Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
D J Sargent
Publications and source records attributed to D J Sargent.
Comparison of artificial neural networks with other statistical approaches: results from medical data sets.
BACKGROUND: In recent years, considerable attention has been given to the development of sophisticated techniques for exploring data sets. One such class of techniques is artificial neural networks (ANNs). Artificial neural networks have many attractive theoretic properties, specifically, the ability to detect non predefined relations such as nonlinear effects and/or interactions. These theoretic advantages come at the cost of reduced interpretability of the model output. Many authors have analyzed the same data set, based on these factors, with both standard statistical methods (such as logistic or Cox regression) and ANN. METHODS: The goal of this work is to review the literature comparing the performance of ANN with standard statistical techniques when applied to medium to large data sets (sample size > 200 patients). A thorough literature search was performed, with specific criteria for a published comparison to be included in this review. RESULTS: In the 28 studies included in this review, ANN outperformed regression in 10 cases (36%), was outperformed by regression in 4 cases (14%), and the 2 methods had similar performance in the remaining 14 cases (50%). However, in the 8 largest studies (sample size > 5000), regression and ANN tied in 7 cases, with regression winning in the remaining case. In addition, there is some suggestion of publication bias. CONCLUSIONS: Neither method achieves the desired performance. Both methods should continue to be used and explored in a complementary manner. However, based on the available data, ANN should not replace standard statistical approaches as the method of choice for the classification of medical data.
Humans↗
A flexible design for multiple armed screening trials.
The goal of a screening trial is to examine several treatments with the intention of selecting one or more treatment(s) for further testing. Such a trial frequently occurs in the phase II setting, with the intention that the selected treatment be formally compared to a standard treatment in a phase III clinical trial. In this framework it is not essential that the very best treatment is definitely selected (such a decision would require a formal phase III trial), rather it is important that a substantially inferior treatment is not selected when a superior treatment exists. The level of evidence required to select a treatment based on this standard is lower than the evidence required to definitively order treatments. This paper introduces a flexible design for such trials, the flexibility coming from the use of a particular decision rule. The proposed rule states that if the observed difference in the success rates of the treatments is larger than some prespecified quantity d, then the treatment with the highest observed success rate is selected. However, if the observed difference is less than or equal to d, other factors may be considered in the selection. The goal of this design is to mirror clinical practice, where a treatment's success probability is often only one of many considerations in determining a treatment recommendation for a particular patient.
Bias↗
A three-outcome design for phase II clinical trials.
The goal of a phase II trial is to make a preliminary determination regarding the activity and tolerability of a new treatment and thus to determine whether the treatment warrants further study in the phase III setting. Phase II clinical trials are typically designed in the hypothesis testing framework with two possible outcomes, either reject the null hypothesis H(0) or reject the alternative hypothesis H(a), based on the observed activity level. However, in cases where the observed activity is "borderline," the decision regarding the future of the agent is not as clear as the prespecified hypothesis test would indicate. In this paper we propose an alternative design that allows for three outcomes: reject H(0), reject H(a), or reject neither. We describe the theoretical properties of this design and illustrate it with several examples. We focus on the clinical implications of the three-outcome design. Control Clin Trials 2001;22:117-125
Clinical Trials, Phase II as Topic↗
A North Central Cancer Treatment Group Phase II trial of 9-aminocamptothecin in previously untreated patients with measurable metastatic colorectal carcinoma.
BACKGROUND: Topoisomerase I inhibitors have demonstrated clinical activity in patients with metastatic colorectal carcinoma. The authors performed a Phase II study to evaluate the objective tumor response rate of 2 different doses and schedules of 9-aminocamptothecin (9-AC) in previously untreated patients with measurable recurrent metastatic colorectal carcinoma. METHODS: Fifty-one patients were registered. One schedule evaluated 9-AC given at 1100 microgram/m(2)/24 hours by continuous infusion for 72 hours along with granulocyte-colony stimulating factor at 5 microgram/kg/day on Days 5 through 12. Another schedule involved 9-AC at 480 microgram/m(2)/24 hours by continuous infusion for 120 hours on Days 1, 8, and 15 given every 4 weeks. RESULTS: Forty-eight of 51 patients (94%) were evaluable (28 patients who received 72-hour infusion and 20 patients who received 120-hour infusion) for response and toxicity. Significant hematologic toxicities were encountered, especially with the 72-hour infusion schedule, in which 43% (12 of 28) and 28% (8 of 28) experienced Grade 4 (National Cancer Institute Common Toxicity Criteria) leukopenia and thrombocytopenia, respectively. Grade 4 neutropenia was encountered in 61% (17 of 28) and 11% (2 of 19) of patients on the 72-hour and 120-hour infusion schedules, respectively. Diarrhea, nausea, vomiting, and hepatotoxicity were troublesome nonhematologic toxicities. Seventy-nine percent (11 of 14) and 57% (4 of 7) of the patients experiencing Grade 3 or 4 nonhematologic toxicity were on the 72-hour infusion schedule. Three patients died of chemotherapy-related toxicity. One response was observed in 48 evaluable patients (2%). CONCLUSIONS: 9-AC did not demonstrate sufficient antitumor activity and had unacceptable toxicity in previously untreated patients with metastatic colorectal carcinoma.
Adult↗
Rapid reporting and review of an increased incidence of a known adverse event.
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Adverse Drug Reaction Reporting Systems↗
Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999.
BACKGROUND: Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. MATERIALS AND METHODS: The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. RESULTS AND CONCLUSIONS: Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). (ABSTRACT TRUNCATED)
Biomarkers, Tumor↗
Statistical issues in tumor marker studies.
CONTEXT: Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. OBJECTIVE: To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. RESULTS: Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. CONCLUSION: Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources.
Biomarkers, Tumor↗
Phase III evaluation of octreotide versus chemotherapy with 5-fluorouracil or 5-fluorouracil plus leucovorin in advanced exocrine pancreatic cancer: a North Central Cancer Treatment Group study.
There continues to be a need for new systemic approaches for the treatment of advanced pancreatic cancer. The purpose of this study was to compare the antitumor activity of the somatostatin analogue octreotide to 5-fluorouracil chemotherapy in a Phase III setting. Eighty-four patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and limited tumor volume were randomized to receive octreotide 200 microg three times daily or 5-fluorouracil with or without leucovorin. After the first 12 patients had been randomized to octreotide, we increased the dose in the remaining patients to 500 microg three times daily. This change was based on early reports in other studies, suggesting that our original dose may not have been effective and that higher doses of octreotide were well tolerated. A planned interim analysis performed after 84 patients were enrolled demonstrated inferior time to progression and survival for the patients randomized to octreotide. Further accrual to the octreotide arm of this protocol was therefore terminated. Octreotide in doses of 200-500 microg three times daily does not delay progression or extend survival in patients with advanced pancreatic cancer compared with treatment with 5-fluorouracil with or without leucovorin.
Adult↗
Phase II study of paclitaxel and cisplatin for advanced urothelial cancer.
PURPOSE: We examined the role of paclitaxel and cisplatin as first line therapy for metastatic urothelial cancer. MATERIALS AND METHODS: A total of 34 patients were enrolled in this study, and all were eligible for treatment and assessable for response. Patients received 135 mg./m.2 paclitaxel intravenously for 3 hours followed by 70 mg./m.2 cisplatin for 2 hours every 3 weeks to a maximum of 6 cycles. RESULTS: Of the patients 70% experienced a major response to treatment, which was partial/regression in 38% and complete in 32%. Toxicity was manageable with no episodes of grade 4 leukopenia or thrombocytopenia. Nonhematological toxicities included primarily nausea, anorexia and neuropathy, which rarely were severe. CONCLUSIONS: This regimen of paclitaxel and cisplatin is effective, safe and convenient to administer in an outpatient setting for advanced urothelial cancer.
Aged↗
Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.
BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P =.02) and time to recurrence (P =.01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P =.02) and time to recurrence (P =.004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P =.006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P =.003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P =. 002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P =.002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.
Adult↗
The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy.
BACKGROUND: Extraprostatic extension (EPE) is an unfavorable prognostic factor in patients with prostate carcinoma. Prior studies have reported the linear extent of EPE measured circumferentially along the edge of the prostate. In this study, the authors defined and evaluated a novel measure of EPE in a large series of radical prostatectomy specimens. These results have important clinical implications in the management of localized prostate carcinoma by brachytherapy and other modalities. METHODS: The authors reviewed the preoperative records and biopsy findings from 376 patients who underwent radical retropubic prostatectomy between September 1991 and June 1993. Whole mount radical prostatectomy specimens were examined, and the location of EPE for each specimen was recorded. The radial EPE distance was measured perpendicular to the edge of the prostate. For specimens with multiple EPE sites, the maximum radial EPE distance was recorded. Established eligibility criteria for prostate brachytherapy were evaluated using these results, with emphasis placed on achieving adequate radiation dose coverage 3-5 mm beyond the capsule or the edge of the prostate. RESULTS: EPE was identified in 105 of 376 specimens (28%) at 248 sites. The radial EPE distance in these specimens had a mean of 0.8 mm (range, 0.04-4.4 mm) and a median of 0.5 mm. Of these 105 patients, the median and mean preoperative prostate specific antigen (PSA) concentrations were 11.8 ng/mL and 17.9 ng/mL, respectively. The mean and range of the Gleason score and prostate volume for all specimens were 6.3 (range, 3-9) and 39 cc (range, 8-294 cc), respectively. In 107 patients who met the selection criteria for prostate brachytherapy eligibility of a PSA level < 10 ng/mL, Gleason score < 7, and gland volume < 60 cc, the maximum and mean radial EPE distances were 0.6 mm and 0.03 mm, respectively. CONCLUSIONS: The radial distance of EPE is an important measure that influences treatment strategies for patients with localized prostate carcinoma. Currently described criteria for the treatment of early stage prostate carcinoma by brachytherapy alone appear satisfactory to ensure effective radiation dose coverage of EPE of prostate tumors. Treating the prostate with a 3-5 mm margin by brachytherapy would encompass all known tumor in approximately 99% of the specimens examined in this study.
Aged↗
Decrease in cranial nerve complications after radiosurgery for acoustic neuromas: a prospective study of dose and volume.
PURPOSE: To determine whether tumor control can be maintained, and cranial nerve complications decreased by reducing the radiosurgical dose to acoustic neuromas. METHODS AND MATERIALS: Forty-two consecutive patients with acoustic neuromas were treated prospectively using an initial standard-dose protocol in which the tumor-margin dose (50% isodose) was 20, 18, and 16 Gy for tumor diameters < or =2 cm, 2.1-3 cm, and 3.1-4 cm, respectively. After analysis of tumor control and complications, the next 40 patients were treated using a reduced-dose protocol in which the tumor-margin dose was 16, 14, and 12 Gy for tumor volumes < or =4.2 cm3, 4.2-14.1 cm3, and > or =14.1 cm3, respectively. RESULTS: Median follow-up was 2.3 years (range 0.1-6) for 80 of 82 patients. The actuarial incidence (Kaplan-Meier) of facial neuropathy at 2 years was 38% (95% confidence interval [CI], 23-53%) for the standard-dose protocol and 8% (95% CI, 0-17%) for the reduced-dose protocol (p = 0.006). Univariate analysis revealed an association between risk of facial neuropathy and use of CT planning, higher radiosurgical dose, and neurofibromatosis, type 2. Multivariate analysis revealed that the only factor associated with increased risk of post-treatment facial neuropathy was a tumor margin dose > or =18 Gy. The incidence of trigeminal neuropathy at 2 years was 29% (95% CI, 15-43%) for the standard-dose protocol and 15% (95% CI, 3-27%) for the reduced-dose protocol (p = 0.17). Univariate analysis revealed an association between maximal tumor diameter and increased risk of trigeminal neuropathy; multivariate analysis revealed no additional statistically significant associations between tumor and dosimetric and patient characteristics and risk of trigeminal neuropathy. Two tumors in the standard-dose protocol required salvage surgery for progression. To date, no tumor in the reduced-dose protocol has shown progression. CONCLUSION: Our analysis suggests that a tumor margin dose of > or =18 Gy is the most significant risk factor for facial nerve complications after acoustic neuroma radiosurgery. Patients receiving a minimal tumor dose of < or =16 Gy are at significantly lower risk for permanent facial neuropathy after radiosurgery. Longer follow-up is required before definitive conclusions can be made about the ultimate rate of tumor control using reduced radiosurgical doses.
Adult↗
Contribution of weather to the seasonality of distal forearm fractures: a population-based study in Rochester, Minnesota.
Distal forearm fractures due to falls were more frequent in the winter (p < 0.0001) among Rochester men and women 35 years of age or older in 1952-89. The winter excess was partially explained by a greater relative risk of distal forearm fractures on days with freezing rain (1.65; 95% CI 1.28-2.13) or snow (1.42; 95% CI 1.17-1.74) among women under 65 years of age and on days with freezing rain (1.63; 95% CI 1.23-2.17) among older women. The greater seasonality of forearm compared with hip fractures is explained by the fact that more of them occur out-of-doors. However, residual effects of season after adjusting for daily weather conditions suggest that other factors may play a role.
Accidental Falls↗
Sample size and design considerations for phase II clinical trials with correlated observations.
Several methods are available for the design of phase II clinical trials with binary endpoints. A primary assumption for most methods is that observations on the endpoint of interest are uncorrelated; however, this assumption is violated if an individual patient provides more than one observation on the endpoint of interest. In such cases, one solution is to use a summary measure for each patient; an alternative solution is to perform an observation-specific analysis using a technique that properly accounts for the correlation. In this paper, we investigate the effect that ignoring correlated observations can have on the design properties of the typical phase II clinical trial. In cases in which an observation-specific analysis is desirable, we propose a simple method that adjusts a standard one- or two-stage phase II design to account for loss of information due to correlated observations. Simulations demonstrate that the method ensures that type I and type II error rate design requirements are met even in the presence of strong correlation. We develop the method in the context of phase II oncology trials, but the method applies readily to other clinical areas in which multiple responses per patient are of interest.
Algorithms↗
Acute treatment-related diarrhea during postoperative adjuvant therapy for high-risk rectal carcinoma.
PURPOSE: The combination of pelvic radiotherapy and 5-fluorouracil-based chemotherapy is associated with an increase in acute gastrointestinal toxicity during rectal adjuvant therapy, most notably an increased incidence of diarrhea. Previous randomized, prospective studies have limited their analysis to presenting rates of severe and life-threatening diarrhea (Grade 3 or greater), and few data are available detailing the extent of mild to moderate diarrhea. To provide baseline data for future studies, we conducted a detailed analysis of diarrhea from a prior clinical trial of adjuvant therapy for rectal cancer. METHODS AND MATERIALS: In a multiinstitutional clinical trial, 204 eligible patients with rectal carcinoma that either was deeply invasive (T3-T4) or involved regional lymph nodes were randomized to receive either postoperative pelvic radiotherapy alone (45 to 50.4 Gy) or pelvic radiotherapy and bolus 5-fluorouracil-based chemotherapy. Toxicity was assessed prospectively. RESULTS: For the 99 eligible patients who received pelvic radiotherapy alone, rates of Grades 0, 1, 2, 3, and 4 diarrhea during treatment were 59, 20, 17, 4, and 0%, respectively. For the 96 eligible patients who received radiotherapy and 5-fluorouracil, the overall rates of grades 0, 1, 2, 3, and 4 diarrhea were 21, 34, 23, 20, and 2%, respectively. The increased rates of diarrhea during adjuvant rectal therapy were manifested across all toxicity levels for patients receiving chemotherapy and pelvic radiotherapy. Of primary clinical importance is the substantial increase in severe or life-threatening diarrhea (Grade 3 or more) (22 vs. 4%,p = 0.001) Additionally, increased rates of any diarrhea and also severe or life-threatening diarrhea were observed in patients who had a low anterior resection compared with those who had an abdominoperineal resection (p < 0.001 and p = 0.006, respectively). CONCLUSION: These results will be of value as a baseline for investigators who want to use treatment toxicity as an end point in cancer control or cancer therapy trials utilizing similar treatment techniques. Patients receiving 5-fluorouracil and pelvic radiotherapy compared with patients receiving pelvic radiotherapy alone and patients with a prior history of a low anterior resection compared with patients who had a prior history of an abdominoperineal resection experienced increased rates of Grades 1 through 4 acute treatment-related diarrhea, and the most important increase occurred as Grade 3 toxicity.
Acute Disease↗
A general framework for random effects survival analysis in the Cox proportional hazards setting.
The use of random effects modeling in statistics has increased greatly in recent years. The introduction of such modeling into event-time analysis has proceeded more slowly, however. Previously, random effects models for survival data have either required assumptions regarding the form of the baseline hazard function or restrictions on the classes of models that can be fit. In this paper, we develop a method of random effect analysis of survival data, the hierarchical Cox model, that is an extension of Cox's original formulation in that the baseline hazard function remains unspecified. This method also allows an arbitrary distribution for the random effects. We accomplish this using Markov chain Monte Carlo methods in a Bayesian setting. The method is illustrated with three models for a dataset with times to multiple occurrences of mammory tumors for 48 rats treated with a carcinogen and then randomized to either treatment or control. This analysis is more satisfying than standard approaches, such as studying the first event for each subject, which does not fully use the data, or assuming independence, which in this case would overestimate the precision.
Animals↗
A flexible approach to time-varying coefficients in the Cox regression setting.
Research on methods for studying time-to-event data (survival analysis) has been extensive in recent years. The basic model in use today represents the hazard function for an individual through a proportional hazards model (Cox, 1972). Typically, it is assumed that a covariate's effect on the hazard function is constant throughout the course of the study. In this paper we propose a method to allow for possible deviations from the standard Cox model, by allowing the effect of a covariate to vary over time. This method is based on a dynamic linear model. We present our method in terms of a Bayesian hierarchical model. We fit the model to the data using Markov chain Monte Carlo methods. Finally, we illustrate the approach with several examples.
Bayes Theorem↗