Prostate stereotactic body radiotherapy­first UK experience.

AIMS: Stereotactic body radiotherapy (SBRT) combines image-guided radiotherapy with hypofractionation, both of which will probably result in improvements in patient outcomes in prostate cancer. Most clinical experience with this technique resides in North America. Here we present the first UK cohort to receive SBRT for prostate cancer. MATERIALS AND METHODS: Fifty-one prostate cancer patients (10 low risk, 35 intermediate risk and 6 high risk) were treated with 36.25 Gy in five fractions over 1-2 weeks and gold seed image guidance. All patients had toxicity International Prostate Symptom score (IPSS) and Radiation Therapy Oncology Group recorded prospectively and prostate-specific antigen was measured 3-6 monthly during follow-up. RESULTS: The median IPSS was 6, 11, 8 and 5 at baseline, 1-3 weeks, 4-6 weeks and 7-12 weeks after treatment. Radiation Therapy Oncology Group genitourinary and gastrointestinal toxicity of grade 2 was seen in 22% and 14%, respectively, at 1-3 weeks after treatment; no patient had grade 3+ toxicity at this time point, although two patients had grade 3 urinary frequency recorded during treatment. The median follow-up for the 42 patients who did not receive androgen deprivation was 14.5 months. Prostate-specific antigen at 13-18 months after treatment was 1.3 ng/ml. CONCLUSION: Prostate SBRT is a promising treatment for organ-confined prostate cancer and is currently being investigated in a UK-led phase III trial.

Is biochemical relapse-free survival after profoundly hypofractionated radiotherapy consistent with current radiobiological models?

AIMS: The α/ß ratio for prostate cancer is thought to be low and less than for the rectum, which is usually the dose-limiting organ. Hypofractionated radiotherapy should therefore improve the therapeutic ratio, increasing cure rates with less toxicity. A number of models for predicting biochemical relapse-free survival have been developed from large series of patients treated with conventional and moderately hypofractionated radiotherapy. The purpose of this study was to test these models when significant numbers of patients treated with profoundly hypofractionated radiotherapy were included. MATERIALS AND METHODS: A systematic review of the literature with regard to hypofractionated radiotherapy for prostate cancer was conducted, focussing on data recently presented on prostate stereotactic body radiotherapy. For the work described here, we have taken published biochemical control rates for a range of moderately and profoundly fractionated schedules and plotted these together with a range of radiobiological models, which are described. RESULTS: The data reviewed show consistency between the various radiobiological model predictions and the currently observed data. CONCLUSION: Current radiobiological models provide accurate predictions of biochemical relapse-free survival, even when profoundly hypofractionated patients are included in the analysis.

Clinical trial: Efficacy of a low or modified fat diet for the prevention of gastrointestinal toxicity in patients receiving radiotherapy treatment for pelvic malignancies.

BACKGROUND: Inflammatory responses to pelvic radiotherapy can result in severe changes to normal gastrointestinal function with potentially severe long-term effects. Reduced or modified fat diets may confer benefit. METHODS: This randomised controlled trial recruited patients with gynaecological, urological or lower gastrointestinal malignancy due to receive radical radiotherapy. Patients were randomised to a low fat (20% total energy from long chain triglycerides), modified fat (20% from long chain triglycerides and 20% from medium chain triglycerides) or normal fat diet (40% total energy from long chain triglycerides). The primary outcome was a difference in change in Inflammatory Bowel Disease Questionnaire--Bowel (IBDQ-B) score, from the start to end of radiotherapy. RESULTS: A total of 117 patients with pelvic tumours (48% urological; 32% gastrointestinal; 20% gynaecological), with mean (SD) age: 65 (11.0) years, male:female ratio: 79:38, were randomised. The mean (SE) fall in paired IBDQ-B score was -7.3 (0.9) points, indicating a worsening toxicity. Differences between groups were not significant: P = 0.914 (low versus modified fat), P = 0.793 (low versus normal fat) and P = 0.890 (modified versus normal fat). The difference in fat intake between low and normal fat groups was 29.5 g [1109 kJ (265 kcal)] amounting to 11% (of total energy intake) compared to the planned 20% differential. Full compliance with fat prescription was only 9% in the normal fat group compared to 93% in the low fat group. CONCLUSIONS: A low or modified fat diet during pelvic radiotherapy did not improve gastrointestinal symptom scores compared to a normal fat intake. An inadequate differential in fat intake between the groups may have confounded the results.

Evaluating inter-fractional changes in volume and position during bladder radiotherapy and the effect of volume limitation as a method of reducing the internal margin of the planning target volume.

AIMS: To quantify the inter-fractional variation in bladder volume and position during a course of bladder radiotherapy, and to assess the feasibility of reducing the planning target volume (PTV) internal margin using an empty bladder protocol. MATERIALS AND METHODS: Weekly computed tomography scans were taken immediately after micturition on 15 patients undergoing radical radiotherapy for bladder cancer. Bladder volume and positional variation were compared by co-registration of the serial computed tomography scans with the initial planning scan and a single 'full' scan at the onset of treatment for each patient. A PTV was generated on the initial planning scan using both our departmental standard of 1.5cm and a reduced 1cm isotropic internal margin around the target (whole bladder) and the relative proportion of the bladder breaching the PTV using both margins compared. RESULTS: The mean post void residual volume from the planning scan was 112cm(3) (standard deviation 42cm(3)). The mean weekly variation in bladder volume relative to the planning volume was 0-12% (standard deviation 20-34%) with no observable trends over time. No statistically significant differences were seen in the proportion of bladder breaching the 1.5 and 1cm internal margin (P=0.18). Regression analysis showed that it is possible to ensure complete coverage of the bladder with a 1cm margin, providing the volume did not exceed over 50% of the initial planning scan volume. CONCLUSION: Using an empty bladder protocol and where on-line imaging is available it is feasible to reduce the internal margin of the PTV from 1.5 to 1cm, providing the volumes do not exceed >50% of the planning scan volume.

Early clinical evaluation of a novel three-dimensional structure delineation software tool (SCULPTER) for radiotherapy treatment planning.

Modern radiotherapy treatment planning (RTP) necessitates increased delineation of target volumes and organs at risk. Conventional manual delineation is a laborious, time-consuming and subjective process. It is prone to inconsistency and variability, but has the potential to be improved using automated segmentation algorithms. We carried out a pilot clinical evaluation of SCULPTER (Structure Creation Using Limited Point Topology Evidence in Radiotherapy) - a novel prototype software tool designed to improve structure delineation for RTP. Anonymized MR and CT image datasets from patients who underwent radiotherapy for bladder or prostate cancer were studied. An experienced radiation oncologist used manual and SCULPTER-assisted methods to create clinically acceptable organ delineations. SCULPTER was also tested by four other RTP professionals. Resulting contours were compared by qualitative inspection and quantitatively by using the volumes of the structures delineated and the time taken for completion. The SCULPTER tool was easy to apply to both MR and CT images and diverse anatomical sites. SCULPTER delineations closely reproduced manual contours with no significant volume differences detected, but SCULPTER delineations were significantly quicker (p<0.05) in most cases. In conclusion, clinical application of SCULPTER resulted in rapid and simple organ delineations with equivalent accuracy to manual methods, demonstrating proof-of-principle of the SCULPTER system and supporting its potential utility in RTP.

A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer.

AIMS: To compare the radiotherapy planning techniques from two multicentre randomised external beam radiotherapy trials in the UK of conformal radiotherapy vs intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Sixteen sequential patients with histologically confirmed localised prostate cancer treated in the conventional or hypofractionated IMRT trial (CHHiP) were planned using both the CHHiP and Medical Research Council RT-01 planning protocols to 74 Gy in 37 daily fractions. The CHHiP plan used a single phase simple forward planned three-field IMRT plan for easy multicentre adoption. The RT-01 plan used two phases: three-field conformal radiotherapy plan to 64 Gy followed by a six-field boost of 10 Gy. After coverage of the planning target volumes according to the respective trial protocols, the dose to the rectum and bladder was assessed for the two planning techniques. RESULTS: There was acceptable planning target volume coverage by both the CHHiP and RT-01 plans. All CHHiP plans produced lower mean irradiated rectal volumes at all measured dose levels compared with the RT-01 plans, particularly for irradiated rectal volumes at 50 and 70 Gy (P<0.05). In the cases when a CHHiP plan failed to meet its own trial dose constraints, the volumes of irradiated rectum were less than if an RT-01 planning technique had been used. The CHHiP plans gave lower mean irradiated bladder volumes at both 50 and 60 Gy, but higher volumes at 74 Gy. These differences in irradiated bladder volumes were significant at the 60 and 74 Gy dose levels (P<0.05) in favour of the CHHiP and RT-01 plans, respectively. CONCLUSION: The forward planned CHHiP IMRT planning solution gives more favourable rectal sparing than the RT-01 plan. This is important to limit any potential increase in late rectal toxicity for prostate cancer patients treated with high-dose conventional or hypofractionated schedules.

Adjuvant chemoradiotherapy for gastric carcinoma: dosimetric implications of conventional gastric bed irradiation and toxicity.

AIMS: Recently, a survival advantage has been shown using adjuvant chemoradiotherapy after complete resection of gastric cancer. If survival advantages are to be maintained, treatment-related complications must be minimised. In this study, we explored the dosimetric implications and toxicity of conventional large field gastric bed irradiation. MATERIALS AND METHODS: Between 2000 and 2002, 16 patients received adjuvant 5-fluorouracil (5-FU) chemoradiotherapy after complete resection of gastric cancer. Radiotherapy was simulator planned using anterior-posterior parallel opposed fields to 45 Gy in 25 daily fractions over 5 weeks. RESULTS: Thirteen patients (81%) completed radiotherapy and eight patients (50%) completed chemotherapy as planned. Toxicity was the main factor for discontinuation. Substantial dose inhomogeneities were shown using retrospective computed tomography recreation of dose-volume histograms (DVHs) of the organs at risk. CONCLUSIONS: Although the delivery of chemoradiotherapy using conventional two-dimensional simulator planning is a feasible technique, significant under-appreciation of dose inhomogeneity exists. Conformal computed tomography planning is vital to document doses received by organs at risk, especially the spinal cord and kidneys, which may receive high doses, and prospectively correlate these with acute and long-term toxicity in order to redefine organ at risk tolerances in the setting of chemoradiation.

New developments in MRI for target volume delineation in radiotherapy.

MRI is being increasingly used in oncology for staging, assessing tumour response and also for treatment planning in radiotherapy. Both conformal and intensity-modulated radiotherapy requires improved means of defining target volumes for treatment planning in order to achieve its intended benefits. MRI can add to the radiotherapy treatment planning (RTP) process by providing excellent and improved characterization of soft tissues compared with CT. Together with its multiplanar capability and increased imaging functionality, these advantages for target volume delineation outweigh its drawbacks of lacking electron density information and potential image distortion. Efficient MR distortion assessment and correction algorithms together with image co-registration and fusion programs can overcome these limitations and permit its use for RTP. MRI developments using new contrast media, such as ultrasmall superparamagnetic iron oxide particles for abnormal lymph node identification, techniques such as dynamic contrast enhanced MRI and diffusion MRI to better characterize tissue and tumour regions as well as ultrafast volumetric or cine MR sequences to define temporal patterns of target and organ at risk deformity and variations in spatial location have all increased the scope and utility of MRI for RTP. Information from these MR developments may permit treatment individualization, strategies of dose escalation and image-guided radiotherapy. These developments will be reviewed to assess their current and potential use for RTP and precision high dose radiotherapy.

Radiotherapeutic techniques for prostate cancer, dose escalation and brachytherapy.

There is evidence to confirm a dose-response relationship in prostate cancer. The relative benefit is dependent on the clinical prognostic risk factors (T stage, Gleason score and presenting prostate-specific antigen [PSA]) being more favourable for intermediate-risk patients. Refinement of prognostic groups and clinical threshold parameters is ongoing. Escalation of dose in prostate radiotherapy using conventional techniques is limited by rectal tolerance. Substantial advances have been made in radiotherapy practice, such as the development of conformal radiotherapy (CFRT) and intensity-modulated radiotherapy (IMRT). Randomised data support the value of CFRT in reducing rectal toxicity. IMRT can permit higher-dose escalation while still respecting known rectal tolerance thresholds. Brachytherapy is a recognised alternative for low-risk prostate cancer subgroups. New radiotherapeutic strategies for prostate cancer include pelvic nodal irradiation, exploiting the presumed low alpha/beta ratio in prostate cancer for hypofractionation and combining external beam with high-dose-rate brachytherapy boosts. New image-guided methodologies will enhance the therapeutic ratio of any radiotherapy technique or dose escalation programme by enabling more reliable and accurate treatment delivery for improved patient outcomes.

An assessment of clinically optimal gold marker length and diameter for pelvic radiotherapy verification using an amorphous silicon flat panel electronic portal imaging device.

Verification of target organ position is essential for the accurate delivery of conformal radiotherapy. Megavoltage electronic portal imaging with flat panel amorphous silicon detectors delivers high quality images that can be used for verification of bony landmark position. Gold markers implanted into the target organ can be visualized and used as a surrogate of actual organ position. On-line compensation for marker displacement, by adjusting patient position, can reduce geometric errors associated with radiation delivery. This study assesses the optimal marker length and diameter to be used with an amorphous silicon (a-Si) flat panel detector and electronic portal images (EPIs), prior to implementation of a clinical programme of gold marker insertion in prostate cancer patients. Seven marker sizes varying from 3 mm to 8 mm in length and 0.8 mm to 1.1 mm in diameter were investigated in a group of patients undergoing pelvic radiotherapy using an 8 MV Elekta SL20 linear accelerator. Markers were placed on the skin entry and exit sites of the treatment beam and EPIs in both lateral and anterior pelvic views were acquired. Three observers independently assessed visibility success and failure using a subjective scoring system. Markers less than 5 mm in length or 0.9 mm in diameter were poorly visualized (<70% visualization success in lateral EPIs). The marker measuring 0.9 mm x 5 mm appears to be clinically optimal in pelvic radiotherapy patients (80% visualization success in lateral EPIs) and will be used for actual organ implantation.

Controversies in the radiotherapeutic management of poor prognosis locally advanced prostate cancer.

The Grand Round was held at the Christie Hospital, Manchester, U.K., on 30 November 2002. It followed a presentation by Dr David Dearnaley from the Royal Marsden Hospital in Sutton on 'Novel approaches and trials in prostate cancer'. Controversies in the management of locally advanced prostate cancer were illustrated by a case presentation and followed by a discussion on the evaluation of disease extent, and the roles of radiotherapy and hormone ablation.

Anal canal cancer and chemoradiation treatment in two patients with systemic lupus erythematosus treated by chronic therapeutic immunosuppression.

Two case reports of anal cancer developing during chronic therapeutic immunosuppression for systemic lupus erythematosus (SLE) and their cancer management are presented. The complex issues of delivery of curative chemoradiation treatment for anal cancer in the context of co-existing autoimmune connective tissue disease (AICD) are discussed. These two cases show that combined chemotherapy and radiation regimens are possible in patients with SLE. However, frequent, careful assessment with judicious and prompt management of haematological and other complications during treatment is important.

Evaluation of the optimal co-planar field arrangement for use in the boost phase of dose escalated conformal radiotherapy for localized prostate cancer.

The aim of this study was to determine the optimal co-planar beam arrangement from a variety of three-field (3F), four-field (4F) and six-field (6F) plans for the boost phase of a dose escalated conformal radiotherapy schedule. Three selected plans (3F 0 degrees, 90 degrees, 270 degrees plan, 4F 45 degrees, 90 degrees, 270 degrees, 315 degrees plan and 6F 40 degrees, 90 degrees, 115 degrees, 245 degrees, 270 degrees, 320 degrees plan) were compared with reference plans (3F 0 degrees, 120 degrees, 240 degrees plan, 4F 0 degrees, 90 degrees, 180 degrees, 270 degrees plan, 6F 55 degrees, 90 degrees, 125 degrees, 235 degrees, 270 degrees, 305 degrees plan and 6F 50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees plan) in 10 patients. Doses of 64 Gy and 74 Gy were prescribed to the isocentre using 6 MV photons. The boost planning target volume comprised the prostate gland alone without a margin. Plans were compared by means of rectal volumes irradiated to >50% (V50), >80% (V80) and >90% (V90) of the prescribed dose. Irradiated volumes were also measured for the bladder (V90) and the femoral heads (V70). All optimal 3F, 4F and 6F plans gave lower irradiated rectal V80 and V90 levels than their corresponding reference plan. The 3F (0 degrees, 90 degrees, 270 degrees) plan consistently provided lower irradiated rectal levels at V50 to V90, with acceptable bladder and femoral head doses compared with the other plans in the study. When the 6F (50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees) plan used at our institution for the boost phase was compared with the 3F (0 degrees, 90 degrees, 270 degrees) plan, the rectal V50 was reduced from 20.8+/-5.2%, to 12.6+/-5.1%, the rectal V80 was reduced from 8.7+/-2.9% to 6.5+/-3.1% and the rectal V90 was reduced from 5.5+/-2.1% to 3.9+/-2.0% (all p<0.001). The bladder V90 and the femoral heads V70 levels were equivalent. For the boost phase when escalating the dose from 64 Gy to 74 Gy, the co-planar plan that allowed optimal rectal sparing was a 3F beam arrangement using gantry angles of 0 degrees, 90 degrees and 270 degrees. This 3F plan provided improved rectal sparing compared with the 6F (50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees) beam arrangement currently used at our institution, with equivalent and acceptable bladder and femoral head doses.

Simultaneous optimization of beam orientations and beam weights in conformal radiotherapy.

A methodology for the concurrent optimization of beam orientations and beam weights in conformal radiotherapy treatment planning has been developed and tested on a cohort of five patients. The algorithm is based on a beam-weight optimization scheme with a downhill simplex optimization engine. The use of random voxels in the dose calculation provides much of the required speed up in the optimization process, and allows the simultaneous optimization of beam orientations and beam weights in a reasonable time. In the implementation of the beam-weight optimization algorithm just 10% of the original patient voxels are used for the dose calculation and cost function evaluation. A fast simulated annealing algorithm controls the optimization of the beam arrangement. The optimization algorithm was able to produce clinically acceptable plans for the five patients in the cohort study. The algorithm equalized the dose to the optic nerves compared to the standard plans and reduced the mean dose to the brain stem by an average of 4.4% (+/- 1.9, 1 SD), p value = 0.007. The dose distribution to the PTV was not compromised by developing beam arrangements via the optimization algorithm. In conclusion, the simultaneous optimization of beam orientations and beam weights has been developed to be routinely used in a realistic time. The results of optimization in a small cohort study show that the optimization can reliably produce clinically acceptable dose distributions and may be able to improve dose distributions compared to those from a human planner.

A comparison of multileaf collimator with conformal blocks for the boost phase of dose-escalated conformal prostate radiotherapy.

A multileaf collimator (MLC) is compared with conformal blocks for delivering the boost phase of dose-escalated conformal prostate radiotherapy. When using conformal blocks, the volume of rectum irradiated to 90% (V90) is lower (1.4+/-1.3%, 1 SD) for a three-field plan with gantry angles 0 degree, 90 degrees, 270 degrees than for a six-field plan with gantry angles 50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees (2.1 +/- 1.3%, P = 0.002). However, when using an MLC in which the leaves and wedge are oriented at right angles, V90 is higher (4.7 +/- 3.0%) for a three-field plan than for a six-field plan (2.7 +/- 1.6%, P=0.05). The larger increase in V90 for the three-field plan when changing from conformal blocks to MLC is mainly due to the limitation imposed upon the MLC orientation by the use of wedges.

Correlations between dose-surface histograms and the incidence of long-term rectal bleeding following conformal or conventional radiotherapy treatment of prostate cancer.

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.

Radiotherapy planning of the pelvis using distortion corrected MR images: the removal of system distortions.

Image distortion is an important consideration in the use of magnetic resonance (MR) images for radiotherapy planning. The distortion is a consequence of system distortion (arising from main magnetic field inhomogeneity and nonlinearities in the applied magnetic field gradients) and of effects arising from the object/patient being imaged. A two stage protocol has been developed to correct both system and object-induced distortion in pelvic images which incorporates measures to maintain the quality, accuracy and consistency of the imaging and correction procedures. The first stage of the correction procedure is described here and involves the removal of system distortion. Object- (patient-) induced effects will be described in a subsequent work. Images are acquired with the patient lying on a flat rigid bed, which reproduces treatment conditions. A frame of marker tubes surrounding the patient and attached to the bed provides quality assurance data in each image. System distortions in the three orthogonal planes are mapped using a separate phantom, which fits closely within the quality control frame. Software has been written which automates the measurement and checking of the many marker positions which the test objects generate and which ensures that patient data are acquired using a consistent imaging protocol. Results are presented which show that the scanner and the phantoms used in measuring distortion give highly reproducible results with mean changes of the order of 0.1 mm between repeated measurements of marker positions in the same imaging session. Effective correction for in plane components of system distortion is demonstrated.