Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease.
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Biomarkers↗
Biomedical subjects
T R Fleming
Publications and source records attributed to T R Fleming.
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↗
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↗
Monitoring clinical trials.
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Clinical Protocols↗
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↗
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↗
Surrogate end points in clinical trials: are we being misled?
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Clinical Trials, Phase II as Topic↗
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↗
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↗
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↗
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↗
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↗
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↗
The data and safety monitoring board and acquired immune deficiency syndrome (AIDS) clinical trials.
The urgency of the Acquired immune deficiency syndrome (AIDS) epidemic has mandated that multiple therapeutic approaches be developed and that these approaches be evaluated through clinical trials. To oversee these trials, the National Institute of Allergy and Infectious Diseases (NIAID) has created three large clinical trial programs monitored by a Data and Safety Monitoring Board (DSMB). For each clinical trial, this Board uses a standardized approach employing contemporary biostatistical, medical, and ethical principles. The DSMB is responsible for reviewing interim data on clinical trial performance, treatment safety and efficacy, and overall study progress. If interim results provide convincing evidence of either excessive adverse effects or significant treatment benefit, the DSMB may recommend early termination of the trial to the NIAID and the study investigators. The responsibility, organization, and operating procedures of this DSMB are presented and illustrated through three clinical trials sponsored by NIAID and monitored by the Board. The rationale and operational model for the DSMB may be a useful example for the development of similar review processes in other HIV clinical trial settings.
Advisory Committees↗
A randomized trial of two schedules of trimetrexate versus 5-fluorouracil in advanced colorectal cancer: a Southwest Oncology Group study.
Trimetrexate (TMQ), a non-classical folate antagonist, was studied in a randomized controlled trial in patients with advanced colorectal cancer and without prior chemotherapy. Patients were randomly assigned to one of three treatments: TMQ at 200 mg/m2 i.v. q 2 weeks, TMQ at 12 mg/m2 i.v. daily x 5 or 5-fluorouracil (5-FU) at 15 mg/kg i.v. weekly. Overall response rates were: 6% (four partial responses in 71 patients, 95% CI of 2-14%) for q 2 week TMQ, 0% (zero of 29, 95% CI of 0-29%) for daily x 5 TMQ and 18% (two complete and nine partial responses in 62 patients, 95% CI of 9-30%) for 5-FU. Median survival estimates were 10.3 months for the q 2 week TMQ schedule, 8.7 months for the daily x 5 TMQ schedule and 13.6 months for the 5-FU schedule. Grade < or = 3 toxicities were significantly more common with TMQ. TMQ does not appear to have significant antitumor activity against colorectal cancer.
Aged↗
Statistical issues in the design of HIV vaccine trials.
HIV vaccine trials present significant challenges related to trial endpoints, vaccine efficacy measurement, and the role of nonvaccine interventions. Infection is a valid endpoint for detecting sterilizing immunity. But if the vaccine prevents AIDS without preventing infection, infection may be a misleading surrogate. Appropriate endpoints must be defined for other mechanisms of vaccine action. Direct, indirect, behavioral, and biological effects all determine vaccine efficacy. False security among HIV-vaccine recipients may make negative behavioral effects an important component of vaccine performance. Both biological potency and a more comprehensive program effectiveness should be measured. These goals may require unblinded designs or community randomization. Nonvaccine interventions are currently the only HIV-prevention strategy. Support for larger scale implementation requires more rigorous evaluation that is less dependent on self-reported behavioral changes. The vaccine trial cohorts provide a unique opportunity to cost-effectively evaluate behavioral interventions.
AIDS Vaccines↗
Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer.
PURPOSE: To determine the effectiveness of fluorouracil plus levamisole administered postoperatively to patients with resected stage II (Dukes' B2) colon cancer. PATIENTS AND METHODS: This randomized controlled clinical trial (INT-0035) was performed by National Cancer Institute-sponsored cancer clinical trials cooperative groups. Patients were assigned to observation only or to fluorouracil (450 mg/m2 intravenously [IV] daily for 5 days and, beginning at 28 days, weekly for 48 weeks) plus levamisole (50 mg orally three times daily for 3 days repeated every 2 weeks for 1 year). Cancer recurrence, survival, and treatment side effects were assessed. RESULTS: Three hundred eighteen eligible patients were analyzed with a median follow-up time of 7 years. Fluorouracil plus levamisole reduced the recurrence rate by 31%, although this trend was not statistically significant (P = .10). A total of 87 patients died: 43 on observation and 44 on fluorouracil plus levamisole. Disparity between effects on recurrence rate and overall survival is partially explained by a higher rate of non-colon cancer-related deaths on fluorouracil plus levamisole (15 v seven) and by the effects of salvage surgery with curative intent. Of seven patients with recurrence who were rendered disease-free by salvage surgery, six were on the observation arm. As was observed in patients treated with fluorouracil plus levamisole for stage III disease, toxicity was acceptable and compliance was excellent. CONCLUSION: Fluorouracil plus levamisole is tolerable and accepted as standard surgical adjuvant therapy for patients with stage III colon cancer, but the data from this study in stage II patients suggest a decreased relapse rate without a significant improvement in survival.
Adenocarcinoma↗
Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study.
PURPOSE: A variety of fluorinated pyrimidine-based regimens for the treatment of disseminated colorectal cancer have been presented in the medical literature. The Southwest Oncology Group designed a screening trial of seven regimens of fluorouracil (5-FU) to assess efficacy and toxicity afforded by biochemical modulation or schedule variations. PATIENTS AND METHODS: Six hundred twenty patients were entered into this trial between August 1989 and January 1993. Eligible patients were classified as having recurrent or disseminated disease that was measurable or nonmeasurable. All eligible patients were evaluated for toxicity and survival; patients with measurable disease were evaluated for response according to standard criteria. RESULTS: No regimen achieved a higher response rate than single-agent bolus 5-FU. Eighty-four percent of patients have been monitored until death. The median survival time for the entire cohort is 14 months. Survival hazards ratios showed a positive trend in favor of the unmodulated infusion regimens, while high-grade toxicities occurred more frequently in the 5-FU bolus arms. The major high-grade toxicities were granulocytopenia and diarrhea. CONCLUSION: In this trial, no regimen provided substantial improvement relative to 5-FU bolus or single-agent therapy for either response or survival in the treatment of disseminated colorectal cancer. The single-agent infusion regimens demonstrated the most encouraging results with a favorable toxicity profile and a 2-month longer survival duration than 5-FU bolus therapy.
Adult↗