Helen Mayles

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial

BACKGROUND Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. METHODS We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3-6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. FINDINGS 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5-61·3), six (4·3%; 95% CI 1·6-9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2-8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2-5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5-6·2) of 138 men, three (2·2%; 0·5-6·3) of 137, and none (0·0%; 97·5% CI 0·0-2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. INTERPRETATION Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. FUNDING Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

Summary Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. Methods CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. Findings Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

Purpose To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

A national dosimetry audit for stereotactic ablative radiotherapy in lung

BACKGROUND AND PURPOSE A UK national dosimetry audit was carried out to assess the accuracy of Stereotactic Ablative Body Radiotherapy (SABR) lung treatment delivery. METHODS AND MATERIALS This mail-based audit used an anthropomorphic thorax phantom containing nine alanine pellets positioned in the lung region for dosimetry, as well as EBT3 film in the axial plane for isodose comparison. Centres used their local planning protocol/technique, creating 27 SABR plans. A range of delivery techniques including conformal, volumetric modulated arc therapy (VMAT) and Cyberknife (CK) were used with six different calculation algorithms (collapsed cone, superposition, pencil-beam (PB), AAA, Acuros and Monte Carlo). RESULTS The mean difference between measured and calculated dose (excluding PB results) was 0.4±1.4% for alanine and 1.4±3.4% for film. PB differences were -6.1% and -12.9% respectively. The median of the absolute maximum isodose-to-isodose distances was 3mm (-6mm to 7mm) and 5mm (-10mm to +19mm) for the 100% and 50% isodose lines respectively. CONCLUSIONS Alanine and film is an effective combination for verifying dosimetric and geometric accuracy. There were some differences across dose algorithms, and geometric accuracy was better for VMAT and CK compared with conformal techniques. The alanine dosimetry results showed that planned and delivered doses were within ±3.0% for 25/27 SABR plans.

OC-0155: UK SABR Consortium Lung Dosimetry Audit; absolute dosimetry results

Purpose/Objective: The UK SABR Lung Consortium dose audit was designed to assess the positional and dosimetric accuracy of SABR lung treatment delivery. The audit has been carried out in 21 radiotherapy centres between October 2013 and July 2014 in order to provide an independent check of safe implementation and to identify problems in the modelling and delivery of SABR lung treatment. Materials and Methods: A mail based audit using EBT3 GafChromic film and alanine dosimeters was designed. A CIRS Model 002LFC anthropomorphic thorax phantom which contained 9 adjacent alanine pellets in the tip of a Farmer chamber shaped insert was scanned, structure sets for the ITV and alanine pellets were pre-delineated, and was sent to radiotherapy centres to be loaded into their treatment planning system. Each centre used this CT scan set to create a SABR plan using their current planning protocol (including dose, fractionation and coverage) and technique. The centres used their own margin to create the PTV. A range of delivery techniques were used including conformal, VMAT and Cyberknife and calculated using local algorithms (AAA, Collapsed Cone, Monte Carlo and Pencil beam). The doses determined by the alanine dosimeters were compared to expected doses determined by treatment plan system (TPS) calculation, film and local ionisation chamber measurements. Results: The mean % difference between the alanine measured doses, the TPS calculated doses, and the local chamber measurements found to be within 2% (1 SD) as given in table 1. As shown, alanine findings were supported by the film results.

OC-0154: UK SABR Consortium Lung Dosimetry Audit; relative dosimetry results

Purpose/Objective: The UK SABR Consortium QA group conducted a postal dosimetry audit of SABR lung plans at 21 UK centres. The purpose of this was to verify the accuracy of calculated dose distributions, improve confidence of centres in the early stages of implementing lung SABR and to establish a benchmark QA method. Here the results of the GafChromic film relative dosimetry arm of the audit are given. Materials and Methods: Individual centres were asked to plan a treatment to a pre-defined PTV in the CIRS Thorax phantom, using their clinical method and prescription dose. EBT3 GafChromic film was used to measure an axial plane of dose. Pins in the phantom facilitated alignment of the film and calculated dose planes. Gantry linac and Cyberknife centres were audited, using a variety of TPS with pencil beam, AAA, CCC, Acuros and Monte Carlo algorithms. Scanned films were compared to dose distributions calculated by the individual centres, using single red-channel dosimetry and a purpose-built Matlab application. Centres were also asked to irradiate additional calibration films to provide output-normalised optical density to dose calibration. Measured and calculated isodoses corresponding to 120, 100, 70 and 50% of prescription dose were compared (figure 1), and conformity and maximum distance to agreement were measured. For the areas bound by the 100, 50 and 30% calculated isodoses, local gamma analysis, mean gamma and gamma pass rate (at 3%, 2mm) and a mean dose comparison was performed. The latter was compared to the alanine dosimetry results. Results: The dosimetry of the calibration films was reproducible to ±0.9% (1.S.D), for doses ranging from 4.3 to 26.9 Gy. The audit relative dosimetry results are reported in table 1. Mean dose differences within the 100% calculated isodose line agreed well with alanine dosimetry; -0.1 ± 2.0 % (1.S.D). Gamma pass rates (%) and mean gamma results varied with some outlying measurements, mostly caused by small dose deviations within the PTV or at low doses. Isodose line agreement (figure 1) was generally much closer at the 70 and 100% dose levels, indicated by the lower S.D. (table 1, column 5). The exception was the centre using a pencil beam algorithm, where the measured prescription dose covered a significantly smaller area than that calculated, consistent with the algorithm’s known limitations calculating dose in low density lung surrounding tumour. Conclusions: Of the 21 UK centres audited, 74% of measurements were within ±3% agreement compared to calculated doses. Where appropriate, outlying centres have been offered support from the QA Group to bring their results into line. The EBT3 GafChromic film was found to be highly suited to a postal audit, reliably giving detailed information about the geometric and dosimetric accuracy of treatment.

Separating components of variation in measurement series using maximum likelihood estimation. Application to patient position data in radiotherapy.

Maximum likelihood estimation (MLE) is presented as a statistical tool to evaluate the contribution of measurement error to any measurement series where the same quantity is measured using different independent methods. The technique was tested against artificial data sets; generated for values of underlying variation in the quantity and measurement error between 0.5 mm and 3 mm. In each case the simulation parameters were determined within 0.1 mm. The technique was applied to analyzing external random positioning errors from positional audit data for 112 pelvic radiotherapy patients. Patient position offsets were measured using portal imaging analysis and external body surface measures. Using MLE to analyze all methods in parallel it was possible to ascertain the measurement error for each method and the underlying positional variation. In the (AP / Lat / SI) directions the standard deviations of the measured patient position errors from portal imaging were (3.3 mm / 2.3 mm / 1.9 mm), arising from underlying variations of (2.7 mm / 1.5 mm / 1.4 mm) and measurement uncertainties of (1.8 mm / 1.8 mm / 1.3 mm), respectively. The measurement errors agree well with published studies. MLE used in this manner could be applied to any study in which the same quantity is measured using independent methods.

Forward and inverse-planned intensity-modulated radiotherapy (IMRT) in the CHHiP trial: A comparison of dosimetry and normal tissue toxicity.

37 Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial investigating the use of hypofractionated radiotherapy dose schedules for treatment of localised prostate cancer. RT treatment employs a complex target volume treated with either a multi-segment “forward” plan or inverse-planned intensity-modulated radiotherapy (IMRT). This study compares dose-volume histogram (DVH) and toxicity data for rectum and bladder for the two planning techniques. Methods: Three hundred thirty seven patients (230 forward-planned [F]; 107 inverse-planned [I]) with prospectively collected 2 year toxicity and DVH data for rectum and bladder dose constraints were included. Patients were paired for comparison by matching on (1) rectum and prostate + seminal vesicle PTV volumes for the rectal dose comparison (53 matched pairs available); and (2) bladder and prostate-alone PTV volumes for bladder dose comparison (61 matched pairs). For the toxicity comparison patients were additionally matched on randomised d...