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Biomedical subjects

S L George

Publications and source records attributed to S L George.

At least 37 records · Page 2Linked to original sources
PubMed1998

An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B.

A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.

Acute Disease↗
PubMed1998

Statistical reviewing policies of medical journals: caveat lector?

OBJECTIVE: To describe the current policies regarding statistical review of clinical research in biomedical journals. DESIGN: Cross-sectional survey. PARTICIPANTS: Editors of biomedical journals that publish original clinical research. MEASUREMENTS: General policies on statistical review, types of persons used for statistical reviewing, compensation of statistical reviewers, percentage of articles subject to such review, percentage of time statistical review makes an important difference, journal circulation, and selectivity. MAIN RESULTS: Of 171 journals, 114 (67%) responded to the survey. About one third of journals had policies that guaranteed statistical review for all accepted manuscripts. In approximately half of the journals, articles were sent for statistical review at the discretion of the editor. There was some evidence that statistical review policies differed between journals of different circulation size. In journals in the top quartile of circulation (> 25,000) the probability of definitely having a statistical review before an acceptance decision was 52%, but it was only 27% in journals in the lower three quartiles (p = .09). The probability of a statistical consultant on staff ranged from 31% in the bottom quarter, to 58% in the middle two, to 82% in the highest quarter (p < .001). Editors judged that statistical review resulted in an important change in a manuscript about half of the time. CONCLUSIONS: Except in the largest circulation medical journals, the probability of formal methodologic review of original clinical research is fairly low. As readers and researchers depend on the journals to assess the validity of the statistical methods and logic used in published reports, this is potentially a serious problem. This situation may exist because the cost of such statistical review can be considerable, and because finding appropriate reviewers can be difficult. It may also exist partly because editors or publishers may not regard such review as important. The professions of medical publishing, statistics, epidemiology, and other quantitative disciplines should work together to address this problem.

Cross-Sectional Studies↗
PubMed1996

Reducing patient eligibility criteria in cancer clinical trials.

PURPOSE: To discuss patient eligibility criteria in phase III cancer clinical trials in the larger setting of the complexity of these trials, to review the various reasons for imposing restrictive eligibility requirements, to discuss the problems caused by these requirements, to argue that these requirements should be greatly relaxed in most cancer clinical trials, to provide some guiding principles and practical suggestions to facilitate such a relaxation, and to give an example of how eligibility requirements were reduced in a recent clinical trial in acute lymphocytic leukemia. METHODS: Implicit and explicit reasons for including eligibility criteria in clinical trials are reviewed. Safety concerns and sample size issues receive special attention. The types of problems restrictive eligibility criteria cause with respect to scientific interpretation, medical applicability, complexity, costs, and patient accrual are described. RESULTS: A list of three items that each eligibility criterion should meet in order to be included is proposed and applied to a recent trial in acute lymphocytic leukemia. CONCLUSION: Phase III clinical trials in cancer should have much broader eligibility criteria than the traditionally restrictive criteria commonly used. Adoption of less restrictive eligibility criteria for most studies would allow broader generalizations, better mimic medical practice, reduce complexity and costs, and permit more rapid accrual without compromising patient safety or requiring major increases in sample size.

Clinical Trials, Phase III as Topic↗
PubMed1995

Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B.

BACKGROUND: Elderly patients with primary acute myelogenous leukemia (AML) are less likely to enter remission than younger adults, in part because of a higher mortality rate related to severe myelosuppression. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to shorten the duration of neutropenia and decrease infectious complications when administered after chemotherapy to patients with lymphomas and solid tumors. METHODS: We randomly assigned 388 patients 60 years of age or older who had newly diagnosed primary AML to receive placebo or GM-CSF (5 micrograms per kilogram of body weight per day intravenously over a period of six hours) in a double-blind manner, beginning the day after the completion of three days of daunorubicin (45 mg per square meter of body-surface area per day) and seven days of cytarabine (200 mg per square meter per day by continuous intravenous infusion). If leukemia cells persisted in the marrow three weeks after the initiation of chemotherapy, further daunorubicin (two days) and cytarabine (five days) were administered. GM-CSF or placebo was given daily until the neutrophil count was at least 1000 per cubic millimeter, there was evidence of the regrowth of leukemia, or severe toxic effects attributable to the study infusion occurred. Patients who had a complete remission were then randomly assigned to receive one of two intensification regimens. RESULTS: Of 388 patients (median age, 69 years), 193 were randomly assigned to receive GM-CSF and 195 to placebo. The rate of complete remission was 51 percent (95 percent confidence interval, 44 to 59 percent) among those assigned to GM-CSF and 54 percent (95 percent confidence interval, 47 to 61 percent) among those assigned to receive placebo (P = 0.61). The reasons for failure (early death, death during marrow hypoplasia, and persistent leukemia), the incidence of severe or lethal infection, and the incidence of the regrowth of leukemia (2 percent overall) were similar in the two groups. The median duration of neutropenia was slightly shorter (P = 0.02) in the patients who received GM-CSF (15 days) than in those who received placebo (17 days), but the clinical importance of this result was minimal because the growth factor failed to lower the treatment-related mortality rate or improve the rate of complete remission. CONCLUSIONS: GM-CSF, in the dose and schedule we used, does not stimulate the regrowth of leukemia, but it also does not decrease the severe myelosuppressive consequences of initial chemotherapy or improve the response rate in patients 60 years of age or older with primary AML. It should not be recommended for use in such patients.

Aged↗
PubMed1995

Granulocyte-macrophage colony-stimulating factor as adjunct therapy in relapsed lymphoid malignancy: implications for economic analyses of phase III clinical trials.

With the increasing concern over the high cost of health care, policy makers have incorporated economic analyses into phase III clinical trials as the randomized clinical trials can provide important information on the efficacy and potential cost-effectiveness of new pharmaceutical agents. Economic analyses of single-hospital experience during phase III trials of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy for high dose chemotherapy with autologous stem cell support found significant shortening of neutropenia with GM-CSF at each hospital, but shortened hospitalization (and lower costs) at only two of three hospitals. In this study, we added data from three additional hospitals and found that the 103 patients who received GM-CSF had, on average, 5.7 days shorter durations of severe neutropenia than the 95 patients who received placebo (p < 0.0001) and 3.4 days shorter in hospitalization (p = 0.06). However, the duration of hospitalization, the primary determinant of health care costs, was shorter for GM-CSF patients in only four of the six centers and the duration of hospitalization of placebo patients was shorter at the other two centers. Careful analyses must be carried out when phase III clinical trial results are used to derive estimates of cost-effectiveness of new pharmaceutical agents. The interpretation of economic analyses of phase III clinical trials raises issues related to the perspective of the investigators, study design, collection of data on resource utilization, learning curve effects and generalizability of the results to other settings.

Antineoplastic Agents↗
PubMed1995

Free-riding and the prisoner's dilemma: problems in funding economic analyses of phase III cancer clinical trials.

PURPOSE: Both economic and clinical data on new agents are important to policy-makers who approve pharmaceuticals for widespread use. Randomized clinical trials have been used to evaluate both clinical results and total medical costs associated with new agents. With new expensive pharmaceutical agents, early assessments of economic benefit have taken on greater importance to physicians and patients. Who should provide financial support to these integrated economic and clinical analyses in clinical trials? Here we describe issues that hinder funding of economic analyses and propose potential support mechanisms. RESULTS: The Cancer and Leukemia Group B (CALGB), a large, national cooperative group of academic and community hospitals in the United States, designed a non-small-cell lung cancer (NSCLC) treatment trial to compare two widely used supportive care regimens that varied 20-fold in cost. One important objective of this trial was to compare the cost-effectiveness of the two regimens. While funding for the clinical trial was supported by grants from the National Cancer Institute and the pharmaceutical companies involved in the trial, no specific funding agency was willing and/or able to provide financial support for the economic analyses. After 2 years of planning, the clinical trial was retracted when the funding for the economic analyses could not be secured. The prisoner's dilemma, individual reluctance to support a common social good, explains the lack of funding. CONCLUSION: Economic theory predicts difficulties in evaluating cost-effectiveness of new pharmaceuticals and reluctance to support economic analyses of clinical trials. Economic analyses will require new sources of funds that will not take scarce resources from clinical trials groups. Options for funding include a new federal agency, coordinated work by existing agencies, or academic centers for economic analysis.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia.

Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras-positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

Adult↗
PubMed1994

Subjective health status of single homeless people in Sheffield.

A census of single homeless people was carried out over a single 12-hour period in Sheffield. Places of residence of homeless people were identified by local workers with homeless people. Participants completed a questionnaire designed to provide data relating to their demography, employment history, contact with welfare agencies, social status, prison history, past and family medical history, contact with health services, perceived health status as measured by the Nottingham Health Profile, and anxiety and depression measured using the Foulds Delusions Symptoms States Inventory/State of Anxiety and Depression DSSI/sAD. Three hundred and seventy-nine single homeless individuals were contacted. Reliable data were available on 340. The population was heterogeneous with respect to perceived health status, but it was significantly worse than a standard London population on all dimensions. Those with a self-reported history of psychiatric illness had a significantly worse perceived health status on all dimensions than those without such a history. Those reporting a history of admission to psychiatric hospital had a significantly worse status in two dimensions: mobility, reflecting greater age, and more significantly social isolation, consistent with findings in other de-institutionalised populations. Anxiety and depression, measured using the Foulds sAD scale, was raised in all groups in the study, but did not differentiate between those with and without a self-reported psychiatric history, or between those with and without a self-reported history of psychiatric admission. This suggests that these symptoms are a result rather than a cause of homelessness, and that a broad social solution to mental illness in homeless people is needed in addition to specific medical interventions.

Adult↗
PubMed1994

Who are the homeless?

To describe the demographic, social and medical morbidity and usage of health services of the population of single homeless individuals in Sheffield, a census was carried out over a 12-hour period at sites which homeless people frequent, as identified by those who work with the homeless. These sites included Salvation Army hostels, reception centres, probation day centres, voluntary organisation hostels, and cheap bed and breakfast accommodation. Data were collected by means of a self-administered questionnaire. A total of 340 single homeless individuals were studied, constituting 80-90% of the single homeless population of Sheffield, as estimated by field workers. The population was younger than those of earlier studies and contained a higher proportion of females (14%). One-fifth of the population had been homeless for less than six months, and 60% had been at their present lodging for less than six months. The population has a higher proportion of both ex-prisoners (49%) and ex-inmates of psychiatric hospitals (36%). Over a quarter admit to a history of alcoholism, and 9% to a history of drug abuse; 65% of the population are registered locally with a GP, and 53% of the population see their GP. Those who are more likely to use an Accident and Emergency Department are less socially integrated and more likely to be alcoholic. This study of the single homeless highlights a need for social change to reduce poverty, provide cheap available housing and provide support for disadvantaged groups.

Adult↗
PubMed1994

Statistical considerations and modeling of clinical utility of tumor markers.

The proper assessment of potential tumor markers in the screening, diagnosis, prognosis, and monitoring of neoplastic diseases depends on careful attention to general principles of good design and analysis of scientific studies, as well as to some specific statistical principles to avoid erroneous conclusions. Published reports on tumor markers should be evaluated critically with these principles in mind. It is well known that statistical problems exist in the medical literature despite the peer review process. In addition, attention to these principles in the design of studies of tumor markers can help ensure their accuracy and validity and avoid the common pitfalls.

Biomarkers, Tumor↗
PubMed1993

Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583.

We investigated whether recombinant alpha 2b interferon (r alpha 2bIFN) would reduce the proportion of bone marrow Philadelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients daily with r alpha 2bIFN at 5 x 10(6)IU/m2 subcutaneously. Patients with complete remission, partial remission, or partial hematologic remission received treatment until progression; those with progressive disease were taken off study and observed for survival. Sixty-three (59%) of the patients achieved at least a partial hematologic remission (24 complete remissions and 39 partial remissions). The median time to response for the 63 responders was 3.4 months, with a median duration of remission of 52 months and with 81% of responders continuing in remission beyond 12 months. The median survival for the 107 patients was 66 months. Of 78 patients with cytogenetic follow-up data, 31 (40%) achieved a partial cytogenetic response (n = 17) or a complete cytogenetic response (n = 14). The percentage of cytogenetic responders among all patients was 29% (31 of 107 patients). The median time to first cytogenetic response was 9 months. A major dose reduction of r alpha 2bIFN (> or = 50%) was required at some time during treatment in 38% of patients, 26% required 10% to 49% dose reductions, and 36% had minor dose reductions of < or = 10%. No association was observed between dose received and the attainment of a cytogenetic response. None of the usual prognostic factors (sex, race, performance status, weight loss, time from diagnosis to treatment, hepatosplenomegaly, age, symptoms, hemoglobin, or platelet, blast, basophil, or white blood cell count) were significantly related to survival. These data provide confirmation that major cytogenetic responses to prolonged administration of subcutaneous r alpha 2bIFN occur in 20% to 38% (95% confidence interval) of chronic-phase Ph-positive patients. Although it is hypothesized that patients achieving major cytogenetic responses to r alpha 2bIFN should have prolonged remission duration and survival compared with nonresponders, analyses of the effect of cytogenetic responders by both "landmark" and time-dependent covariate techniques fail to provide statistically significant evidence for an effect of cytogenetic response on remission duration or survival. This may be due in part to an effect size insufficiently large to be detected with the number of patients treated in this study. Thus, confirmation of remission duration or survival benefit, if any, of r alpha 2bIFN therapy in Ph-positive chronic-phase CML must await the outcome of randomized trials comparing IFN with conventional agents.

Adolescent↗
PubMed1993

Skin melanoma. Cured fraction and survival time as functions of thickness, site, histologic type, age, and sex.

BACKGROUND: Previously, nonparametric or semiparametric methods have been used to determine the relationship of various prognostic covariates with survival of skin cancer. Unfortunately, these methods do not readily distinguish between factors that modulate cure and those that modulate survival time among uncured patients. METHODS: The multivariate lognormal model can be used to detect the association of cured fraction and median survival time with specific prognostic covariates. This model was applied to survival data from 2004 patients with skin melanoma using the following prognostic covariates: thickness, site, and histologic type of the tumor and sex and age of the patient. RESULTS: This analysis revealed that a low cured fraction was associated with thick lesions and location other than trunk or extremity, whereas a short median survival time was associated with thick lesions and tumor located on the trunk. Advanced age was highly associated only with short median survival time. CONCLUSION: The lognormal survival model offers insight into the biology of skin melanoma by distinguishing the roles played by likelihood of cure and survival time. The differential associations of various covariates with these two parameters suggest that biologic mechanisms that govern cure are not identical to those that govern survival time.

Age Factors↗
PubMed1993

Cumulative minutes with T90 greater than Tempindex is predictive of response of superficial malignancies to hyperthermia and radiation.

PURPOSE: To better define thermal parameters related to tumor response in superficial malignancies treated with combined hyperthermia and radiation therapy. METHODS AND MATERIALS: Patients were randomized to receive one or two hyperthermia treatments per week with hyperthermia given during each week of irradiation. Hyperthermia was given for 60 min with treatments begun within 1 hr following irradiation. Power was increased to patient tolerance or normal tissue temperature of 43.0 degrees C. Irradiation was generally given 5 times per week with doses prescribed to normal tissue tolerance (generally 24-70 Gy at 1.8-2.5 Gy per fraction). Multipoint thermometry was used with temperatures obtained every 5 min. RESULTS: One hundred eleven individual treatment fields containing 1 or more tumor nodules were completely evaluable. The complete and overall response rates were 46% and 80%, respectively. Forty-one percent of all treatment fields (51% of responding lesions) remained controlled at 2 years. Multivariate analysis revealed that the cumulative minutes that the temperature achieved by 90% of the measured tumor sites (T90) was > or = 40.0 degrees C, tumor histology, tumor volume, and radiation dose were significantly associated with complete tumor response. The complete response rate was not significantly affected by the number of hyperthermia treatments given per week. The incidence of clinically significant complications was low. CONCLUSIONS: These results support the usefulness of the cumulative minute system in describing time-temperature relationships. The significance of thermal variables with regard to tumor response strongly supports the contention that hyperthermia can be a useful adjunct to irradiation for the local control of cancer.

Adult↗
PubMed1993

Sensitivity of hyperthermia trial outcomes to temperature and time: implications for thermal goals of treatment.

PURPOSE: In previous work we have found that the cumulative minutes of treatment for which 90% of measured intratumoral temperatures (T90) exceeded 39.5 degrees C was highly associated with complete response of superficial tumors. Similarly, the cumulative time for which 50% of intratumoral temperatures (T50) exceeded 41.5 degrees C was highly associated with the presence of > 80% necrosis in soft tissue sarcomas resected after radiotherapy and hyperthermia. In the present work we have calculated the time for isoeffective treatments with T90 = 43 degrees C and T50 = 43 degrees C, respectively, using published thermal isoeffective dose formulae. The purpose of these calculations was to determine the sensitivity of treatment outcome to variations in thermal isoeffective dose. METHODS AND MATERIALS: The basis for the calculations were the thermal parameters and treatment outcomes in three patient populations: 44 patients with moderate or high grade soft tissue sarcoma treated preoperatively with hyperthermia and radiation; 105 patients with superficial tumors treated with hyperthermia and radiation, and 59 patients with deep tumors treated with hyperthermia and radiation. RESULTS: The thermal dose values calculated are strongly associated with outcome in multivariate logistic regression analysis. Simple dose-response equations result from the analysis, and we use these equations to assess the sensitivity of outcome upon variations in thermal dose. This information, in turn, allows us to estimate the number of patients required in Phase II and III trials of hyperthermia and radiation therapy. CONCLUSIONS: For regimens of 5 to 10 hyperthermia treatments, improvements in median T90 (superficial tumors) and T50 (deep tumors) parameters by 1.2-1.5 degrees C could result in response rates high enough (compared to radiotherapy alone) to justify Phase III trials. A similar improvement in response rates would require an increase in overall duration of treatment by a factor of 3 to 5. This would be difficult to achieve while also avoiding thermal tolerance induction. Achieving these temperature goals may be possible with improvements in hyperthermia technology. Alternatively, there may be ways to increase the sensitivity of cells to temperatures that can be achieved currently, such as pH reduction or chemosensitization.

Combined Modality Therapy↗
PubMed1993

A survey of monitoring practices in cancer clinical trials.

This paper reports the results of a survey of data monitoring practices of the 12 clinical co-operative groups in cancer sponsored by the National Cancer Institute in the United States. Most of these co-operative groups conduct a large number of active clinical trials in a wide variety of cancers. The number of active phase III trials in 1991 was 244 with nearly 24,000 patients entered on these trials. The survey instrument used in this paper was modified from one originally developed by Geller and Stylianou, supplemented by questions on the responsibilities of data monitoring committees based on Hawkins. Topics covered included general policies and procedures on the monitoring of clinical trials in these groups as well as specific questions on the responsibilities and operational procedures of formal data monitoring committees. Although formal statistical stopping rules are almost always employed in cancer trials in these co-operative groups, use of a formal data monitoring committee is a relatively new, but increasing practice. For a variety of economic and practical reasons, the members of data monitoring committees for cancer trials are rarely independent of the study participants.

Clinical Trials as Topic↗
PubMed1993

Sample size requirements and length of study for testing interaction in a 2 x k factorial design when time-to-failure is the outcome [corrected].

This paper provides equations for calculating the sample size necessary to test an interaction effect in an 2 x k factorial design when time-to-failure is the outcome of interest. The results are a direct extension of those used by George and Desu and Makuch and Simon who provide sample size requirements for comparing two and k treatment groups, respectively. Duration of a clinical trial concerned with an interaction is calculated using the results of Rubinstein, Gail, and Santner. The results in the present paper can also be used to investigate the impact that an unforeseen interaction has on the power to detect a treatment main effect. This impact can be substantial, even for moderate interactions.

Aspirin↗
PubMed1993

Is there consensus on the placement of older adults?

In implementing Caring for People, local authorities and health authorities must decide the most appropriate source of provision of long-stay residential care for older adults. A review of the planning and funding arrangements introduced by Caring for People was conducted, referenced by professional opinion, to find how far a consensus on the above could be achieved.

Aged↗