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Biomedical subjects

T R Fleming

Publications and source records attributed to T R Fleming.

At least 19 recordsLinked to original sources
PubMed2000

Survival analysis in clinical trials: past developments and future directions.

The field of survival analysis emerged in the 20th century and experienced tremendous growth during the latter half of the century. The developments in this field that have had the most profound impact on clinical trials are the Kaplan-Meier (1958, Journal of the American Statistical Association 53, 457-481) method for estimating the survival function, the log-rank statistic (Mantel, 1966, Cancer Chemotherapy Report 50, 163-170) for comparing two survival distributions, and the Cox (1972, Journal of the Royal Statistical Society, Series B 34, 187-220) proportional hazards model for quantifying the effects of covariates on the survival time. The counting-process martingale theory pioneered by Aalen (1975, Statistical inference for a family of counting processes, Ph.D. dissertation, University of California, Berkeley) provides a unified framework for studying the small- and large-sample properties of survival analysis statistics. Significant progress has been achieved and further developments are expected in many other areas, including the accelerated failure time model, multivariate failure time data, interval-censored data, dependent censoring, dynamic treatment regimes and causal inference, joint modeling of failure time and longitudinal data, and Baysian methods.

Biometry↗
PubMed2000

Evaluating the safety of interventions for prevention of perinatal transmission of HIV.

Efficient approaches are needed for obtaining reliable insights into the safety, in developing and developed country settings, of interventions for prevention of mother-to-child transmission (MCT) of HIV. A randomized trial designed with an appropriate sample size and adequate duration of follow-up provides a powerful tool for obtaining causal evidence regarding the safety and efficacy of MTC prevention interventions. Such trials are ideal for detecting adverse effects (AEs) that occur in the short or moderate term and with moderate to high frequency. Passive and active surveillance procedures, where practical, can provide valuable insights regarding long-term or rare AEs. Ideally, surveillance procedures should be carefully planned sufficiently early to allow prospective definition and uniform collection of important classes of AEs, enhancing the sensitivity and specificity of these surveillance data.

Anti-HIV Agents↗
PubMed1999

Assessing effects on long-term survival after early termination of randomized trials.

In this paper we present an approach to using historical control data to augment information from a randomized controlled clinical trial, when it is not possible to continue the control regimen to obtain the most reliable and valid assessment of long term treatment effects. Using an adjustment procedure to the historical control data, we investigate a method of estimating the long term survival function for the clinical trial control group and for evaluating the long term treatment effect. The suggested method is simple to interpret, and particularly motivated in clinical trial settings when ethical considerations preclude the long term follow-up of placebo controls. A simulation study reveals that the bias in parameter estimates that arises in the setting of group sequential monitoring will be attenuated when long term historical control information is used in the proposed manner. Data from the first and second National Wilms' Tumor studies are used to illustrate the method.

Bias↗
PubMed1999

Safety and toxicity of nonoxynol-9 gel as a rectal microbicide.

BACKGROUND AND OBJECTIVES: Methods of HIV and STD prevention, which can be controlled by the receptive partner, are a high priority for research and development. Studies on the safety of Nonoxynol-9 (N-9) on the vaginal mucosa have yielded conflicting results. No Phase I study has evaluated the effect of N-9 on the rectal mucosa. GOALS: To assess the safety of 52.5 mg of N-9 in a 1.5-g gel when applied one to four applicators per day to the rectum and penis. STUDY DESIGN: The study included 25 HIV-negative and 10 HIV-positive, monogamous gay male couples in which each partner was exclusively insertive or receptive while using N-9 gel. Each participant served as his own control during placebo gel use compared to during N-9 gel use. Receptive partners underwent anoscopic examination after 1 week of placebo use and after 2, 5, and 6 weeks of N-9 gel use, with rectal biopsies obtained after 1 week of placebo use and after 5 and 6 weeks of N-9 gel use. Insertive partners had safety monitoring after 1 week of placebo use and after 2, 5, and 6 weeks of N-9. RESULTS: No rectal ulcers were detected; superficial rectal erosions were noted in two HIV-negative participants. Abnormal or slightly abnormal histologic abnormalities of rectal biopsies were detected in 31 (89%) receptive participants after N-9 gel use compared to 24 (69%) participants after 1 week of placebo gel use. Meatal ulceration, not caused by herpes simplex virus, was detected in one HIV-negative participant. CONCLUSION: Low-dose N-9 gel was not associated with macroscopic rectal and penile epithelial disruption or inflammation, but histologic abnormalities were commonly observed during N-9 gel as well as during placebo gel use.

Adult↗
PubMed1999

Issues in the design of clinical trials: insights from the trastuzumab (Herceptin) experience.

A guiding objective of phase III clinical trials should be to achieve reliable evaluation of safety and efficacy of interventions in a real-world setting, ie, as the interventions would be delivered in clinical practice. This guiding objective motivates several principles of design. The control regimen should truly reflect standard of care; in turn, one should be reluctant to use placebos that might not be inert or that might adversely impact quality of life. The choice of concomitant therapy should be sufficiently flexible as to allow for treatment options that would be widely representative of routine care. Eligibility criteria should be as inclusive as the intended labeling, specifically excluding only those patients expected to be at high risk for toxicity or have a low likelihood of benefit. Study procedures should be simplified to avoid unnecessary inconvenience to patients and investigators and to reduce trial costs. Clinical end points should be chosen that unequivocally reflect tangible benefit to patients. Experiences from the phase III trial of trastuzumab (Herceptin; Genentech, San Francisco, CA) in metastatic breast cancer, a human immunodeficiency virus/acquired immunodeficiency syndrome trial, and a trial in cardiology will be used to provide additional motivation for several of these principles. These trials provide valuable insights into the challenging issues arising in the design and conduct of clinical trials.

Antibodies, Monoclonal↗
PubMed1998

Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group.

BACKGROUND: Follow-up testing after surgery for colon cancer is recommended principally to identify resectable recurrences, but data on the efficacy of, outcomes of, and optimal strategies for this testing are limited. OBJECTIVES: To determine the relation between follow-up tests and salvage surgery, assess outcomes, and document surgical mortality. DESIGN: Retrospective cohort study. SETTING: A North American multi-institutional trial comparing postoperative chemotherapy plus follow-up with follow-up alone. PATIENTS: 1247 patients with resected stage II and stage III colon cancer. INTERVENTION: The protocol mandated follow-up testing that could be supplemented at the discretion of treating physicians. Indications of recurrent disease were documented. MEASUREMENTS: Recurrence, resectable recurrence, surgical mortality, and survival were studied. RESULTS: 548 patients had recurrence of colon cancer. Salvage surgery was attempted in 222 patients (41%). In 109 patients (20%), curative-intent surgery was done for hepatic recurrence (28 patients), pulmonary metastasis (20 patients), local recurrence (24 patients), or recurrence at other sites (37 patients). Most curative-intent surgical procedures were motivated by follow-up testing (36 patients), elevated carcinoembryonic antigen level (41 patients), or symptoms (27 patients). The median follow-up time after curative-intent surgery exceeded 5 years; the estimated 5-year disease-free survival rate was 23%. A solitary lesion was a favorable prognostic factor. The surgical mortality rate was 2%. Curative-intent resections were done in 15 patients with second primary colorectal cancer; 12 of these patients have survived disease-free. CONCLUSIONS: Second operations for colon cancer that are triggered by follow-up testing or symptoms are common and can result in long-term disease-free survival.

Colonic Neoplasms↗
PubMed1997

Estimating the proportion of treatment effect explained by a surrogate marker.

In this paper, we measure the extent to which a biological marker is a surrogate endpoint for a clinical event by the proportional reduction in the regression coefficient for the treatment indicator due to the inclusion of the marker in the Cox regression model. We estimate this proportion by applying the partial likelihood function to two Cox models postulated on the same failure time variable. We show that the resultant estimator is asymptotically normal with a simple variance estimator. One can construct confidence intervals for the proportion by using the direct normal approximation to the point estimator or by using Fieller's theorem. Extensive simulation studies demonstrate that the proposed methods are appropriate for practical use. We provide applications to HIV/AIDS clinical trials.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Phase II trial of low-dose N-(phosphonacetyl)-disodium L-aspartic acid and high-dose 24-hour infusional 5-fluorouracil in advanced gastric adenocarcinoma. A Southwest Oncology Group study.

N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) followed 24 hours later by a 24-hour infusion of 5-FU (2600 mg/M2) for an initial period of 8 weeks. No objective responses were noted. PALA and 5-FU is inactive against gastric adenocarcinoma at the doses and schedule used in this trial.

Adenocarcinoma↗
PubMed1996

Phase II trial of trimetrexate in advanced esophageal cancer: a southwest oncology group study.

Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily x 5 schedule, every 3 weeks; a starting dose of 12 mg/m2 was used for patients with no prior irradiation, and of 8 mg/m2 for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade > or = 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade > or = 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.

Antimetabolites, Antineoplastic↗
PubMed1995

Phase II study of 5-fluorouracil and folinic acid in the treatment of patients with advanced gastric cancer. A Southwest Oncology Group study.

BACKGROUND: The biochemical modulation of 5-fluorouracil (5-FU) by the reduced folate folinic acid (FA) in the treatment of patients with advanced gastric cancer was examined. METHODS: The Southwest Oncology Group performed parallel randomized Phase II trials of two schedules of 5-FU and FA in 80 patients with advanced gastric cancer. Of 76 analyzable patients, 36 were randomized to receive bolus FA (200 mg/m2, days 1-4) along with continuous infusion 5-FU (1000 mg/m2, days 1-4) and 40 were randomized to receive bolus FA (200 mg/m2, days 1-5) before the bolus 5-FU (375 mg/m2, days 1-5). RESULTS: There were three (8%) partial responses (95% confidence interval [CI] 2%-22%) on the continuous infusion arm. The bolus arm had two (5%) complete responses and six (15%) partial responses for an overall response rate of 20% (95% CI 9%-36%). The median duration of response was 4.6 months for the infusion patients and 16.6 months for the bolus patients. Survival was poor, with median survival of 5 months on both regimens. Gastrointestinal toxicity was substantial, with Grade 3 mucositis observed in 36% of patients on the continuous infusion regimen versus only 10% of patients on the bolus regimen. Grade 3 or higher hematologic toxicity occurred more often in the bolus arm than in the continuous infusion arm (28% vs. 14%, respectively). Two toxic deaths occurred, one related to sepsis the other secondary to coronary insufficiency. CONCLUSIONS: Biochemical modulation of 5-FU by FA using the dose and schedules tested has only modest activity in the treatment of advanced gastric cancer.

Adenocarcinoma↗
PubMed1995

Adjuvant continuous infusion 5-FU, whole-abdominal radiation, and tumor bed boost in high-risk stage III colon carcinoma: a Southwest Oncology Group Pilot study.

PURPOSE: Results of a combined modality adjuvant pilot program of low-dose continuous-infusion 5-fluorouracil, whole-abdominal radiation, and tumor bed boost in patients with colon cancer with involved nodes and serosal involvement are presented. METHODS AND MATERIALS: Forty-one eligible patients with completely resected T3N1-2M0 colon cancer (modified Astler-Coller C2) were treated with 5-fluorouracil (5-FU) at a dose of 200 mg/m2/day by continuous infusion and 30 Gy of concomitant whole-abdominal radiation in 1 Gy fractions. An additional 16 Gy boost to the tumor bed was administered in 1.6 Gy fractions. After completion of combined modality treatment and a 21-day rest period, patients received 4 days of 5-FU at a dose of 1000 mg/m2 by continuous infusion every 28 days for nine cycles. RESULTS: Five-year disease-free and overall survival estimates were 58 and 67%, respectively, for all T3N1-2 patients. Five-year disease-free and overall survival estimates for the 19 patients with four or fewer nodes were both 61%. Five-year disease-free survival and overall survival estimates for the 20 patients with more than four involved nodes were 55% and 74%, respectively (the exact number of involved nodes were unknown for two patients). Disease-free and overall survival estimates for patients treated with 5-FU and radiation compare favorably to the 5-FU plus levamisole arm of the intergroup adjuvant colon study (Int 0035/SWOG 8591) in patients with more than four positive nodes where the 5-year disease-free and overall survival estimates were 35% and 39%, respectively. Disease-free and overall survival estimates for patients with four or fewer nodes in the 5-FU plus levamisole arm of the intergroup study were 64 and 68%, which is not markedly different from results obtained with radiation and 5-FU in the current study. There were no treatment-related fatalities. Seventeen percent of patients had severe and 7% had life-threatening toxicity of any kind. One patient had an acute partial bowel obstruction and two patients had chronic low grade enteritis. CONCLUSION: Continuous infusion 5-FU and whole-abdominal radiation with tumor bed boost should be further investigated in a larger trial of T3N1-2 colon cancer.

Adult↗
PubMed1995

Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report.

OBJECTIVE: To determine the effectiveness of two adjuvant therapy regimens in improving surgical cure rates in stage III (Dukes stage C) colon cancer. DESIGN: Randomized, concurrently controlled clinical trial. SETTING: Major cancer centers, universities, and community clinics affiliated with the North Cancer Treatment Group, the Southwest Oncology Group, and the Eastern Cooperative Oncology Group. PATIENTS: Those who had had curative-intent resections of stage III colon cancer in the previous 1 to 5 weeks. INTERVENTION: Patients were assigned to observation only, to levamisole alone (50 mg orally three times/d for 3 days, repeated every 2 weeks for 1 year), or to this regimen of levamisole plus fluorouracil (450 mg/m2 body surface area intravenously daily for 5 days and then, beginning at 28 days, weekly for 48 weeks). MEASUREMENTS: Rates of cancer recurrence and death. Early- and late-treatment side effects. RESULTS: With all 929 eligible patients able to be followed for 5 years or more (median follow-up, 6.5 years), fluorouracil plus levamisole reduced the recurrence rate by 40% (P < 0.0001) and the death rate by 33% (P = 0.0007). Levamisole reduced the recurrence rate by only 2% and the death rate by only 6%. With few exceptions, toxicity was mild and patient compliance was excellent. No evidence of late side effects was seen. CONCLUSION: Fluorouracil plus levamisole is tolerable adjuvant therapy to surgery; it has been confirmed to substantially increase cure rates for patients with high-risk (stage III) colon cancer. It should be considered standard treatment for all such patients not entered into clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study.

PURPOSE: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. PATIENTS AND METHODS: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. RESULTS: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p = 0.45) and overall survival (p = 0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins > 1 cm, had superior survival compared to cases not meeting these requirements (p < 0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). CONCLUSION: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

Adenocarcinoma↗