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Highlights • PIVOTALboost evaluates benefits/toxicity of pelvic node RT and focal boost dose escalation. • Unfavourable intermediate/high risk and bulky local disease are most likely to benefit. • Functional MRI imaging is used to select patients for different types of dose escalation. • HDR brachytherapy or focal dose escalation with IMRT are used as options. • Training and support is provided to reduce variations of contouring and radiotherapy planning. • The trial is recruiting patients in 38 radiotherapy centres through the UK.

Highlights • Dosimetric benefits to the penile bulb was seen in patients treated with IGRT and reduced CTV-PTV margins. • Patients who had a lower planned dose to the penile bulb reported less erectile dysfunction. • A threshold mean penile bulb dose for erectile dysfunction was determined to around 20 Gy., Background and purpose The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy. Materials and methods Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed. Results Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p

Aims The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. Materials and methods Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. Results In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. Conclusion Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

Purpose: Investigating the feasibility of using low-cost commercially available silica beads as novel thermo-luminescence dosimeters (TLD) for postal dosimetry audit. Methods: A mail-based dosimetry audit was designed to assess the positional and dosimetric accuracy of SABR-lung treatment delivery using alanine and EBT3-film, placed in a CIRS-anthropomorphic thorax phantom. In conjunction, the silica beads were dosimetrically characterised as TLDs and cross-calibrated against the alanine. A CT-scan of the phantom with pre-delineated volumes was sent to 20 RT centres and used to create a SABR plan using local current protocols and techniques. The silica beads were held in an insert, designed to match that of the alanine holder and ionisation chamber to give the same measurement length. The doses determined by the silica beads were compared to those measured by alanine, the local ionisation chamber, film and the TPS calculation. Results: The mean percentage difference between the doses measured by the silica beads and the calculated doses by the TPS was found to be 0.7% and differed by 0.6%, 0.7%, and 1.3% from the alanine, film and local ionisation chamber measurements respectively. Conclusions: Results obtained with the silica beads agree well with those obtained from conventional detectors including alanine, film and ionisation chambers. This together with the waterproof and inert characteristics and minimal dose fading associated with silica bead TLDs confirm their potential as a postal dosimetry audit tool in both water and plastic phantoms which could withstand challenges of temperature and humidity variation, as well as postal service delays.

Highlights • Introduction of daily online prostate IGRT was feasible in a national randomised trial. • Dosimetric benefits seen in patients treated with IGRT and reduced CTV-PTV margins. • Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins., Background and purpose Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy. Materials and methods CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy. Results Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3–60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p

373 Background: The PIVOTALboost trial (ISRCTN80146950) recruits patients with intermediate and high risk, localised prostate cancer; it tests the role of pelvic node radiotherapy and the effectiveness of a focal intra-prostate IMRT boost. Prior to opening to recruitment a contouring QA program was designed aiming to improve consistency in clinical outlining. Methods: Intra-prostatic boosting was a new treatment method for all but 3 trial centers. Guidelines for boost contouring and pelvic node outlining were circulated. Clinicians were sent two different cases with the clinical case description, biopsy details, the diagnostic pre-biopsy multi-parametric MRI (T2W and DWI sequences) and planning CT and MRI scans. They were asked to contour prostate, seminal vesicle (CTVp, CTVpsv), lymph node (CTVn) for 1 case and boost volume (GTVpb) for both cases. The 3 lead trial clinicians contoured the cases independently, agreed on gold standard outlines and criteria for failing the submission. Center’ benchmark case submissions were reviewed and standardized feedback forms returned to each clinician. General issues were addressed during a trial launch workshop. Results: There was good agreement of the contours for CTVp, CTVpsv and CTVn between the 3 lead clinicians for the gold standard; more discussions were required to agree GTVpb. Criteria for re-submission were: contours >6mm beyond or >3mm inside the superior and inferior level, included OARs, excluded SV base or extracapsular extension. In addition, for GTVpb, the wrong segment, extension outside CTVp, outlining abnormalities or < 50% of the gold standard. 35 center and 54 clinicians submitted outlines: for CTVp/psv 24/54 failed, CTVn 14/54 failed, GTVpb 23/48 failed (6 investigators did not submit a volume). All center passed the re-submission; for the on trial outlining review, 9 centres have not recruited a patient for the on trial review process, 18 passed and 8 failed. Conclusions: Errors and inconsistencies were common in the benchmark outlining exercises for the trial. Individual feedback, guidelines and clinical support has reduced outlining variations without delaying the opening of the trial; it has helped to standardize contouring and engage clinicians in the trial process. Clinical trial information: 80146950.

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.

50 Background: PIVOTALBoost is a Phase III randomised controlled trial (CRUK/16/018) of radiotherapy to prostate and pelvic nodes versus prostate alone with or without prostate boost. To minimise impact of target volume delineation (TVD) variation on trial outcome, pre-trial radiotherapy quality assurance (RTQA) was implemented to identify and correct potential variations. Methods: Participating centres offering a prostate boost submitted two pre-accrual outlining benchmark cases: one with a central zone boost (GTVpb) only and another with GTVpb (peripheral zone), CTVp/psv and CTVn. A detailed outlining protocol and diagnostic information were provided to centres. Submitted outlines were compared to consensus volumes created by the trial management group (TMG). The TMG deemed the volumes acceptable or as having acceptable or unacceptable variation. Detailed feedback was provided for each submission. Unacceptable variations required resubmission. Results: 32 investigators submitted pre-trial outlines. GTVpb was the most incorrectly outlined volume; 22 (69%) outliners had unacceptable errors for case 2 GTVpb, 17 (53%) for case 1 GTVpb. Most common GTVpb error was inferior extent of lesion followed by incorrect lesion outlined. 12 (38%) of outliners had unacceptable errors for CTVp/psv, most commonly due to delineation at the prostate apex. 8 (25%) outliners had unacceptable CTVn mostly due to incorrect vessel delineation. Of 26 (81%) outliners required to resubmit at least 1 case, 3(12%) required a second resubmission due to unacceptable errors on first resubmission. Conclusions: The majority of pre-trial outlining submissions had unacceptable errors requiring resubmission of at least one case. This was predominantly due to boost delineation error which is a relatively new skill for prostate clinical oncologists in the UK. This suggests robust on-trial RTQA is imperative to minimise further variation. Clinical trial information: ISRCTN80146950.

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.

Summary 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.

Purpose To establish planning solutions for a concomitant three-level radiation dose distribution to the breast using linear accelerator- or tomotherapy-based intensity-modulated radiotherapy (IMRT), for the U.K. Intensity Modulated and Partial Organ (IMPORT) High trial. Methods and Materials Computed tomography data sets for 9 patients undergoing breast conservation surgery with implanted tumor bed gold markers were used to prepare three-level dose distributions encompassing the whole breast (36 Gy), partial breast (40 Gy), and tumor bed boost (48 or 53 Gy) treated concomitantly in 15 fractions within 3 weeks. Forward and inverse planned IMRT and tomotherapy were investigated as solutions. A standard electron field was compared with a photon field arrangement encompassing the tumor bed boost volume. The out-of-field doses were measured for all methods. Results Dose–volume constraints of volume >90% receiving 32.4 Gy and volume >95% receiving 50.4 Gy for the whole breast and tumor bed were achieved. The constraint of volume >90% receiving 36 Gy for the partial breast was fulfilled in the inverse IMRT and tomotherapy plans and in 7 of 9 cases of a forward planned IMRT distribution. An electron boost to the tumor bed was inadequate in 8 of 9 cases. The IMRT methods delivered a greater whole body dose than the standard breast tangents. A contralateral lung volume >2.5 Gy was increased in the inverse IMRT and tomotherapy plans, although it did not exceed the constraint. Conclusion We have demonstrated a set of widely applicable solutions that fulfilled the stringent clinical trial requirements for the delivery of a concomitant three-level dose distribution to the breast.

135 Background: ED remains a common toxicity of prostate RT despite technological advances. Penile bulb (PB) dose has been proposed as a predictor of ED post RT. The main objective of this study was to develop NTCP models for ED. Methods: 162 men treated within the CHHiP IGRT substudy (CRUK/06/16) had baseline clinical data, PB dosimetric data & evaluation of ED using EPIC-26 at least 3 years post RT. Planning CT and reference dose distributions were imported into analysis software (VODCA, MSS GmbH) and PB retrospectively contoured by one clinician. The defined endpoint (severe ED) was a standardised average value of 0-33 for EPIC-26 sexual domain. Predictive models of ED were generated using PB dose in EQD2 (α/β ratio = 3Gy) & clinical data (age, diabetes, hypertension, NCCN risk group, baseline PSA, hormone therapy, IGRT, margin size, PB volume). Multivariate logistic regression method using resampling methods was applied to select model order and parameters. Models were fitted using logistic regression of the form Probability = eA(x)/1+eA(x), where A(x) = constant + sum of (variables * associated regression coefficients). Model performance was evaluated through area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow (HL) goodness-of-fit test. Results: 101/162 (62%) men had severe ED with statistically significant difference in PB max and mean dose between those patients with or without severe ED (max: 61.8Gy vs 43Gy & mean: 27.4Gy vs 14Gy respectively; p = 0.001). In the univariate analyses, age, diabetes, risk group, PB mean and max doses were significantly associated with EPIC calculated severe ED. The optimal NTCP model (AUC 0.78; CI 0.71-0.86: p for HL = 0.75) for EPIC calculated severe ED included age, PB mean dose and diabetes where A(x) = -10.13+(0.14*age)+(0.03*PB mean dose)+(2.88 if diabetic). A comparable model using clinician completed outcomes will be reported. Conclusions: This study provides the first known clinical prediction model for ED including PB dose, with good model performance. The determined predictors for the NTCP model of severe ED in this cohort were PB mean dose, age & diabetes. External validation of this model is desirable. Clinical trial information: 97182923.

Introduction During commissioning of the Pinnacle (Philips) treatment planning system (TPS) the margining algorithm was investigated and was found to produce larger PTVs than Plato (Nucletron) for identical GTVs. Subsequent comparison of PTV volumes resulting from the QA outlining exercise for the CHHIP (Conventional or Hypofractionated High Dose IMRT for Prostate Ca.) trial confirmed that there were differences in TPS's margining algorithms. Margining and the clinical impact of the different PTVs in seven different planning and virtual simulation systems (Pinnacle, Plato, Prosoma (MedCom), Eclipse (7.3 and 7.5) (Varian), MasterPlan (Nucletron), Xio (CMS) and Advantage Windows (AW) (GE)) is investigated, and a simple test for 3D margining consistency is proposed. Methods Using each TPS, two different sets of prostate GTVs on 2.5mm and 5mm slices were margined according to the CHHIP protocol to produce PTV3 (prostate+5mm/0mm post), PTV2 (PTV3+5mm) and PTV1 (prostate and seminal vesicles+10mm). GTVs and PTVs were imported into Pinnacle for volume calculation. DVHs for 5mm slice plans, created using the smallest PTVs, were recalculated on the largest PTV dataset and vice versa. Since adding a margin of 50mm to a structure should give the same result as adding five margins of 10mm, this was tested for each TPS (consistency test) using an octahedron as the GTV and CT datasets with 2.5mm and 5mm slices. Results The CHHIP PTV3 and PTV1 volumes had a standard deviation, across the seven systems, of 5% and PTV2 (margined twice) 9%, on the 5mm slices. For 2.5mm slices the standard deviations were 4% and 6%. The ratio of the Pinnacle and the Eclipse 7.3 PTV2 volumes was 1.25. Rectal doses were significantly increased when encompassing Pinnacle PTVs ( V 50 =42.8%), compared to Eclipse 7.3 PTVs ( V 50 =36.4%). Conversely, fields that adequately treated an Eclipse 7.3 PTV2 were inadequate for a Pinnacle PTV2. AW and Plato PTV volumes were the most consistent (0.3%) and (−0.4%). However, the 1×50mm margin in Pinnacle produced a 15.9% larger volume than 5×10mm margins, while for Eclipse 7.3 the single margined volume was 14.3% smaller. These inconsistencies were reduced to ∼5% by adjusting the superior/inferior margins. Conclusions Accurate margin algorithms are necessary to ensure that volume expansion does not add extra uncertainty to the radiotherapy planning process. We have found significant differences in the 3D margining algorithms of TPSs, devised a simple test to predict inconsistency and suggested corrective action to minimise the variation.

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.

Objective: To determine if subsets of patients may benefit from smaller or larger margins when using laser setup and bony anatomy verification of breast tumour bed (TB) boost radiotherapy (RT). Methods: Verification imaging data acquired using cone-beam CT, megavoltage CT or two-dimensional kilovoltage imaging on 218 patients were used (1574 images). TB setup errors for laser-only setup (dlaser) and for bony anatomy verification (dbone) were determined using clips implanted into the TB as a gold standard for the TB position. Cases were grouped by centre-, patient- and treatment-related factors, including breast volume, TB position, seroma visibility and surgical technique. Systematic (Σ) and random (σ) TB setup errors were compared between groups, and TB planning target volume margins (MTB) were calculated. Results: For the study population, Σlaser was between 2.8 and 3.4 mm, and Σbone was between 2.2 and 2.6 mm, respectively. Females with larger breasts (p = 0.03), easily visible seroma (p ≤ 0.02) and open surgical technique (p ≤ 0.04) had larger Σlaser. Σbone was larger for females with larger breasts (p = 0.02) and lateral tumours (p = 0.04). Females with medial tumours (p

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.

Purpose To report on local tumor control after 106 Ru brachytherapy for choroidal melanoma. Methods and Materials A total of 458 patients with choroidal melanoma were treated at a single institution between January 1993 and December 2001. The tumors had a median longest basal dimension of 10.6 mm and a median height of 3.2 mm. The brachytherapy was administered using a 15- or 20-mm plaque. For posterior tumors, the plaque was positioned eccentrically with its posterior edge aligned with the posterior tumor margin to reduce the radiation dose to the optic disk and fovea. A minimal scleral dose sufficient to cause visible choroidal atrophy provided a permanent ophthalmoscopic record of the distribution of choroidal irradiation. If radiotherapy to the posterior tumor was uncertain, adjunctive transpupillary thermotherapy was administered 6 months postoperatively. Results The actuarial rates of tumor recurrence were 1%, 2%, and 3% at 2, 5, and 7 years, respectively. Local tumor recurrence correlated with the longest basal tumor dimension (Cox univariate analysis, p = 0.02, risk ratio 1.41, 95% confidence interval 1.06–1.88). Seven of the nine eyes with recurrent tumor were salvaged with additional conservative therapy. Conclusion The low rate of local tumor recurrence suggests that ruthenium plaque radiotherapy is effective with good case selection and if special measures are taken to ensure that the plaque is positioned correctly.

Purpose To present the American Brachytherapy Society (ABS) guidelines for plaque brachytherapy of choroidal melanoma and retinoblastoma. Methods and Materials An international multicenter Ophthalmic Oncology Task Force (OOTF) was assembled to include 47 radiation oncologists, medical physicists, and ophthalmic oncologists from 10 countries. The ABS-OOTF produced collaborative guidelines, based on their eye cancer–specific clinical experience and knowledge of the literature. This work was reviewed and approved by the ABS Board of Directors as well as within the journal's peer-reivew process. Results The ABS-OOTF reached consensus that ophthalmic plaque radiation therapy is best performed in subspecialty brachytherapy centers. Quality assurance, methods of plaque construction, and dosimetry should be consistent with the 2012 joint guidelines of the American Association of Physicists in Medicine and ABS. Implantation of plaque sources should be performed by subspecialty-trained surgeons. Although there exist select restrictions related to tumor size and location, the ABS-OOTF agreed that most melanomas of the iris, ciliary body, and choroid could be treated with plaque brachytherapy. The ABS-OOTF reached consensus that tumors with gross orbital extension and blind painful eyes and those with no light perception vision are unsuitable for brachytherapy. In contrast, only select retinoblastomas are eligible for plaque brachytherapy. Prescription doses, dose rates, treatment durations, and clinical methods are described. Conclusions Plaque brachytherapy is an effective eye and vision-sparing method to treat patients with intraocular tumors. Practitioners are encouraged to use ABS-OOTF guidelines to enhance their practice.

2 Background: We aimed to explore the dose response relationship for two 3 Gray (Gy) hypofractionated radiotherapy (hRT) schedules for localised prostate cancer (PCa). Methods: hRT schedules of 60Gy/20 fractions (f) and 57Gy/19f were compared with conventional RT (cRT) 74Gy/37f; iso-effective for alpha-beta ratios of 2.5Gy and 1.5Gy respectively. The trial was powered to demonstrate non-inferiority between each hRT schedule and cRT, with 3,213 patients (pt) needed to rule out 5% inferiority (80% power, 1-sided alpha 5%) assuming 70% event-free rate in cRT, corresponding to a critical hazard ratio (HR) of 1.21. The trial was not formally powered to directly compare the two hRT schedules. Pt with N0 T1b-T3a localised PCa were randomized (1:1:1 ratio). The primary endpoint was PCa progression (freedom from biochemical failure by Phoenix consensus guidelines or PCa recurrence). Acute toxicity was assessed up to 18 weeks post treatment and late side effects to 5 years (yr) by RTOG, LENT-SOM and patient reported outcomes (PROs). Results: 3,216 pts were randomized between 2002 and 2011; 1,065 (74Gy), 1,074 (60Gy), 1,077 (57Gy). Baseline characteristics were well balanced across groups: median age 69 yr; NCCN risk group 15% low, 73% intermediate, 12% high. With median follow up 5.2yr, 5yr progression-free rate (95% CI) was 74Gy: 88.3% (86.0%, 90.2%); 60Gy: 90.6% (88.5%, 92.3%), 57Gy: 85.9 (83.4, 88.0); HR60/74: 0.83, 90% CI (0.68, 1.03), HR57/74: 1.20, 90% CI (0.99, 1.45). Significantly more events were observed with 57Gy compared to 60Gy; HR57/60: 1.44, 90% CI (1.18, 1.75), log-rank p=0.003. No significant difference in acute RTOG bladder or bowel toxicity was observed between hRT schedules. Late toxicity profile was favorable; with grade 2+ RTOG bladder (60Gy: 16/960 (1.7%); 57Gy: 11/962 (1.1%), p=0.34) and bowel (60Gy: 28/960 (2.9%); 57Gy: 17/962 (1.8%), p=0.10) toxicity at 2yr. Analysis of LENT-SOM and PROs supported these results. Conclusions: With 5 yr follow-up treatment with a 3Gy schedule of 60Gy/20f shows improved treatment efficacy compared to 57Gy/19f and is non-inferior to 74Gy/37f with a similar low level of acute and late normal tissue damage. Clinical trial information: ISRCTN97182923.

To report on conservation of visual acuity after Ruthenium(106) (Ru-106) brachytherapy of choroidal melanoma.This study was a noncomparative interventional case series of 458 patients with choroidal melanoma treated at a single center between January 1993 and December 2001. The intervention consisted of Ru-106 brachytherapy delivering minimum scleral and apex doses of 300 Gy and 80 Gy, respectively, using a 15-mm or 20-mm plaque. For discrete, posterior tumors, the plaque was positioned eccentrically with its posterior edge aligned with the posterior tumor margin. To ensure correct plaque positioning, any overlying extraocular muscles were dis-inserted, and the locations of both tumor and plaque edges were confirmed by transillumination and indentation. The main outcome measures were conservation of vision of 20/40 or better, 20/200 or better, and Counting Fingers or better, according to baseline variables.The actuarial rate of conservation of 20/40 or better was 55% at 9 years, loss of such vision correlating with posterior tumor extension (p0.001), temporal tumor location (p = 0.001), increased tumor height (p = 0.01), and older age (p0.01) (Cox multivariate analysis). Similar analyses showed conservation of 20/200 or better in 57% of eyes at 9 years, loss correlating with reduced initial visual acuity (p0.001), posterior tumor extension (p0.001), and temporal tumor location (p = 0.006). Counting Fingers or better vision was conserved in 83% of patients at 9 years, loss correlating with increased tumor height (p0.0001). Local tumor recurrence occurred in 9 patients (actuarial rate, 3% at 9 years).Ruthenium(106) brachytherapy of posterior choroidal melanoma achieves good conservation of vision if the tumor does not extend close to the optic nerve or fovea.

Background and purpose Clinical trials have indicated the need for irradiation of the tumour-bearing quadrant in patients with operable breast cancer treated by conservation therapy even under circumstances where there has been complete pathologic clearance. The aim of this phase II trial was to replace whole breast irradiation with brachytherapy to the tumour bed. Patients and methods A series of 50 patients with operable breast cancers measuring ≤4 cm diameter were treated by combination therapy comprising tumour excision axillary clearance and synoperative insertion of a rigid implant to the tumour bed. The implant was after-loaded with medium dose rate Cs 137 sources giving a dose of 45Gy in daily four fractions of about 6 h duration. No external beam radiotherapy was given. Results After a median follow-up of 6.3 years, of the 49 evaluable patients, 80% were alive without relapse. Of the 9 patients (18%) who developed a breast relapse, the site of recurrence was in the index quadrant in 7 cases (78%). Of the series, 26 (81%) gave a subjective rating of cosmetic outcome which was excellent or good. Objectively the treated breast was deemed to be normal in 11 (42%) and abnormal in 15 (58%). Conclusions This phase II study suggests that in a selected group of patients with early breast cancer, external whole breast radiotherapy can be replaced by interstitial irradiation to the tumour bed without compromising local disease control and giving an excellent or good cosmetic outcome in the majority of cases.

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 dose schedule. Results: Forward-planned patients had significantly larger volumes of rectum irradiated to 50 to 70Gy and bladder at 50 to 60Gy. In contrast, inverse-planned patients had significantly larger volumes of bladder irradiated to 74 Gy. Acute bowel toxicity (G2+ toxicity within 18 weeks of start of RT) was significantly worse in forward-planned patients (27/53 [52%] F vs 11/53 [21%] I; Mann-Whitney p=0.0002). There were no significant differences in acute urinary symptoms. Late toxicity was rare in both planning groups with only two patients (0 F; 2 I) reporting RTOG G2+ bowel/bladder effects at 24 months. Considering LENTSOM data, there was a suggestion of less late bowel toxicity in the inverse group (G1+ at 18 months: 16/53 (30%) F vs. 6/53 (11%) I; p=0.008). Patient reported outcomes of bowel habits showed no consistent differences between planning methods, although there was a tendency for worse urinary function scores in the inverse group at 12 months. Conclusions: Both planning techniques were associated with low late toxicity. Significant differences were found between DVHs from forward and inverse plans. There were some associations between DVH differences and normal tissue effects; these resolved by 2 years. Clinical trial information: CRUK/06/016.

using the linac control system (LCS) software 'Elekta RTD 7'. Later the LCS was replaced by Integrity 1.1 which allows Elekta users to introduce continuous variable dose rate (CVDR) on their linac instead of dose rate variation in discrete steps. Starting from the settings used in the clinical plan, different plans were generated by changing TPS and LCS VMAT-parameters. All plans were delivered to investigate their influence on linac behaviour during delivery. Parameters varied in the TPS were 1) minimum and maximum allowed dose rate, 2) constant or continuous variable gantry speed and 3) maximum gantry speed change per segment. Parameters varied in the LCS were 1) discrete dose rate variation or CVDR, 2) maximum allowed gantry speed and 3) gantry inertia compensation distance (ICD). All plans were generated using the same dose and dose-volume objectives. Differences in target coverage and organ at risk sparing were negligible, and the resulting dose distributions met in all instances the planning criteria. Plan efficiency was analyzed by recording the delivery time. Linac behaviour was characterized by comparing the actual gantry angle with the requested gantry angle. Results: Introduction of CVDR improved delivery efficiency and linac behaviour most. When using maximum allowed gantry speed, occasionally the delivery was still inhibited by the LCS. Reducing both the maximum allowed gantry speed from the initial 6°/s to 5°/s and changing to CVDR resulted in delivery without interruptions keeping the delivery time the same. Changes made to the other variables did not result in faster delivery or behaviour changes of the gantry rotation. The only exception was increasing the ICD value which resulted in a smoother gantry rotation motion but also in a prolonged delivery time. Conclusions: Introduction of CVDR minimized most of the irregular gantry rotation resulting in faster plan delivery. Depending on the gantry acceleration or deceleration requested by the LCS inhibits may still occur, although less frequent compared to delivery using discrete dose rates. For inhibit-free plan delivery a reduction of the maximum allowed gantry speed is also required. Clinics which do not have the CVDR option available may already improve linac behaviour by reducing the maximum allowed gantry speed or increase the ICD distance. Both options will result in slightly prolonged delivery times. Although much improvement has been made using CVDR and gantry speed limitations, more data is needed to clarify the influence of LCS parameters. This knowledge will ease and speed up the introduction of smooth and inhibit-free VMAT delivery for other disease sites.

BackgroundWhole-breast radiotherapy (WBRT) is the standard treatment for breast cancer following breast-conserving surgery. Evidence shows that tumour recurrences occur near the original cancer: the tumour bed. New treatment developments include increasing dose to the tumour bed during WBRT (synchronous integrated boost) and irradiating only the region around the tumour bed, for patients at high and low risk of tumour recurrence, respectively. Currently, standard imaging uses bony anatomy to ensure accurate delivery of WBRT. It is debatable whether or not more targeted treatments such as synchronous integrated boost and partial-breast radiotherapy require image-guided radiotherapy (IGRT) focusing on implanted tumour bed clips (clip-based IGRT).ObjectivesPrimary – to compare accuracy of patient set-up using standard imaging compared with clip-based IGRT. Secondary – comparison of imaging techniques using (1) tumour bed radiotherapy safety margins, (2) volume of breast tissue irradiated around tumour bed, (3) estimated breast toxicity following development of a normal tissue control probability model and (4) time taken.DesignMulticentre observational study embedded within a national randomised trial: IMPORT-HIGH (Intensity Modulated and Partial Organ Radiotherapy – HIGHer-risk patient group) testing synchronous integrated boost and using clip-based IGRT.SettingFive radiotherapy departments, participating in IMPORT-HIGH.ParticipantsTwo-hundred and eighteen patients receiving breast radiotherapy within IMPORT-HIGH.InterventionsThere was no direct intervention in patients’ treatment. Experimental and control intervention were clip-based IGRT and standard imaging, respectively. IMPORT-HIGH patients received clip-based IGRT as routine; standard imaging data were obtained from clip-based IGRT images.Main outcome measuresDifference in (1) set-up errors, (2) safety margins, (3) volume of breast tissue irradiated, (4) breast toxicity and (5) time, between clip-based IGRT and standard imaging.ResultsThe primary outcome of overall mean difference in clip-based IGRT and standard imaging using daily set-up errors was 2–2.6 mm (p 3(range 11–193 cm3) compared with standard imaging. Difference in median time required to perform clip-based IGRT compared with standard imaging was X-ray imaging technique dependent (range 8–76 seconds). It was not possible to estimate differences in breast toxicity, the normal tissue control probability model indicated that for breast fibrosis maximum radiotherapy dose is more important than volume of tissue irradiated.Conclusions and implications for clinical practiceMargins of less than 8 mm cannot be used safely without clip-based IGRT for patients receiving concomitant tumour bed boost, as there is a risk of geographical miss of the tumour bed being treated. In principle, smaller but accurately placed margins may influence local control and toxicity rates, but this needs to be evaluated from mature clinical trial data in the future.FundingThe National Institute for Health Research Efficacy and Mechanism Evaluation programme.