High-dose chemotherapy for breast cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
D F Heitjan
Publications and source records attributed to D F Heitjan.
Bayesian estimation of cost-effectiveness ratios from clinical trials.
Estimation of the incremental cost-effectiveness ratio (ICER) is difficult for several reasons: treatments that decrease both cost and effectiveness and treatments that increase both cost and effectiveness can yield identical values of the ICER; the ICER is a discontinuous function of the mean difference in effectiveness; and the standard estimate of the ICER is a ratio. To address these difficulties, we have developed a Bayesian methodology that involves computing posterior probabilities for the four quadrants and separate interval estimates of ICER for the quadrants of interest. We compute these quantities by simulating draws from the posterior distribution of the cost and effectiveness parameters and tabulating the appropriate posterior probabilities and quantiles. We demonstrate the method by re-analysing three previously published clinical trials.
Bayes Theorem↗
The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure.
BACKGROUND: Because left ventricular assist devices have recently been approved by the Food and Drug Administration to support the circulation of patients with end-stage heart failure awaiting cardiac transplantation, these devices are increasingly being considered as a potential alternative to biologic cardiac replacement. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial is a multicenter study supported by the National Heart, Lung, and Blood Institute to compare long-term implantation of left ventricular assist devices with optimal medical management for patients with end-stage heart failure who require, but do not qualify to receive cardiac transplantation. METHODS: We discuss the rationale for conducting REMATCH, the obstacles to designing this and other randomized surgical trials, the lessons learned in conducting the multicenter pilot study, and the features of the REMATCH study design (objectives, target population, treatments, end points, analysis, and trial organization). CONCLUSIONS: We consider what will be learned from REMATCH, expectations for expanding the use of left ventricular assist devices, and future directions for assessing clinical procedures.
Heart Failure↗
Volume-outcome relationships in cardiovascular operations: New York State, 1990-1995.
BACKGROUND: It has been known for nearly 20 years that, in cardiovascular operations, a significant inverse relationship exists between clinical outcomes and the volume of procedures performed. Interestingly, this relationship persists 2 decades after it was recognized. OBJECTIVE: The purpose of this study was to examine the relationship between hospital volume and in-hospital deaths in 3 cardiovascular procedures: coronary artery bypass grafting, elective repair of abdominal aortic aneurysms, and repair of congenital cardiac defects. METHODS: The database includes all patients who were hospitalized in New York State during the years 1990 to 1995. Using standard logistic regression techniques, we analyzed the relationship between hospital volume and outcome. RESULTS: No correlation exists between hospital volume and in-hospital deaths in coronary artery bypass grafting. Statewide, 31 hospitals performed 97,137 operations over the 6-year period (overall mortality rate, 2. 75%). By contrast, most of the hospitals statewide (195 of 230 hospitals) performed 9847 elective abdominal aortic aneurysm repairs with an overall mortality rate of 5.5%. In abdominal aortic aneurysm operations, a significant inverse relationship between hospital volume and in-hospital deaths was determined. Sixteen hospitals performed 7199 repairs for congenital cardiac defects. A significant inverse relationship (which was most pronounced for neonates) was found between volume and death. CONCLUSIONS: The importance of these findings lies in the rather striking difference between the volume-outcome relationship found for operations for abdominal aortic aneurysms and congenital cardiac defects and the lack of such a relationship for coronary artery bypass grafting. This observation may be largely explained by the quality improvement program in New York State for bypass operations since 1989. If so, these results have important implications for expanding the scope of quality improvement efforts in New York State.
Adolescent↗
Causal inference in a clinical trial: a comparative example.
Recently there has been much interest in methods for analyzing clinical trials of treatments that are subject to noncompliance. In this paper I study a small, simple dataset from a clinical trial of immunosuppressive therapy in the treatment of multiple sclerosis. I apply and compare a range of methods: the as-randomized (intention-to-treat) analysis, the as-treated analysis, estimates based on a nonignorable selection model, and Rubin's causal model. The results differ substantially even in this small dataset that exhibits modest noncompliance. For this reason, data analysts should be clear about which parameters are of greatest importance in the analysis of a clinical trial.
Azathioprine↗
Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2.
PURPOSE: To determine the survival benefit and cost-effectiveness of screening Ashkenazi Jewish women for three specific BRCA1/2 gene mutations. METHODS: We used a Markov model and Monte Carlo analysis to estimate the survival benefit and cost-effectiveness of screening for three specific mutations in a population in which their prevalence is 2.5% and the associated cancer risks are 56% for breast cancer and 16% for ovarian cancer. We assumed that the sensitivity and specificity of the test were 98% and 99%, respectively, that bilateral prophylactic oophorectomy would reduce ovarian cancer risk by 45%, and that bilateral prophylactic mastectomy would reduce breast cancer risk by 90%. We used Medicare payment data for treatment costs and Surveillance, Epidemiology, and End Results data for cancer survival. RESULTS: Our model suggests that genetic screening of this population could prolong average nondiscounted survival by 38 days (95% probability interval, 22 to 57 days) for combined surgery, 33 days (95% probability interval, 18 to 43 days) for mastectomy, 11 days (95% probability interval, 4 to 25 days) for oophorectomy, and 6 days (95% probability interval, 3 to 8 days) for surveillance. The respective cost-effectiveness ratios per life-year saved, with a discount rate of 3%, are $20,717, $29,970, $72,780, and $134,273. CONCLUSION: In this Ashkenazi Jewish population, with a high prevalence of BRCA1/2 mutations, genetic screening may significantly increase average survival and, depending on costs and screening/treatment strategies, may be cost-effective by the standards of accepted cancer screening tests. According to our model, screening is cost-effective only if all women who test positive undergo prophylactic surgery. These estimates require confirmation through prospective observational studies and clinical trials.
Adult↗
Geographic variations in the rates of operative procedures involving the shoulder, including total shoulder replacement, humeral head replacement, and rotator cuff repair.
BACKGROUND: Although geographic variations in the rates of orthopaedic procedures have been well documented, considerable controversy remains regarding the factors that drive these variations, particularly the role of the availability of orthopaedic surgeons. Moreover, little attention has been specifically focused on variations in the rates of commonly performed shoulder procedures. METHODS: The current study documents state-to-state variations in the rates of total shoulder replacement, humeral head replacement, and rotator cuff repair and examines factors that might account for these variations. The regional incidences of these three procedures were analyzed with use of the Health Care Financing Administration Medicare database (MEDPAR, 1992). The rates were age-adjusted, and variations were measured with use of high:low ratios, variation coefficients, and systematic components of variation. Potential causes of variation were analyzed with use of Spearman and partial correlations as well as with Poisson regression. RESULTS: Rates for the three procedures that were studied varied from one state to another by as much as tenfold. Humeral head replacement had the lowest rate of variation according to all three measures. All three procedures were performed less often in states that were more densely populated. With the numbers available for study, no consistent, significant relationship was found between the density of orthopaedists and shoulder surgeons and the rates of any procedure. CONCLUSIONS: The striking variations that were noted for these commonly performed procedures showed that there is a clear need for well designed clinical research to further define the factors that account for the variations and to examine the effectiveness and appropriate indications for the procedures.
Aged↗
Treatment of head and neck cancer.
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Combined Modality Therapy↗
Rapid reduction in blood flow to the rat ventral prostate gland after castration: preliminary evidence that androgens influence prostate size by regulating blood flow to the prostate gland and prostatic endothelial cell survival.
BACKGROUND: Androgenic steroids regulate the development and size of the mammalian prostate gland. The mechanism(s) for this growth control might involve a direct effect on prostate cell proliferation and survival as well as more complex effects on the tissue environment supporting nourishment and oxygenation. In this study, we evaluated an animal model of androgen action on the prostate, the rat ventral prostate gland, to determine whether acute androgen withdrawal, by means of castration, might alter the primary blood flow to the prostate gland and for the effects of castration on prostatic endothelial cell viability. METHODS: Groups of rats studied included intact control males, males that had been surgically castrated, or males that received a sham-surgical castration. Relative blood flow (RBF) to the rat ventral prostate glands and rat bladders were measured at 18 and 24 hr after castration or sham castration using a fluorescent microsphere infusion technique. Thin sections from fixed and embedded rat ventral prostate glands obtained from unoperated or 12-hr castrated rats were analyzed by the TUNEL immunostaining technique to microscopically identify and quantify apoptotic epithelial, stromal, and endothelial cells. RESULTS: RBF to the rat ventral prostate was reduced by 38%, at 18 hr after castration when compared with intact or sham-operated rats and by 45% at 24 hr after castration (P=0.038 unoperated/0.025 sham operated). In contrast, RBF to the bladder was not significantly different between any of the groups in the 24-hr castrate experiment. TUNEL staining analysis of ventral prostate tissues obtained from 12-hr castrated rats showed only rare TUNEL-positive epithelial cells similar to the control tissue but significantly increased TUNEL labeling for endothelial and other ventral prostate stromal cells. CONCLUSIONS: Castration resulted in a rapid and significant reduction of blood flow to the mature rat ventral prostate gland that was not seen in the bladder. This reduction precedes the appearance of apoptosis in the epithelial cells of the tissue but more coincided with the appearance of TUNEL-positive prostate vascular endothelial and stromal cells, suggesting that androgens support the survival of cells in the vascular and stromal compartment of the rat prostate as well as in the prostatic epithelium. These preliminary data support the concept that androgen action on the prostate might involve primary regulation of prostate blood flow and prostate vascular cell vitality.
Androgens↗
Changes in biochemical disease-free survival rates as a result of adoption of the consensus conference definition in patients with clinically localized prostate cancer treated with external-beam radiotherapy.
PURPOSE: The optimal definition of biochemical recurrence of prostate cancer after definitive radiotherapy remains elusive. Different institutions have developed their own definitions, and a consensus conference (CC) sponsored by the American Society for Therapeutic Radiology and Oncology has recently proposed another definition. This study compares the definition previously used at our institution with the definition proposed by the CC. METHODS: Two hundred and eight patients were treated for localized prostate cancer with conformal external-beam radiotherapy between 1989-1993 at our institution and followed for at least 24 months. Patients were categorized as failures according to our institutional definition and the CC definition. Our definition (CPMC) required two increases in serum prostate specific antigen (PSA) over at least a 3-month period with a final value of at least 1 ng/ml or a single value resulting in clinical intervention. The CC definition required three consecutive increases in PSA. This was modified to also consider those patients with one or two increases leading to clinical intervention as failures. Differences in the failure rates between the two definitions were evaluated and factors influencing these differences were explored. In an additional analysis, CC was modified such that patients with one or two PSA increases were censored at the time of the PSA prior to the increases (CC-II), rather than at the last PSA (CC). The median follow-up time was 31 months. RESULTS: There were 36 fewer failures according to CC (n = 96) compared with CPMC (n = 132) (p < 0.001). Twenty cases called failures by CPMC subsequently had a decrease in PSA ("false failures"). The other 16 patients have had two increases in PSA, but are awaiting their next follow-up visit to obtain a third PSA ("pending failures"). Analysis of factors predicting "pending failures" showed Gleason score to be the sole predictor of this change in status in multivariate analysis (p = 0.03) with patients with lower-grade tumors being more likely to change status (Gleason 2-6: 15% vs. Gleason 7-10: 1%). On the other hand, "false failures," compared to true failures, had a lower mean PSA nadir (1.7 ng/ml vs. 7.0 ng/ml, p < 0.001) and significantly smaller mean increases in PSA (1st increase: 0.6 ng/ml vs. 3.4 ng/ml, p = 0.006; 2nd increase: 0.4 ng/ml vs. 4.8 ng/ml, p = 0.002). In 85% (17 of 20) of these patients, at least one of the increases was < or = 0.3 ng/ml compared with 44% (42 of 96) of the true failures (p = 0.0008). CC-II resulted in a small decrease in BDFS rates compared with CC, but did not affect the overall difference between CC and CPMC. A modified definition that defines failure as two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases would result in a "false" failure rate of only 3% (3 of 99) and identify 56% (54 of 96) of the true failures after only two PSA increases. CONCLUSION: The CPMC definition of two PSA increases can falsely identify patients as failures, particularly if the increases in PSA are small (i.e., < or = 0.3 ng/ml). The CC definition requiring three increases in PSA can falsely identify patients as disease-free when the time to failure is long relative to the follow-up time. We propose a that a definition that combines aspects of both definitions (two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases) may be a better definition of biochemical failure.
Consensus Statements as Topic↗
Biologic classification as an alternative to anatomic staging for clinically localized prostate cancer: a proposal based on patients treated with external beam radiotherapy.
OBJECTIVES: The prognostic significance of clinical stage in patients with prostate cancer who are treated with external beam radiotherapy is unclear. This study evaluates multiple pretreatment factors, including clinical stage, to determine which are the best prognostic factors, and develops a classification system based on these factors. METHODS: All 249 evaluable patients with clinically localized adenocarcinoma of the prostate treated with definitive conformal external beam radiotherapy without androgen deprivation at our institution between 1989 and 1993 were analyzed. Clinical stage, serum PSA level, Gleason score, race, and history of transurethral resection of the prostate (TURP) were evaluated for their ability to predict biochemical disease-free survival (BDFS). Factors predictive of BDFS were then used to construct a classification system. The classification system was then analyzed for its ability to predict BDFS, distant metastases, local recurrence, and clinical disease free survival in univariate and multivariate analyses. Median follow-up was 27 months. RESULTS: Gleason score and PSA predicted BDFS in multivariate analysis (both P <0.0001), whereas clinical stage, race, and history of a TURP did not. These two biologic factors were combined into a four-level classification system. This classification system was analyzed together with Gleason score and PSA and was found to be the only predictor of BDFS on multivariate analysis (P <0.0001). In addition, this classification system was the only predictor of distant metastases in multivariate analysis (P <0.0001). CONCLUSIONS: The classification system derived herein based on the biologic factors of Gleason score and serum PSA levels is the sole predictor of distant metastases and biochemical recurrence for patients treated with definitive conformal external beam radiotherapy for clinically localized prostate cancer. This classification system may be useful when comparing competing therapies and stratifying patients in clinical trials, but requires validation from other institutions and other therapies prior to its widespread use.
Adenocarcinoma↗
Urinary continence after radical prostatectomy: the Columbia experience.
PURPOSE: We determine the incidence of urinary incontinence after radical prostatectomy and the factors that may influence this incidence. MATERIALS AND METHODS: A total of 615 men who underwent radical retropubic prostatectomy performed by 1 of us (C. A. O. or M. C. B.) at our center between 1988 and 1996 were mailed a questionnaire regarding preoperative and postoperative voiding habits. Data collected included preoperative and postoperative continence status, interval to postoperative continence status, associated urinary symptoms, willingness to undergo radical prostatectomy again if given the chance and additional postoperative procedures. Patient age, date of surgery and duration of followup were also noted. RESULTS: Of the 615 patients 480 (78.2%), a mean of 62.6 years old, responded to the questionnaire. Mean followup was 3.3 years (range 1 to 8.8). Continence was defined as no regular use of pads. Of the respondents 91.8% were considered continent, 92% had achieved final continence status by 6 months postoperatively, 10.6% required 1 or more additional procedures related to urinary control and 90% would undergo surgery again if given the chance. Of the patients considered incontinent postoperatively 44% had associated urgency. Age, year of surgery and preoperative urinary leakage or post-void dribbling had no significant impact on postoperative continence status. CONCLUSIONS: Using an anonymous self-administered questionnaire we found an 8.2% incontinence rate after radical prostatectomy. This rate was similar to that in large, single institutional studies in which physician interview was used to elicit responses but significantly less than that in a national sample of Medicare patients also given a self-administered questionnaire. With minimal potential for adverse consequences in the hands of experienced surgeons, radical prostatectomy remains well tolerated with excellent patient satisfaction.
Aged↗
Bayesian interim analysis of phase II cancer clinical trials.
Many popular sequential phase II clinical trial designs optimize some criterion subject to constraints on the error probabilities at null and alternative values of the response rate. Such designs may forfeit optimality if one fails to conduct analyses strictly according to plan. Moreover, a decision, say, to accept the experimental therapy at one interim analysis does not necessarily imply the same degree of evidence as the same decision when made at another analysis. I propose an alternative design that bases decisions on the ability of the data to persuade either a sceptic or an enthusiast. My standard of evidence, called the persuasion probability, is based on the Bayesian posterior probability that the experimental treatment is superior to the standard. The design calls for termination at any interim analysis at which an observed persuasion probability exceeds its critical value. I investigate the standards of evidence implied by some frequentist procedures and calculate frequentist properties of persuasion-probability designs.
Acute Disease↗
Detection of circulating prostate carcinoma cells via an enhanced reverse transcriptase-polymerase chain reaction assay in patients with early stage prostate carcinoma. Independence from other pretreatment characteristics.
BACKGROUND: Circulating prostate cells can be detected in the venous blood of patients with clinically localized prostate carcinoma by applying reverse transcriptase-polymerase chain reaction (RT-PCR) techniques using primers specific for the prostate specific antigen (PSA) gene. This study evaluates whether the detection of circulating cells correlates with established prognostic factors, treatment, and pathologic stage. METHODS: Two hundred and twenty-seven patients with clinically localized adenocarcinoma of the prostate had an RT-PCR assay performed as part of their staging evaluation. No treatment decisions were made on the basis of the RT-PCR results. Of these, 156 patients were treated with radical prostatectomy (RP) and 71 with radical external beam radiotherapy (EBRT). Forty-eight patients were treated with hormonal therapy prior to RP (n = 39) or EBRT (n = 9). The prognostic factors analyzed for their relationship to RT-PCR were clinical stage, pretreatment serum PSA levels, Gleason score of the biopsy specimen, and Gleason score of the surgical specimen. An analysis of the relationship between treatment and RT-PCR results was also performed. Multivariate logistic regression analysis of predictors of RT-PCR positivity was performed as well. In addition, univariate and multivariate analyses of predictors of pathologic stage, including RT-PCR, were performed. RESULTS: Sixty-one patients (26.9%) had a positive RT-PCR assay. There was no relationship between clinical stage, pretreatment PSA, biopsy Gleason score, or surgical Gleason score and RT-PCR positivity. In univariate analysis, patients treated with RP had a higher rate of RT-PCR positivity than patients treated with EBRT (P = 0.054). However, in multivariate logistic regression analysis no factor, including treatment with RP, was a significant predictor of RT-PCR positivity. RT-PCR and pretreatment PSA predicted pathologic stage in univariate and multivariate analyses (P < 0.0001 and P = 0.002, respectively). CONCLUSIONS: The detection of circulating prostate cells using RT-PCR occurs in approximately 25% of early stage prostate carcinoma patients and is independent of other established prognostic factors. In addition, a positive RT-PCR assay is a strong predictor of pathologic upstaging in patients with clinically organ-confined disease.
Analysis of Variance↗
Modelling repeated-series longitudinal data.
We present a model for describing repeated-series longitudinal data, that is, longitudinal data where each unit may yield multiple series of the same variable. Such data arise commonly in ophthalmologic studies, where one obtains measurements on the same variable for the right and left eyes at each clinic visit. We model the mean as a linear function of predictors, and assume that the error term is a sum of a random subject effect and a vector AR(1) process. We fit the model by maximum likelihood and assess the adequacy of the error assumptions by an extension of the empirical semivariogram. We apply our model for data from a clinical trial comparing two treatments for ocular hypertension and glaucoma, with intra-ocular pressure as the primary endpoint. Results suggest that autocorrelation within and between eyes is a significant feature of the variance model. Standard errors depend critically on the variance assumption.
Algorithms↗
Pretreatment prostate specific antigen doubling times: use in patients before radical prostatectomy.
PURPOSE: We determined whether pre-radical prostatectomy prostate specific antigen (PSA) doubling time could predict pathological stage at radical prostatectomy or PSA failure postoperatively. We also sought to compare PSA doubling times from men with prostate cancer treated with radical prostatectomy to a group treated with radiation therapy. MATERIALS AND METHODS: Detailed followup was available for 150 patients with clinically localized prostate cancer who underwent radical prostatectomy from January 1993 to August 1995. PSA doubling time was calculated for all patients with 3 or more pre-radical prostatectomy PSA levels using linear regression. We assessed the association between PSA doubling time and PSA failure, pathologic stage at radical prostatectomy, final PSA before treatment and Gleason score. We compared our PSA doubling time values and distribution to a published series of patients with prostate cancer who had undergone radiation therapy. RESULTS: A total of 56 patients had 3 or more PSA values before treatment. Median followup was 17.3 months. PSA doubling time did not correlate with PSA failure, final PSA or Gleason score, but it did with pathological stage at radical prostatectomy (p = 0.0035 for positive margins, p = 0.025 for positive seminal vesicles). Our PSA doubling time and PSA failure rates did not differ from the radiation therapy population with similar followup times. CONCLUSIONS: Although studies from the radiation literature have shown PSA doubling time to be useful in predicting PSA failure after treatment for prostate cancer, our results do not confirm this finding. We did find a correlation with pathologic stage at radical prostatectomy, and so longer followup with more patients may confirm this in the future. We also found no significant differences in PSA doubling time between our patients and a group treated with radiation. At least for this parameter, patients with prostate cancer referred for radical prostatectomy and radiation therapy may be similar.
Aged↗
Harvest quality and factors affecting collection and engraftment of CD34+ cells in patients with breast cancer scheduled for high-dose chemotherapy and peripheral blood progenitor cell support.
The use of CFU-GM and CD34+ cell enumeration for assessing harvest quality and factors affecting peripheral blood progenitor cell (PBPC) harvest and engraftment were investigated in 45 women with high-risk and metastatic breast cancer scheduled for dose-intensive cyclophosphamide, thiotepa, and carboplatin (CTCb). PBPC were mobilized with standard breast cancer regimens or cyclophosphamide (1.5 g/m2) and 5 micrograms/kg/day G-CSF and used together with G-CSF for hematopoietic support post-CTCb. There was a significant correlation between peripheral blood CD34+ cells/microliter and harvest CD34+/kg (r = 0.73, p < 0.0001) and between harvest CFU-GM and CD34+ cells/kg (r = 0.5, p < 0.0001). CFU-GM clonogenic assays were of no clinical use beyond that of CD34+ cell enumeration, with the latter allowing for real-time decisions regarding harvesting. Multiple stepwise regression identified the number of prior chemotherapy cycles as the only significant clinical predictor of CD34+ cell yield. For 34 patients proceeding to CTCb with PBPC support, multiple stepwise regression identified as the best predictors for engraftment CFU-GM and CD34+ cells/kg for neutrophils and CFU-GM, CD34+ cells/kg, and the number of prior cycles of chemotherapy for platelets, respectively. A threshold dose of 1 x 10(6) CD34+ cells/kg, obtained in 87% of these heavily pretreated breast cancer patients, was adequate to ensure engraftment within 15 days. There was no significant difference in length of hospital stay or blood product use between patients receiving 1-2.5 x 10(6) CD34+ cells/kg and greater than 2.5 x 10(6) CD34+ cells/kg, although median time to engraftment of neutrophils (9 days versus 8 days, p = 0.007) and platelets (12 days versus 9 days, p = 0.006) was significantly longer. The established threshold of > or = 1 x 10(6) CD34+ cells/kg will allow for more confident consideration of using aliquots of this threshold dose for hematopoietic support in sequential high-dose regimens inclusive of CTCb.
Adult↗
Annotation: what can be done about missing data? Approaches to imputation.
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Models, Statistical↗