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David P Dearnaley

Publications and source records attributed to David P Dearnaley.

29 records · Page 2Linked to original sources
PubMed2004

Questionnaire based quality assurance for the RT01 trial of dose escalation in conformal radiotherapy for prostate cancer (ISRCTN 47772397).

BACKGROUND AND PURPOSE: In order to ensure the validity of the outcome of the Medical Research Council's 'RTO1 trial' of dose escalation in conformal radiotherapy for prostate cancer it was considered important that the quality of treatment delivery should meet an adequate standard across all contributing centres. A questionnaire was therefore devised to ensure that all aspects of the planning and delivery process were adequately covered. PATIENTS AND METHODS: The questionnaire considered each step in the planning and delivery process and drew the attention of the participants to the specific requirements of the trial. Before entering patients into the trial each participating centre had to complete the questionnaire and an outlining exercise (reported elsewhere). RESULTS: It was not practicable to define a detailed universally acceptable protocol for the whole process of delivery of conformal radiotherapy, not least because of the different equipment available for planning and treatment in different centres. The questionnaire identified some areas of difference in practice between centres where there may be a need for the development of a consensus as to best practice, particularly in the area of patient set-up. Occasionally it was necessary to follow up responses to questions that had been misunderstood or inadequately answered, but in most cases these issues proved to be easily resolved. CONCLUSIONS: The questionnaire proved to be a useful self-assessment tool as well as enabling the quality assurance group to ensure that the standards of the trial were being met. Subsequent follow-up visits confirmed the usefulness and validity of this self assessment process.

Adult↗
PubMed2003

A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial).

BACKGROUND: The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression-free survival (BPFS) times among men with bone metastases from prostate cancer. METHODS: Between June 1994 and July 1998, 311 men who were starting or responding to first-line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate (2080 mg/day) or placebo for a maximum of 3 years. The primary endpoint of the trial was symptomatic BPFS. Secondary endpoints included overall survival, treatment toxicity, and change in World Health Organization (WHO) performance status. Time-to-event data were analyzed using the log-rank chi-square test and Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Baseline characteristics were balanced across the two groups. After a median follow-up of 59 months, the sodium clodronate group showed statistically nonsignificant better symptomatic BPFS (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.61 to 1.02; P =.066) and overall survival (HR = 0.80, 95% CI = 0.62 to 1.03; P =.082) than the control group. Patients in the clodronate group were less likely to have a worsened WHO performance status (HR = 0.71, 95% CI = 0.56 to 0.92; P =.008). However, the clodronate group reported more gastrointestinal problems and increased lactate dehydrogenase levels and required more frequent modification of the trial drug dose (HR for any adverse event = 1.71, 95% CI = 1.21 to 2.41; P =.002). Results of subgroup analyses suggested that clodronate might be more effective the sooner after diagnosis of metastatic bone disease it is started. CONCLUSION: These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted.

Administration, Oral↗
PubMed2003

A model-based method for the prediction of whole-body absorbed dose and bone marrow toxicity for 186Re-HEDP treatment of skeletal metastases from prostate cancer.

In high-activity rhenium-186 hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment of bone metastatic disease from prostate cancer the dose-limiting factor is haematological toxicity. In this study, we examined the correlation of the injected activity and the whole-body absorbed dose with treatment toxicity and response. Since the best response is likely to be related to the maximum possible injected activity limited by the whole-body absorbed dose, the relationship between pre-therapy biochemical and physiological parameters and the whole-body absorbed dose was studied to derive an algorithm to predict the whole-body absorbed dose prior to injection of the radionuclide. The whole-body retention of radioactivity was measured at several time points after injection in a cohort of patients receiving activities ranging between 2,468 MBq and 5,497 MBq. The whole-body absorbed dose was calculated by fitting a sequential series of exponential phases to the whole-body time-activity data and by integrating this fit over time to obtain the whole-body cumulated activity. This was then converted to absorbed dose using the Medical Internal Radiation Dose (MIRD) committee methodology. Treatment toxicity was estimated by the relative decrease in white cell (WC) and platelet (Plt) counts after the injection of the radionuclide, and by their absolute nadir values. The criterion for a treatment response was a 50% or greater decrease in prostate-specific antigen (PSA) value lasting for 4 weeks. Alkaline phosphatase (AlkPh), chromium-51 ethylene diamine tetra-acetate ((51)Cr-EDTA) clearance rate and weight were measured before injection of the radionuclide. The whole-body absorbed dose showed a significant correlation with WC and Plt toxicity ( P=0.005 and 0.003 for the relative decrease and P=0.006 and 0.003 for the nadir values of WC and Plt counts respectively) in a multivariate analysis which included injected activity, whole-body absorbed dose, pre-treatment WC and Plt baseline counts, PSA and AlkPh values, and the pre-treatment Soloway score. The injected activity did not show any correlation with WC or Plt toxicity, but it did correlate with PSA response ( P=0.005). These results suggest that the administration of higher activities would be likely to generate a better response, but that the quantity of activity that can be administered is limited by the whole-body absorbed dose. We have derived and evaluated a model that estimates the whole-body absorbed dose on an individual patient basis prior to injection. This model uses the level of injected activity and pre-injection measurements of AlkPh, weight and (51)Cr-EDTA clearance. It gave good estimates of the whole-body absorbed dose, with an average difference between predicted and measured values of 15%. Furthermore, the whole-body absorbed dose predicted using this algorithm correlated with treatment toxicity. It could therefore be used to administer levels of activity on a patient-specific basis, which would help in the optimisation of targeted radionuclide therapy. We believe that algorithms of this kind, which use pre-injection biochemical and physiological measurements, could assist in the design of escalation trials based on a toxicity-limiting whole-body absorbed dose, rather than using the more conventional activity escalation approach.

Body Burden↗
PubMed2003

Class solutions for conformal external beam prostate radiotherapy.

PURPOSE: To determine a class solution coplanar plan from comparisons of three-field (3F), four-field (4F), and six-field (6F) plans in conformal non-intensity-modulated prostate radiotherapy. METHODS AND MATERIALS: Doses to two clinical target volumes, prostate only (PO) and prostate plus seminal vesicles (PSV) were evaluated in each of 10 patients using a variety of 3F, 4F, and 6F plans with a planning target volume margin of 10 mm. All plans were prescribed to 64 and 74 Gy. The class solution plan for each of 3F, 4F, and 6F was chosen from a variety of symmetrical and asymmetrical field arrangements that had been previously assessed. The class solution plans, 3F (0, 90, 270 degrees ), 4F (35, 90, 270, 325 degrees ), and 6F (50/lat/25) were compared with reference plans: 3F (0, 120, 240 degrees ), 4F (0, 90, 180, 270 degrees ), and 6F (55, 90, 125, 235, 270, 305 degrees ). Rectal volumes irradiated to greater than 50% (V(50)), 80% (V(80)), and 90% (V(90)) of the prescribed dose, normal tissue complication probabilities (NTCP) for rectum, bladder, and femoral heads (FH), and tumor control probabilities (TCP) were assessed. FH tolerance was set at 52 Gy to 10% volume. RESULTS: The field arrangement that gave the lowest irradiated rectal volume with acceptable bladder and FH doses was a 3F (0, 90, 270 degrees ) class solution plan. This plan gave a reduction in rectal V(80) of 1.2-12.4% for the PO group and 2.3-23.8% for the PSV group compared with the other plans. The reduction in rectal V(90) was 0.2-11.9% for the PO group and 1.5-23.3% for the PSV group using the 3F (0, 90, 270 degrees ) plan. This plan provided one of the lowest rectal NTCPs, but the difference was not significant when compared with the 4F class solution plan. When target volumes with 10-mm margins remain unchanged to 74 Gy, the irradiated rectal volumes for all plans were higher and rectal NTCPs can be trebled. CONCLUSION: The use of appropriate beam arrangements can provide a class solution plan using only 3 fields compared with 4 or 6 fields for the parameters considered. Both 3F (0, 90, 270 degrees ) and 4F (35, 90, 270, 325 degrees ) plans can be used as a class solution plan. Other practical issues that may influence the choice of class solution include delivery time with smaller number of fields, ease of verification, the use of 10-mm multileaf collimation vs. conformal blocks, and field shape fitting limitations when using dynamic wedges.

Adenocarcinoma↗
PubMed2003

A Monte-Carlo method for interface dosimetry of beta emitters.

Biologically targeted radiotherapy optimization requires accurate dose estimation, from macroscopic to cellular/subcellular dimensions. In particular, dose perturbations produced at interfaces between dissimilar media could affect therapy outcome. The magnitude of these perturbations depends on a complex set of parameters. This study investigates perturbations on electron dose for materials with atomic numbers (Z) up to 79 (79Au) at their interface with water as a function of Z, energy, distance from interface and geometry. A Monte-Carlo method that produces absorbed dose distributions in a voxel geometry has been developed using EGSnrc transport routines. Heterogeneous media and activity distributions can be input into this code. The backscatter dose factor (BSDF), which quantifies interface dose perturbations, was estimated using this code. The BSDF magnitude ranged from approximately 3% to approximately 50%, depending on source energy and Z. The BSDF decreased with increasing energy and showed a logarithmic dependence on Z. Empirical functions were fit to the results, that could be used to correct dose calculations performed using dose-point-kernels estimated in water, to cases involving different scattering materials. The BSDF was found to be highly dependent on interface geometry and scoring volume; thus it is vital that BSDFs are used only in geometry conditions that are similar to those in which they were originally produced.

Beta Particles↗
PubMed2002

Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.

Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were </=55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.

Adult↗
PubMed2002

Late recurrence in 1263 men with testicular germ cell tumors. Multivariate analysis of risk factors and implications for management.

BACKGROUND: Testicular germ cell tumors are highly curable. However, 10-30% of patients have recurrence after initial treatment. The time-course of recurrence has implications for the duration of follow-up. This study was undertaken to assess the risk and time-course of recurrence and to identify patients at higher risk of late recurrence. METHODS: The records of 1263 patients with primary testicular germ cell tumors presenting to the Royal Marsden Hospital between December 1979 and December 1993 were reviewed. In all, 255 episodes of recurrence were documented (including 44 patients with multiple recurrences) and used to calculate recurrence-free survivals. RESULTS: Fifty-three patients (15 seminomas; 38 nonseminomatous germ cell tumors [NSGCT]) had recurrence more than 2 years after initial presentation. A multivariate analysis of risk of recurrence after 2 years identified positive markers at presentation and the presence of differentiated teratomas in postchemotherapy surgical specimens as significant predictors. Very late recurrence (> 5 years) occurred mainly in patients with metastatic NSGCT (12 of 14 patients) with a 1% annual risk of recurrence between 5 and 10 years. Very late recurrence was also seen in one case of metastatic seminoma and one case of Stage I NSGCT managed by surveillance. Most late recurrences (n = 9) were detected at routine annual follow-up visits but five had recurrences with symptoms leading to an unscheduled clinic visit. CONCLUSION: Late recurrences are rare in patients with testicular germ cell tumors and follow-up to detect recurrence may not be needed after 5 years, except in those presenting with metastatic NSGCTs.

Adolescent↗
PubMed2002

Influence of cytokine gene polymorphisms on the development of prostate cancer.

Polymorphisms in the promoter regions of cytokine genes may influence prostate cancer (PC) development via regulation of the antitumor immune response and/or pathways of tumor angiogenesis. PC patients (247) and 263 controls were genotyped for interleukin (IL)-1beta-511, IL-8-251, IL-10-1082, tumor necrosis factor-alpha-308, and vascular endothelial growth factor (VEGF)-1154 single nucleotide polymorphisms. Patient control comparisons revealed that IL-8 TT and VEGF AA genotypes were decreased in patients compared with controls [23.9 versus 32.3%; P = 0.04, odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.44-0.99 and 6.3 versus 12.9%; P = 0.01, OR = 0.45, 95% CI 0.24-0.86, respectively], whereas the IL-10 AA genotype was significantly increased in patients compared with controls (31.6 versus 20.6%; P = 0.01, OR = 1.78, 95% CI 1.14-2.77). Stratification according to prognostic indicators showed association between IL-8 genotype and log prostate-specific antigen level (P = 0.05). These results suggest that single nucleotide polymorphisms associated with differential production of IL-8, IL-10, and VEGF are risk factors for PC, possibly acting via their influence on angiogenesis.

Aged↗
PubMed2002

Metastatic nonseminomatous germ cell tumors of the testis: results of elective and salvage surgery for patients with residual retroperitoneal masses.

BACKGROUND: A mass may persist in the para-aortic region after patients undergo chemotherapy for metastatic, nonseminomatous germ cell tumor of the testis (NSGCT). Retroperitoneal lymphadenectomy removes the mass, which may contain residual active malignancy, and allows histologic assessment of the effectiveness of the chemotherapy. Whereas some have favored early, elective removal of such masses, others have chosen to observe them, reserving salvage surgery for patients who experience disease recurrence. A retrospective analysis was undertaken to define the outcome in these two groups of patients. METHODS: After receiving chemotherapy for metastatic NSGCT, 442 men underwent lymphadenectomy for residual masses (measuring > or = 1 cm in greatest dimension) between 1976 and 1999, inclusive. Three hundred thirty men underwent elective surgery within 3 months of the completion of chemotherapy, and 112 men underwent salvage surgery after receiving reinduction chemotherapy for tumor recurrence. RESULTS: The residual mass was removed completely in 87% and 72% of patients in the elective and salvage lymphadenectomy groups, respectively; was removed with difficulty and possibly incompletely in 9% and 21% of patients, respectively; and was definitely removed incompletely in 4% and 7% of patients, respectively. The operative mortality rate was 0.9% in the elective surgery group and 1.8% in the salvage surgery group. There was malignant teratoma, undifferentiated in 8.5% of patients in the elective surgery group and in 49% of patients in the salvage surgery group (P < 0.001). Differentiated teratoma and necrosis/fibrosis were present in 66.0% and 25.4% of patients in the elective surgery group, respectively, and in 38.4% and 12.5% of patients in the salvage surgery group, respectively. The authors were unable to produce a clinically useful model to predict the presence of necrosis/fibrosis only in either group. The 5-year recurrence free and overall survival rates were 83% and 89%, respectively, in the elective surgery group and 62% and 56%, respectively, in the salvage surgery group. For the salvage surgery group, the completeness of surgical excision and the presence of undifferentiated teratoma were of overriding importance for overall survival. A variety of other patient-related, tumor-related, and surgery-related factors also were significant in the final model for the elective surgery group. CONCLUSIONS: The current results demonstrate the low level of morbidity that can be obtained, even in the salvage surgery group, and the importance of complete surgical resection in this setting. Because it is not possible to predict with sufficient accuracy which patients will have favorable pathology (necrosis/fibrosis), the authors continue to recommend elective surgery for all suitable men with residual masses after they receive first-line chemotherapy.

Adolescent↗