Biomedical subjects
Publications and source records attributed to D P Dearnaley.
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The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed 55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.
We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.
Phase III studies have demonstrated the clinical benefit of adding neo-adjuvant androgen deprivation to radical radiotherapy for clinically localised prostate cancer. We have developed a nomogram to describe the probability of PSA control for patients treated in this way. Five hundred and seventeen men with clinically localised prostate cancer were treated with 3-6 months of neo-adjuvant androgen deprivation and radical radiotherapy (64Gy in 32#) between 1988 and 1998. Median presenting PSA was 20 ng x ml(-1), and 56% of patients had T3/4 disease. Multivariate analysis of pre-treatment factors was performed, and a nomogram developed to describe PSA-failure-free survival probability. At a median follow-up of 44 months, 233 men had developed PSA failure. Presenting PSA, histological grade and clinical T stage were all highly predictive of PSA failure on multivariate analysis. The nomogram score for an individual patient is given by the summation of PSA (<10=0, 10-19=16, 20-49=44, > or =50=100), grade (Gleason 2-4=0, 5-7=44, 8-10=81) and T stage (T1/2=0, T3/4=35). For a nomogram score of 0, 50, 100 and 150 points the 2 year PSA control rate was 93, 87, 75 and 54%, and the 5 year PSA control rate was 82, 67, 44 and 18%. These results are comparable to those using surgery or higher doses of radical radiotherapy alone. The nomogram illustrates the results of multivariate analysis in a visually-striking way, and facilitates comparisons with other treatment methods.
Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.
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Dynamic intensity modulated radiation therapy (IMRT) to treat prostate and pelvic nodes using the Varian 120-leaf Millennium multileaf collimator (MLC) has been implemented in our clinic. This paper describes the procedures that have been undertaken to achieve this, including some of the commissioning aspects of Helios, verification of the dynamic dose delivery, and quality assurance (QA) of the dose delivered to the patient. Commissioning of Helios included measurements of transmission through the 120-leaf MLC, which were found to be 1.7% for 6 mV and 1.8% for 10 MV. The rounded leaf edge effect, known as the dosimetric separation, was also determined using two independent methods. Values of 1.05 and 1.65 mm were obtained for 6 and 10 MV beams. Five test patients were planned for prostate and pelvic node irradiation to 70 and 50 Gy, respectively. Dose and fluence verification were carried out on specially designed phantoms and dose points in the prostate were measured to be within 2.0% (mean 0.9%, s.d. 0.6%) of the calculated dose and in the nodes within 3.0% (mean 1.6%, s.d. 1.1%). Following the results of this commissioning and implementation study, we have started to treat men with a target Volume including the prostate and pelvic nodes using Helios optimized dynamic IMRT delivery in a dose escalation protocol.
The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose-volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7-31.2% depending on the alpha/beta ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4-27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.
PURPOSE: To assess 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques to see whether doses to critical structures could be reduced while maintaining planning target volume (PTV) coverage in patients receiving conventional radiotherapy (RT) for carcinoma of the maxillary sinus because of the risk of radiation-induced complications, particularly visual loss. METHODS AND MATERIALS: Six patients who had recently received conventional RT for carcinoma of the maxillary sinus were studied. Conventional RT, 3D-CRT, and step-and-shoot IMRT plans were prepared using the same 2-field arrangement. The effect of reducing the number of segments in the IMRT beams was investigated. RESULTS: 3D-CRT and IMRT reduced the brain and ipsilateral parotid gland doses compared with the conventional plans. IMRT reduced doses to both optic nerves; for the contralateral optic nerve, 15-segment IMRT plans delivered an average maximal dose of 56.4 Gy (range 53.9-59.3) compared with 65.7 Gy (range 65.3-65.9) and 64.2 Gy (range 61.4-65.6) for conventional RT and 3D-CRT, respectively. IMRT also gave improved PTV homogeneity and improved coverage, with an average of 8.5% (range 7.0-11.7%) of the volume receiving <95% of the prescription dose (64 Gy) compared with 14.7% (range 14.1-15.9%) and 15.1% (range 14.4-16.1%) with conventional RT and 3D-CRT, respectively. Little difference was found between the 15 and 7-segment plans, but 5 segments resulted in a reduced minimal PTV dose. CONCLUSIONS: IMRT offers significant advantages over conventional RT and 3D-CRT techniques for treatment of maxillary sinus tumors. Good results can be obtained from 7 segments per beam without compromising the PTV coverage. This number of segments is practical for implementation in a busy RT department.
BACKGROUND AND PURPOSE: In a randomized trial, the incidence of rectal bleeding among patients treated for prostate cancer using conformal radiotherapy was significantly lower (p = 0.002) than that among those treated conventionally. Here the relationship between rectal dose distributions and incidences of bleeding is assessed. METHODS AND MATERIALS: Rectal dose-surface histograms (DSHs) have been calculated for 79 trial patients. The relationship between the DSHs and incidences of Grade 1-3 bleeding has been explored using both semiempiric and biologic (parallel) model-based approaches. RESULTS: Semiempiric analysis of the trial data suggests that it is more useful to work with DSH fractional surface areas multiplied by outlined rectal lengths than with either raw DSH fractional areas or fractional areas multiplied by absolute total outlined rectal surface area. Fitting the parallel model to length-multiplied rectal DSHs and complication data reveals the existence of a significant volume effect, the rate of Grade 1-3 bleeding falling by 1.1% (95% confidence interval [0.04, 2.2]%) for each 1% decrease in the fraction of rectal wall (outlined over an 11-cm length) receiving a dose of more than 57 Gy. CONCLUSION: The existence of this volume effect suggests that dose escalation can be achieved using conformal techniques, although the extent to which doses may be safely escalated cannot be reliably estimated from the trial data.
PURPOSE: The aim of this paper is to illustrate the potential gain in tumor control probability (TCP) of prostate cancer patients by individualizing the prescription dose according to both normal-tissue (N-T) dose-volume and radiosensitivity data. METHODS AND MATERIALS: Two exercises have been carried out. Firstly, patients' dose prescriptions were individualised on the basis of N-T dose-volume histograms (DVHs) alone and secondly modeling potential differences in N-T sensitivity as well. In both cases, the change in tumor control that may be achieved by individualizing patients' dose was estimated assuming that after the dose adjustments, every patient had (1) the same value of normal tissue complication probability (NTCP) (5%) and (2) NTCP equal to the average NTCP before individualization (i.e., without increasing the average NTCP). The Lyman-Kutcher-Burman NTCP model was used to predict the N-T response curves with two different sets of parameters. The first exercise, based only on individual NT DVHs (i.e., assuming all patient equally radiosensitive), was over a real population of 50 prostate cancer patients. The second exercise modeled a 10,000-prostate-cancer patient population with varying NT dose-volume distributions and radiosensitivity (through allowing TD(50) to vary). RESULTS: A gain of more than 9% in TCP was predicted when doses were individualized based only on DVHs so that every patient had 5% NTCP after dose adjustments. By adding the estimate of radiosensitivity, the gain increased to more than 15%. When the individualisation was performed without increasing the mean NTCP, then the potential gain in TCP was almost 5% (for adjustment based on DVH distribution solely) increasing to 7% with the additional consideration of radiosensitivity. CONCLUSIONS: There is a potential gain (increase in local tumor control) from dose individualisation strategies based on both N-T dose-volume data and radiosensitivity (assuming that this is available). Dose prescription individualization based only on dose-volume data can be exploited provided that reliable N-T response models are available. There will be additional gains if some estimate of N-T radiosensitivity is available to allow further patient stratification, identification of patients with high radiosensitivity being particularly important.
PURPOSE: To assess the results of treatment in 33 patients with stage IIA/B seminoma who were treated with carboplatin and radiotherapy (RT) between January 1989 and December 1996. PATIENTS AND METHODS: Thirty patients received single course single agent carboplatin (400 mg/m2 or area under curve (AUC 7), two patients received two courses carboplatin, and one patient received single course carboplatin and etoposide, all 4-6 weeks prior to infra-diaphragmatic RT. Results were retrospectively compared with those obtained for 80 patients treated from 1970 to 1998 with radiotherapy alone. RESULTS: There was minimal toxicity associated with the use of carboplatin prior to RT. With a median follow-up of 4 years (range 2-70 months) 2/33 patients treated with chemotherapy and RT have relapsed, 5-year relapse free survival (RFS) = 96.9% (95% confidence interval (CI) 72.9-99.4%), and one patient has died of progressive disease, 5-year overall survival (OS) = 96.7%. With a median follow-up of 11.2 years (range 6 months to 25.8 years) 15/80 patients treated with RT alone have relapsed, 5-year RFS = 80.7% (95% CI 70.1-87.9%), including 13/61 patients treated with infra-diaphragmatic RT, 5-year RFS = 77.9%, and 2/19 treated with additional supra-diaphragmatic RT, 5-year RFS = 89.5% (P = 0.277). Eleven out of 80 patients have died, 5-year OS = 94.7%. For stage IIA, 1/14 patients treated with chemotherapy and RT have relapsed, 5-year RFS = 92.3%, compared with 5/34 treated with infra-diaphragmatic RT alone 5-year, RFS = 84.9% (P = 0.527). For stage IIB, 1/19 patients relapsed (at 69 months) following chemotherapy and RT (5-year RFS = 100%), whereas 8/27 relapsed following infra-diaphragmatic RT alone, 5-year RFS = 69.4% (P = 0.0595). CONCLUSION: Infradiaphragmatic RT alone cures the majority of patients with stage II seminoma, but the relapse rate remains high particularly for patients with stage IIB disease. As compared with historical controls, carboplatin with RT appears to reduce the relapse rate in stage II seminoma with minimal additional toxicity and the results approach statistical significance for stage IIB patients. Confirmation would require a phase III randomized comparison.
BACKGROUND AND PURPOSE: To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution. MATERIALS AND METHODS: The planning target volume (PTV), contra-lateral parotid gland, oral cavity, brain-stem, brain and cochlea were outlined on CT planning scans of six patients with parotid gland tumours. Optimised conventional RT and 3DCRT plans were created and compared with inverse-planned IMRT dose distributions using dose-volume histograms. The aim was to reduce the radiation dose to organs at risk and improve the PTV dose distribution. A beam-direction optimisation algorithm was used to improve the dose distribution of the IMRT plans, and a class solution for parotid gland IMRT was investigated. RESULTS: 3DCRT plans produced an equivalent PTV irradiation and reduced the dose to the cochlea, oral cavity, brain, and other normal tissues compared with conventional RT. IMRT further reduced the radiation dose to the cochlea and oral cavity compared with 3DCRT. For nine- and seven-field IMRT techniques, there was an increase in low-dose radiation to non-target tissue and the contra-lateral parotid gland. IMRT plans produced using three to five optimised intensity-modulated beam directions maintained the advantages of the more complex IMRT plans, and reduced the contra-lateral parotid gland dose to acceptable levels. Three- and four-field non-coplanar beam arrangements increased the volume of brain irradiated, and increased PTV dose inhomogeneity. A four-field class solution consisting of paired ipsilateral coplanar anterior and posterior oblique beams (15, 45, 145 and 170 degrees from the anterior plane) was developed which maintained the benefits without the complexity of individual patient optimisation. CONCLUSIONS: For patients with parotid gland tumours, reduction in the radiation dose to critical normal tissues was demonstrated with 3DCRT compared with conventional RT. IMRT produced a further reduction in the dose to the cochlea and oral cavity. With nine and seven fields, the dose to the contra-lateral parotid gland was increased, but this was avoided by optimisation of the beam directions. The benefits of IMRT were maintained with three or four fields when the beam angles were optimised, but were also achieved using a four-field class solution. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.
BACKGROUND AND PURPOSE: External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated. MATERIALS AND METHODS: A planning study was performed on patients with thyroid carcinoma. Plans were generated to irradiate the thyroid bed alone or to treat the thyroid bed and the loco-regional lymph nodes in two phases. Conventional plans with minimal beam shaping were compared to three-dimensional conformal radiotherapy (3DCRT) and inverse-planned IMRT plans to assess target coverage and normal tissue sparing. IMRT techniques were optimized to find the minimum number of equispaced beams required to achieve the clinical benefit and a concomitant boost technique was explored. RESULTS: For the thyroid bed alone and the thyroid bed plus loco-regional lymph nodes, conventional and conformal techniques produced low minimum doses to the planning target volume (PTV) if spinal cord tolerance was respected. 3DCRT reduced the irradiated volume of normal tissue (P=0.01). IMRT plans achieved the goal dose to the PTV (P<0.01) and also reduced the spinal cord maximum dose (P<0.01). IMRT, using a concomitant boost technique, produced better target coverage than a two-phase technique. For both the two-phase and concomitant boost techniques, IMRT plans with seven and five equispaced fields produced similar dose distributions to nine fields, but three fields were significantly worse. CONCLUSIONS: 3DCRT reduced normal tissue irradiation compared to conventional techniques, but did not improve PTV or spinal cord doses. IMRT improved the PTV coverage and reduced the spinal cord dose. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer.
BACKGROUND AND PURPOSE: To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy. MATERIALS AND METHODS: A treatment planning study was performed to compare two-phase conformal radiotherapy (CFRT) with IMRT in five patients. The CFRT plans consisted of anterior, posterior and bilateral posterior oblique fields, while the IMRT plans consisted of either nine equispaced fields (9F), or four fields (4F) with orientations equal to the CFRT plans. IMRT plans with seven, five or three equispaced fields were also investigated in one patient. Treatment plans were compared using dose-volume histograms and normal tissue complication probabilities. RESULTS: The 9F IMRT plan was unable to improve on the homogeneity of dose to the planning target volume (PTV), compared with the CFRT plan (dose range, 16.9+/-4.5 (1 SD) vs. 12.4+/-3.9%; P=0.06). Similarly, the 9F IMRT plan was unable to reduce the mean lung dose (11.7+/-3.2 vs. 11.0+/-2.9 Gy; P=0.2). Similar results were obtained for seven, five and three equispaced fields in the single patient studied. The 4F IMRT plan provided comparable PTV dose homogeneity with the CFRT plan (11.8+/-3.3 vs. 12.4+/-3.9%; P=0.6), with reduced mean lung dose (9.5+/-2.3 vs 11.0+/-2.9 Gy; P=0.001). CONCLUSIONS: IMRT using nine equispaced fields provided no improvement over CFRT. This was because the larger number of fields in the IMRT plan distributed a low dose over the entire lung. In contrast, IMRT using four fields equal to the CFRT fields offered an improvement in lung sparing. Thus, IMRT with a few carefully chosen field directions may lead to a modest reduction in pneumonitis, or allow tumour dose escalation within the currently accepted lung toxicity.
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To evaluate an alternative treatment for advanced or metastatic urothelial cancers, a dose-intensive combination chemotherapy regimen using carboplatin, methotrexate, vincristine and cisplatin was given to 60 patients over a 3-year period (1990 to 1993). There were 26 patients with locally advanced disease and 34 with metastatic disease; 49 patients were evaluable for response. A complete response was noted in four patients (8%) and a partial response in 15 (31%), for an overall response rate of 39%. The median survival was 12 months. Two- and 5-year survival rates were 25.5% (95% confidence interval CI) 15.2-37.0) and 7.3% (95% CI 2.2-16.4) respectively. Failure-free survival was 15.3% (95% CI 7.5-25.6) at 2 years and 5.9% (95% CI 1.6-14.4) at 5 years, with a median of 8 months. For the responders, the median duration of response was 14 months, with a range of 2-59+ months. Toxicity included myelosuppression (28% grade 4/5 neutropenia, 19% grade 4 thrombocytopenia), peripheral neuropathy (54% grade 1 and 23% grade 2/3) and ototoxicity (21% grade 1, 19% grade 2). This schedule of dose-intensified platinum-based chemotherapy for bladder cancer resulted in significant neurotoxicity without evidence of enhanced response rates or survival. Regimens such as methotrexate, vinblastine, doxorubicin and cisplatin should remain standard. Accelerated regimens may be useful in situations were it is necessary to administer chemotherapy over a short time (e.g. as part of combined modality treatment).
This study was carried out to evaluate the possible long-term endocrine effect of short-term neoadjuvant leuteinizing hormone-releasing hormone analogue (LHRHa) administration in localized prostate cancer. A total of 419 men were treated for 3-6 months at The Royal Marsden NHS Trust by neoadjuvant androgen suppression using monthly depot injections of LHRHa before radical radiotherapy. Serum testosterone (852 measurements), leuteinizing hormone (LH) (799 measurements), and follicle-stimulating hormone (FSH) levels (801 measurements) were grouped according to their timing in relation to hormonal treatment and then analysed. Suppression of pituitary gonadotrophins and testosterone after the administration of LHRHa and their recovery after cessation of the drug was clearly observed. Median serum testosterone levels decreased from 16 nmol/l to 14 nmol/l when comparing prehormonal and follow-up phases. The same comparison showed an increase in median serum LH and FSH levels, with the median LH rising from 5 u/l to 8 u/l and the median serum FSH rising from 6 u/l to 20 u/l. On long-term follow-up, three of 256 men have remained with testosterone levels in the castrate range. Similar highly significant results were seen in subgroup of 103 men who had both pre-LHRHa and follow-up hormone levels analysed (P=0.012, P<0.001, P<0.001 for testosterone, LH and FSH respectively). Our data suggest the possibility of residual gonadal dysfunction after short-term LHRHa administration and radical radiotherapy in localized prostate cancer. Serum testosterone levels are restored to normal levels in the majority of patients, with a compensatory increase in serum levels of LH.