Edwin Aird

Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

BACKGROUND In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial. METHODS The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397. FINDINGS Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% CI 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade >/=2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >/=2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score >/=30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade >/=2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade >/=2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score >/=30) scale (HR 1.05 [0.81-1.36]). INTERPRETATION Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: Long-term results from the MRC RT01 randomised controlled trial

BACKGROUND The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. METHODS RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. FINDINGS Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003). INTERPRETATION At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. FUNDING UK Medical Research Council.

DOSE-VOLUME CONSTRAINTS TO REDUCE RECTAL SIDE EFFECTS FROM PROSTATE RADIOTHERAPY: EVIDENCE FROM MRC RT01 TRIAL ISRCTN 47772397

PURPOSE Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important. METHODS AND MATERIALS Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. RESULTS A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30<or=80%, V40<or=65%, V50<or=55%, V60<or=40%, V65<or=30%, V70<or=15%, and V75<or=3%. CONCLUSION Considering the entire dose distribution to the rectum by applying dose-volume constraints such as those tested here in the present will reduce the incidence of late rectal toxicity.

Quality assurance for prospective EORTC radiation oncology trials: the challenges of advanced technology in a multicenter international setting.

The European Organization for the Research and Treatment of Cancer (EORTC) is a pan-European structure charged with improving cancer treatment through the testing of new therapeutic strategies in phases I-III clinical studies. Properly conducted trials in radiation oncology are required to demonstrate superiority of a new treatment over the current standard. The Radiation Oncology Group (ROG) has initiated a complex quality assurance (QA) program to ensure safe and effective treatment delivery. Most modern trials are multicenter and multidisciplinary, further increasing the importance of early, strict and consistent QA in radiotherapy (RT). QART measures confirm whether a site possesses minimum staff and equipment for participation. Dummy runs, reviews of patient treatment plans and complex dosimetry checks verify the ability of an institution to comply with the protocol. Data required for evaluation are increasingly exchanged digitally, allowing detailed plan reconstruction, evaluation of target volume delineation and recalculation of dose-volume parameters for comparison against predefined standards. The five tiers of QA implemented in EORTC trials are reviewed, along with past, current and future QART initiatives. As substantial human and financial resources are increasingly invested in QART, the importance of cost-benefit analysis of QA and its impact on clinical outcome cannot be overstated.

Precision in reporting the dose given in a course of radiotherapy

A knowledge of the precise dose given in a course of radiotherapy is vital to the interpretation of the result. Despite this, an acceptable level of reporting was found in only 72 (36%) of 200 papers published in the two leading journals of radiation oncology. Analysis of the treatment data of the cases with head and neck tumours in the pilot study of CHART showed that the mean of the minimum tumour doses given was 5.1% lower than the mean of those at the intersection points. Had the same total dose been prescribed to the intersection point instead of the minimum there would have been a similar lowering of dose. There is evidence from published clinical data and a suggestion from an analysis of the CHART pilot study data that a dose difference as small as 5% may lead to real impairment or enhancement of tumour response, as well as altering the risk of morbidity. Inadequate reporting may lead to a false interpretation of a study and to its wrongful application. It is strongly recommended that it should be editorial policy to publish only those papers where the radiation dose is fully described.

Profile of European radiotherapy departments contributing to the EORTC Radiation Oncology Group (ROG) in the 21st century

PURPOSE Since 1982, the Radiation Oncology Group of the EORTC (EORTC ROG) has pursued an extensive Quality Assurance (QA) program involving all centres actively participating in its clinical research. The first step is the evaluation of the structure and of the human, technical and organisational resources of the centres, to assess their ability to comply with the current requirements for high-tech radiotherapy (RT). MATERIALS AND METHODS A facility questionnaire (FQ) was developed in 1989 and adapted over the years to match the evolution of RT techniques. We report on the contents of the current FQ that was completed online by 98 active EORTC ROG member institutions from 19 countries, between December 2005 and October 2007. RESULTS Similar to the data collected previously, large variations in equipment, staffing and workload between centres remain. Currently only 15 centres still use a Cobalt unit. All centres perform 3D Conformal RT, 79% of them can perform IMRT and 54% are able to deliver stereotactic RT. An external reference dosimetry audit (ERDA) was performed in 88% of the centres for photons and in 73% for electrons, but it was recent (<2 years) in only 74% and 60%, respectively. CONCLUSION The use of the FQ helps maintain the minimum quality requirements within the EORTC ROG network: recommendations are made on the basis of the analysis of its results. The present analysis shows that modern RT techniques are widely implemented in the clinic but also that ERDA should be performed more frequently. Repeated assessment using the FQ is warranted to document the future evolution of the EORTC ROG institutions.

Three-dimensional distribution of radiation within the breast: an intercomparison of departments participating in the START trial of breast radiotherapy fractionation

PURPOSE To examine the ability of computer planning systems to calculate the dose to the breast correctly in three dimensions. Both the absolute dose at the center of the breast and the accuracy of the isodose distributions were investigated. METHODS AND MATERIALS Measurements were performed in a water-filled breast phantom using an ionization chamber. Thirty-six sets of data obtained during the Standardization of Breast Radiotherapy breast fractionation trial quality assurance program were included in the analysis. The planning systems were grouped according to the algorithms used on the basis of the definitions given in International Commission on Radiation Units and Measurements Report No. 24. RESULTS Thirty-two of the 36 planning systems overestimated the dose to the center of the breast, with a mean measured/calculated dose ratio of 0.979 (SD 0.013). The relative dose within 2 cm of the lung was also overestimated. CONCLUSION Only one algorithm (collapsed cone) investigated in this study was able to calculate the dose at the center of the breast correctly in tangential breast radiotherapy. With modern algorithms, it is important to include a correction for the lower density of the lung, because the dose close to the interface between breast and lung tissue will also be lower than anticipated.

EORTC Radiation Oncology Group quality assurance platform: Establishment of a digital central review facility

OBJECTIVE Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning

PURPOSE Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas. MATERIALS AND METHODS RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF x CF); dose homogeneity in PTV (U). RESULTS Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV-PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated > 10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV(Dmin), improving CF. U correlated with PTV(Dmax). CONCLUSION Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

Contribution to normal tissue dose from concomitant radiation for two common kV-CBCT systems and one MVCT system used in radiotherapy.

BACKGROUND AND PURPOSE This study outlines the measured doses for three concomitant imaging modalities used in radiotherapy. MATERIAL AND METHODS Doses were measured using thermo luminescent dosemeters within pelvis and thorax anthropomorphic phantoms for the Varian On Board Imager (OBI), Elekta X-ray Volume Imager (XVI) and Tomotherapy HiArt II systems. Organ sites were selected to include those organs which would be irradiated by the treatment beam during the therapy exposure. RESULTS Doses for kilovoltage imaging systems are comparable within the pelvis phantom at 20-30 mGy. Thorax phantom doses are lower, especially where user specified protocols are used at 5-10 mGy. Tomotherapy doses are typically less than 10 mGy for both phantoms. CONCLUSIONS Concomitant imaging dose is a small fraction of the therapy dose, however, for a high fraction technique, the imaging dose can become comparable to the therapy dose outside primary target volume. Recommendations for optimisation of imaging in radiotherapy are presented.