PubMed Health⌕ Search

Biomedical subjects

R Chappell

Publications and source records attributed to R Chappell.

At least 19 recordsLinked to original sources
PubMed2001

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.

Adult↗
PubMed2001

Is alpha/beta for prostate tumors really low?

PURPOSE: Brenner and Hall's 1999 paper estimating an alpha/beta value of 1.5 Gy for prostate tumors has stimulated much interest in the question of whether this ratio (of intrinsic radiosensitivity to repair capacity) is much lower in prostate tumors than in other types of tumors that proliferate faster. The implications for possibly treating prostatic cancer using fewer and larger fractions are important. In this paper we review updated clinical data and present somewhat different calculations to estimate alpha/beta. METHODS AND MATERIALS: Seventeen clinical papers published from 1995 to 2000 were reviewed to obtain estimates of biochemical control from radiotherapy alone using external beam, I-125 implants, or Pd-103 implants. The focus was on intermediate risk patients. Three methods of estimating alpha/beta were employed. First, a simple two-step graphical comparison of isoeffective doses from external beam and implant modalities was made, to see which value of alpha/beta predicted the observed identity of biologic effect. Second, the same data were subjected to Direct Analysis (maximum likelihood estimation), from which an estimate of alpha/beta and also of the T(12) of repair of sublethal damage in the tumors (both with confidence intervals) were obtained. Third, preliminary clinical data comparing two different sizes of high-dose boost doses were analyzed in which significantly different bNED was observed at 2 years. RESULTS: The second method gave the definitive result of alpha/beta = 1.49 Gy (95% CI 1.25-1.76) and T(12) = 1.90 h (95% CI 1.42-2.86 h). The first method gave a range from 1.4 to 1.9 Gy and showed that if mean or median dose were used instead of prescribed dose, the estimate of alpha/beta would be substantially below 1 Gy. The third method, although based on early follow-up, was consistent with low values of alpha/beta in the region of 2 Gy or below. The estimate for T(12) is the first value reported for prostate tumors in situ. CONCLUSIONS: All the estimates point toward low values of alpha/beta, at least as low as the estimates of Brenner and Hall, and possibly lower than the expected values of about 3 Gy for late complications. Hypofractionation trials for intermediate-risk prostatic cancer appear to be indicated.

Algorithms↗
PubMed2001

A new approach to dose escalation in non-small-cell lung cancer.

PURPOSE: To describe the radiobiological rationale for dose-per-fraction escalation in non-small-cell lung cancer (NSCLC) and to devise a novel Phase I scheme to implement this strategy using advanced radiotherapy delivery technologies. METHODS AND MATERIALS: The data from previous dose escalation trials in NSCLC are reanalyzed to establish a dose-response relationship in this disease. We also use data relating prolongation in treatment time to survival to compute the potential doubling time for lung tumors. On the basis of these results, and using a Bayesian model to determine the probability of pneumonitis as a function of mean normalized lung dose, a dose-per-fraction escalation strategy is developed. RESULTS: Standard approaches to dose escalation using 2 Gy per fraction, five fractions per week, require doses in excess of 85 Gy to achieve 50% long-term control rate. This is partly because NSCLCs repopulate rapidly, with a 1.6% per day loss in survival from prolongation in overall treatment time beyond 6 weeks, and a cell doubling time of only 2.5 to 3.3 days. A dose-per-fraction escalation strategy, with a constant number of fractions, 25, and overall time, 5 weeks, is projected to produce tumor control rates predicted to be 10%-15% better than 2 Gy per fraction dose escalation, with equivalent late effects. This Phase I clinical study is divided into three parts. Step 1 examines the feasibility of the maximum breath-holding technique and junctioning of tomotherapy slices. Step 2 treats 10 patients with 30 fractions of 2 Gy over 6 weeks and then reduces duration to 5 weeks using fewer but larger fractions in 10 patients. Step 3 will consist of a dose-per-fraction escalation study on roughly 50 patients, maintaining 25 fractions in 5 weeks. Bayesian methodology (a modification of the Continual Reassessment Method) will be used in Step 3 to allow consistent and efficient escalation within five volume bins. CONCLUSION: A dose-per-fraction escalation approach in NSCLC should yield superior outcomes, compared to standard dose escalation approaches using a fixed dose per fraction, for a given level of pneumonitis and late toxicity. Highly conformal radiotherapy techniques, such as intensity modulated radiotherapy (IMRT) and helical tomotherapy with its adaptive capabilities, will be necessary to achieve significant dose-per-fraction escalation without unacceptable lung and esophageal morbidity.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Retrospective analysis on treating nasopharyngeal carcinoma with accelerated fractionation (6 fractions per week) in comparison with conventional fractionation (5 fractions per week): report on 3-year tumor control and normal tissue toxicity.

BACKGROUND AND PURPOSE: To assess the therapeutic gain achieved by accelerated fractionation for non-keratinizing/undifferentiated nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: During January 1994 to October 1997, 325 patients were treated to a total dose of 66 Gy in 33-37 fractions: 167 (irradiated before mid-January 1996) with 5 daily fractions (CF) and subsequent 158 with 6 daily fractions (AF) per week. Their median treatment times were 46 and 39 days, respectively. Additional boost to parapharyngeal extension had been given to 181 and Cisplatin-based chemotherapy to 57 patients (24 concurrent with radiotherapy). RESULTS: The AF group had significantly higher progression-free rate than the CF group (74 vs. 63% at 3 years, P=0.02 by the log-rank test). However, the difference in disease-specific survival (86 vs. 80%, P=0.39) and overall survival (81 vs. 78%, P=0.9) did not reach statistical significance. Strongly significant improvement in local failure-free rate was achieved for patients with T3-4 tumors (87 vs. 62%, P<0.01). Multivariate analyses showed that fractionation was an independent significant factor for overall progression: hazard ratio=0.63, 95% confidence interval: 0.41-0.98, P=0.04. Among the 268 patients treated with radiotherapy alone, those treated by AF had significantly higher incidence of acute reaction grade > or=3 (72 vs. 13%, P<0.01). However, all patients completed the scheduled dose without excessive prolongation, and no significant increase in late complications was observed (20 vs. 15% at 3 years, P=0.19). CONCLUSIONS: The current analyses suggested that acceleration to 6 daily fractions per week could significantly improve the progression-free rate for NPC without excessive late toxicity. Improvement in local control was confined to T3-4 tumors.

Adult↗
PubMed2001

Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin.

PURPOSE: The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites. EXPERIMENTAL DESIGN: In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood vessel formation in nonneoplastic tissue was evaluated by creating a skin wound site on the arm with a punch biopsy device. The wound site was sampled with a second biopsy after a 7-day interval. This sequential biopsy procedure was performed prior to and 3 weeks after initiation of endostatin treatment. Vascular density, endothelial cell kinetics, and blood vessel maturity were determined in tumor and skin wound samples. The ultrastructure of tumor blood vessels was examined by electron microscopy. RESULTS: As expected, the tumors were of variable vascular density. Skin wounding induced a vascular granulation tissue containing a high percentage of proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistically significant difference was detected between pretreatment and treatment samples of tumors and of skin wounds for any of the parameters tested. CONCLUSIONS: Endostatin treatment was not associated with any recognizable vascular changes in tumor samples and did not perturb wound healing at the doses and the treatment schedule used.

Angiogenesis Inhibitors↗
PubMed2000

Total biological effect on late reactive tissues following reirradiation for recurrent nasopharyngeal carcinoma.

PURPOSE: To assess the additional damage of normal tissues attributable to reirradiation and the magnitude of partial recovery following the initial course. METHODS AND MATERIALS: Symptomatic late complication rates (excluding xerostomia) in 3635 patients receiving one course (Group 1) and 487 patients receiving two courses of external radiotherapy (Group 2) for nasopharyngeal carcinoma were retrospectively analyzed and compared. RESULTS: Group 2 had significantly lower actuarial complication-free survival rates than Group 1: 48% versus 81% at 5 years. The post-retreatment incidence was significantly affected by biologically effective dose (BED) (assuming an alpha/beta ratio of 3 Gy) of the first course: hazard ratio (HR) = 1.04 per Gy(3) (p = 0.01), but only marginally by that of the second course: HR = 1.01 per Gy(3) (p = 0.06). If the summated BED was taken as the dose unit, it was estimated that a total BED of 143 Gy(3) would induce a 20% incidence at 5 years, while the corresponding dose projected from Group 1 was 111 Gy(3). The gap effect was insignificant in the overall analyses, but a trend of decreasing risk with increasing interval was observed in patients with gap > or = 2 years: HR = 0.86 per year (p = 0.07). CONCLUSION: The major determinant of post-retreatment complication is the severity of damage during the initial course. The sum of total doses tolerated is higher than that expected with a single-course treatment, suggesting occurrence of partial recovery (particularly in those reirradiated after an interval of 2 years or more).

Adolescent↗
PubMed2000

Sequential designs for phase I clinical trials with late-onset toxicities.

Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.

Anticarcinogenic Agents↗
PubMed2000

The use of patient registers to estimate migration.

This article presents information discussed at the recent regional seminars on population statistics. It describes a new data source for estimating internal migration between local and health authorities in England and Wales, discusses the way that the data have been collected and processed, and how limitations in the raw data have been addressed. It then goes on to explain the way that the new internal migration estimates have been used in the calculation of population estimates for local and health authorities. This is a change to the method of estimating migration in the calculation of population estimates.

Censuses↗
PubMed1999

Staging of nasopharyngeal carcinoma: from Ho's to the new UICC system.

The independent significance of different tumor factors in 4,514 patients with undifferentiated or non-keratinizing carcinoma of the nasopharynx irradiated at the Queen Elizabeth Hospital during 1976-1985 were analyzed retrospectively. Multivariate analyses showed that the most significant primary factors included cranial nerve palsy, erosion of base of skull and oropharynx. For tumors within the nasopharynx, there was no difference in survival between those with involvement of 1 site vs. more than 1 sites. Patients with cranial nerve palsy had significantly worse prognosis than those with bony erosion alone. Although the nodal characteristics (size, level of extension, fixation, laterality and multiplicity) were inter-related, their independent impact all reached statistical significance. However, the criteria used currently could be simplified: laterality should be revised to unilateral vs. bilateral, level to upper-mid vs. lower neck, and size to < or =6 cm vs. >6 cm. Grouping of N2 together with N3 into Stage IV was inappropriate as the former had significantly better prognosis. Our findings, together with review of the publications, provided clinical data for developing the current UICC staging system for nasopharyngeal carcinoma. Such major revision resulted not only in better distinction of hazards, but also more even distribution of cases between different stages.

Adolescent↗
PubMed1999

Recurrent nasopharyngeal carcinoma: the puzzles of long latency.

PURPOSE: To study the peculiar characteristics of relapses with long latency following radical treatment for nasopharyngeal carcinoma. METHODS AND MATERIALS: 847 patients with nasopharyngeal recurrence were retrospectively studied, focusing on the independent effects of latency on different outcome aspects and its relationship with other prognostic factors. RESULTS: The proportion of recurrence with latency <2 years (Group A), 2-<5 years (Group B), and 25 years (Group C) were 52%, 39%, and 9%, respectively. A higher proportion of Group C originated from patients with node-negative early primary, but fewer of them were still confined within the nasopharynx at detection of recurrence. There was no significant difference in the choice of salvage modality, but among those reirradiated, more of Group C were treated with external beams to a higher dose. The difference in local salvage rate was not statistically significant, but the 5-year distant failure-free rates of the 3 groups were 57%, 67%, and 83%, respectively; and the corresponding disease-specific survival (DSS) were 14%, 20%, and 35%. Multivariate analysis confirmed the independent significance of latency in predicting distant failure (hazard ratio = 0.81 per year, p < 0.01) and cancer deaths (hazard ratio = 0.90 per year, p < 0.01). CONCLUSIONS: Nasopharyngeal recurrence with long latency showed different natural behavior: the prognosis was significantly better due to lower risk of distant failure.

Adolescent↗
PubMed1999

Caution on the use of altered fractionation for nasopharyngeal carcinoma.

Randomized trials and overviews on the value of altered fractionation for head and neck cancers are reviewed. Attention is drawn to the unexpectedly high incidence of temporal lobe necrosis incurred in patients with nasopharyngeal carcinoma. Preliminary analyses suggest that incomplete repair is likely to be the major factor, even a 6-h interfraction interval may be inadequate if substantial volumes of nervous tissues are included within the target volume.

Carcinoma↗
PubMed1999

A note on inconsistency of NPMLE of the distribution function from left truncated and case I interval censored data.

We show that under reasonable conditions the nonparametric maximum likelihood estimate (NPMLE) of the distribution function from left-truncated and case 1 interval-censored data is inconsistent, in contrast to the consistency properties of the NPMLE from only left-truncated data or only interval-censored data. However, the conditional NPMLE is shown to be consistent. Numerical examples are provided to illustrate their finite sample properties.

Adult↗
PubMed1999

Modeling daily and subdaily cycles in rat sleep data.

We developed a statistical model for rat sleep-wake behavior over the 24-hour day; this model could be used for animals exposed to shorter cycles of light and dark conditions. Rat behavior was classified either as "wake" or "sleep," as determined by analysis of electrophysiological data. The proposed model consists of three parts: the first two explain cyclic effects relating to the lighting conditions, whereas the last part reflects any acyclic effect. Hypothesis tests were conducted on the magnitude of the parts. The model also accounts for correlated errors.

Activity Cycles↗
PubMed1998

Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma.

PURPOSE: To study the relative effects of different radiation factors on temporal lobe necrosis (TLN) and predictive accuracy of different biological equivalent models. METHODS AND MATERIALS: Consecutive patients (1008) treated radically with four different fractionation schedules during 1976-1985 for T1 nasopharyngeal carcinoma were retrospectively analyzed. All were irradiated by megavoltage photons using the same technique. Their age ranged from 18-84 years, and 92% of patients had complete follow-up. The fractional dose to inferomedial parts of both temporal lobes ranged from 2.5-4.2 Gy, total dose 45.6-60 Gy, and overall time 38-75 days. RESULTS: Despite a lower total dose of 50.4 Gy, the 621 patients irradiated with 4.2 Gy per fraction had a significantly higher incidence of temporal lobe necrosis than the 320 patients treated to 60 Gy with 2.5 Gy per fraction: the 10-year actuarial incidence being 18.6% vs. 4.6%, p < 0.001. Multivariate survival analysis showed that fractional effect (product of total dose and fractional dose) was the most significant factor: p = 0.0022, hazard ratio (HR) = 1.044 per Gy2. Overall time and age were both insignificant. The alpha/beta ratio calculated from our data was 2.9 Gy (95% CI: -1.8, 7.6 Gy). Biological effective dose (BED(Gy3)), neuret, and brain tolerance unit all showed strongly significant correlation with the necrotic rate (p < 0.001), and gave similar predictions. The hazard of TLN increased by 14% per Gy3, and it was estimated that 64 Gy (at conventional fractionation of 2 Gy daily) would lead to a 5% necrotic rate at 10 years. Not only did the nominal standard dose (NSD) show the lowest value in terms of log likelihood and standardized HR, but its predictions on TLN deviated markedly from clinically observed rates. CONCLUSION: Fractional effect is the most significant factor affecting cerebral necrosis, and overall time has little protective effect. The BED formula, assuming an alpha/beta ratio of 3 Gy, is an appropriate model for predicting late effects on the temporal lobe, and NSD could give seriously misleading predictions.

Adolescent↗
PubMed1998

A nonparametric estimator of survival functions for arbitrarily truncated and censored data.

It is well-known that the nonparametric maximum likelihood estimator (NPMLE) may severely under-estimate the survival function with left truncated data. Based on the Nelson estimator (for right censored data) and self-consistency we suggest a nonparametric estimator of the survival function, the iterative Nelson estimator (INE), for arbitrarily truncated and censored data, where only few nonparametric estimators are available. By simulation we show that the INE does well in overcoming the under-estimation of the survival function from the NPMLE for left-truncated and interval-censored data. An interesting application of the INE is as a diagnostic tool for other estimators, such as the monotone MLE or parametric MLEs. The methodology is illustrated by application to two real world problems: the Channing House and the Massachusetts Health Care Panel Study data sets.

Epidemiologic Methods↗