Zip code-specific hospitalization data were grouped into small geographic areas or hospital market communities (HMCs). Discharge rates were calculated, and profiles of the socioeconomic characteristics of each of the HMCs were developed. A Poisson regression model with an extrasystematic component of variance was used to analyze the association of HMC socioeconomic characteristics with age-adjusted hospital use. RESULTS: We found that four socioeconomic variables, average annual income per capita, percent of the population with four years of college, percent of the population living in an urban area, and percent of families with incomes below the poverty line, explained 26.6% (R2) of the variation in overall hospital discharge rates (p less than 0.001). Moreover, we found that the ability of the model to explain variability was influenced by the type of disease, and that these socioeconomic variables had a consistent effect across the range of DRGs. Finally, we noted that, over the period of 1980 to 1987, socioeconomic factors remained important in explaining hospital use despite the dramatic changes in the delivery of care over this period. CONCLUSION: Socioeconomic factors play a significant role in explaining the observed variation in hospital discharge rates for musculoskeletal diseases. Models utilizing only physician practice variation to account for the population-based differences in discharge rates are overly simplistic. In order to ensure that vulnerable subsets of the population are not harmed by the introduction of cost-containment strategies based on simplistic models, more attention must be paid to the socioeconomic and epidemiologic factors related to hospital use.

Bone Diseases

Association of disease-free survival and percent of ideal dose in adjuvant breast chemotherapy.

The relationship between percent of ideal dose and disease-free survival was examined in 256 Stage II and III patients who participated in a 2-year breast adjuvant chemotherapy trial consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) given postoperatively. When analyzed analogously to previous work, the results confirmed a dose-response relationship: that is, there appeared to be an improved disease-free survival for patients receiving higher doses of adjuvant chemotherapy. The major criticism of such an analysis is its bias. This bias was addressed by considering only patients who were still receiving therapy at 6, 12, and 24 months; then, the dose-response relationship was no longer seen. Although causality cannot be inferred, the apparent differences in disease-free survival among the dose groups can be attributed to recurrences in the first 2 years among patients receiving lower doses of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols

Patterns of surgical and nonsurgical hospital use in Michigan communities from 1980 through 1984.

Hospital discharge rates vary substantially among 60 communities in Michigan. (R2 = 90 percent and R2 = 85 percent of the systematic variance is explained by community effects for nonsurgical and surgical discharges, respectively.) The ranking of communities by discharge rates is stable over a five-year period (Spearman rho = 0.78 for nonsurgical discharges and 0.72 for surgical discharges). Surgical discharge rates decreased substantially (4 percent per year) over this time period, while nonsurgical rates showed no consistent pattern. Communities with exceptional discharge rates showed no substantial or significant regression toward the mean through the five-year study.

Adolescent

Prognostic factors in advanced ovarian carcinoma.

Nineteen factors were analyzed for prognostic significance in a series of 89 women with advanced (stage III or IV) ovarian carcinoma treated with chemotherapy after initial debulking surgery. Seventy-eight of these women received cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) treatment, and 11 received cyclophosphamide initially with Adriamycin and cisplatin administered at the time of recurrence. Median survival and remission duration were 25 and 19 months, respectively. Using survival as an end point, significant prognostic factors in univariate analyses included the total residual mass after debulking (P = .0007), largest residual mass after debulking (P = .0008), and stage (P = .0098). Using remission duration as an end point, significant prognostic factors in univariate analyses included total residual mass after debulking (P = .007) and the largest residual mass after debulking (P = .0020). The prognostic variables were then considered as possible predictors of survival in a multivariate analysis using the Cox proportional hazards model resulting in the following expression: lambda i(t)/lambda o(t) = exp(0.5928 (log TRM - 1.8117) + 0.6450 (stage - 0.3827) + 0.6673 (C4 - 0.4198) - 0.8596 (CAP - 0.8642)), where lambda i(t)/lambda o(t) is the risk of dying for a particular patient compared with the average risk of the entire group; log TRM is the log of the volume of the total residual mass in cm3 plus 1.0; stage = 0 if stage III, 1 if stage IV; C4 = 0 if cytologic grade is 1, 2, or 3 and 1 if grade 4; CAP = 0 if treatment is cyclophosphamide and 1 if CAP. Median survival times of patients with relative risk greater than 1 and less than 1 are 43 and 19 months respectively. If this model is confirmed in a prospective study, then it could be used to assign risk and assess treatment options for similar patients at diagnosis.

Age Factors

A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.

Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.

Actuarial Analysis

Phase I and clinical pharmacological evaluation of 4'-deoxydoxorubicin in patients with advanced cancer.

We have conducted a Phase I and initial clinical pharmacological evaluation of 4'-deoxydoxorubicin (4'-DXDX), administering the drug i.v. on an every 21-day schedule to 60 patients with advanced cancer. Patients were treated at six dosage levels ranging from 10 to 35 mg/sq m. Leukopenia was the dose-limiting toxic effect, and no cardiac, renal, or hepatic toxicity was observed; stomatitis was not seen; and there were no drug-related deaths. Significant alopecia was rare at doses less than 35 mg/sq m, mild nausea and vomiting occurred in one-third of patients at myelosuppressive doses; 12 patients had a transient local urticarial reaction. In the 30 patients with measurable disease, two partial remissions were seen, lasting 5 months in a patient with a nasopharyngeal adenocarcinoma, and 7 months in a patient with endometrial adenocarcinoma. The recommended dose of 4'-DXDX for Phase II studies is 30 mg/sq m in good-risk patients and 25 mg/sq m in moderate-risk or heavily pretreated patients. Pharmacokinetic studies were carried out in ten patients, four of whom received 4'-DXDX at a dose of 10 mg/sq m and six at 30 mg/sq m. Disappearance of 4'-DXDX from plasma was triphasic with a rapid initial phase clearance showing a t1/2 alpha of 1 to 2 min and a prolonged terminal phase with a median t1/2 gamma in excess of 90 h in patients receiving 30 mg/sq m.

Adult