Radiotherapy trial quality assurance processes: a systematic review.

Quality assurance remains a neglected component of many trials, particularly for technical interventions, such as surgery and radiotherapy, for which quality of treatment is an important component in defining outcomes. We aimed to evaluate evidence for the processes used in radiotherapy quality assurance of clinical trials. A systematic review was undertaken focusing on use of a pre-trial outlining benchmark case and subsequent on-trial individual case reviews of outlining for recruited patients. These pre-trial and on-trial checks are used to ensure consistency and standardisation of treatment for each patient recruited to the trial by confirming protocol compliance. Non-adherence to the trial protocol has been shown to have a negative effect on trial outcomes. 29 studies published between January, 2000, and December, 2022, were identified that reported on either outlining benchmark case results or outlining individual case review results, or both. The trials identified varied in their use of radiotherapy quality assurance practices and reporting of outcomes was inconsistent. Deviations from trial protocols were frequent, particularly regarding outlining. Studies correlating benchmark case results with on-trial individual case reviews provided mixed results, meaning firm conclusions could not be drawn regarding the influence of the pre-trial benchmark case on subsequent on-trial performance. The optimal radiotherapy quality assurance processes were unclear, and there was little evidence available. Improved reporting of outcomes from radiotherapy quality assurance programmes is needed to develop an evidence base for the optimal approach to radiotherapy quality assurance in trials.

CBCT-based deformable dose accumulation of external beam radiotherapy in cervical cancer.

Background: Delivered radiotherapy doses do not exactly match those planned for a course of treatment, largely due to inter-fraction changes in anatomy. In this study, accumulated delivered dose was calculated for a sample of cervical cancer patients, by deformably registering daily cone beam computed tomography (CBCT) images to the planning computed tomography (CT) scan. Planned and accumulated doses were compared for the clinical target volume (CTV), bladder, and rectum.Material and Methods: For 10 patients receiving 45 Gy in 25 fractions of external beam radiotherapy, daily dose distributions were calculated on CBCT. These images were deformed onto the planning CT and the dose was accumulated using Velocity 4.1 (Varian Medical Systems, Palo Alto, USA). The quality of deformable image registration was evaluated visually and by calculating Dice similarity coefficients and mean distance to agreement.Results: V95%>99% was achieved for the primary CTV in 9/10 patients for the planned dose distribution and 7/10 patients for the accumulated dose distribution. Primary CTV coverage by 95% of the prescription dose was reduced in one patient, due to an increase in anterior-posterior separation. Comparison of planned and accumulated dose volume histograms (DVHs) for the bladder and rectum found agreement within 5% at low and intermediate doses, but differences exceeded 20% at higher doses. Direct addition of CBCT DVHs was seen to be a poor estimate for the accumulated DVH at higher doses.Conclusion: Computation of delivered radiotherapy dose that accounts for inter-fraction anatomical changes is important for establishing dose-effect relationships. Updating delivered dose distributions after each fraction would support informed clinical decision making on any potential treatment interventions.

A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer.

BACKGROUND: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. METHODS: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. RESULTS: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen-nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094-0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24-0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08-0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). CONCLUSION: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.

Dosimetric comparison of volumetric modulated arc therapy (VMAT) and high-dose-rate brachytherapy (HDR-BT) for superficial skin irradiation with significant curvature in one or more planes.

PURPOSE: This study compares the plan quality of high-dose-rate brachytherapy (HDR-BT) and volumetric modulated arc therapy (VMAT) for superficial irradiation of large areas of skin with significant curvature in one or more planes. METHODS: A total of 14 patients from two centres previously treated with either HDR-BT or VMAT were retrospectively replanned using the alternative technique. Sites included scalp and lower limbs. Identical computed tomography (CT) scans, clinical target volume (CTV) and organs at risk (OARs) and prescription were used for both techniques. Conformity, skin surface dose and OAR doses were compared. RESULTS: Conformity index was consistently better with VMAT than HDR-BT (p < 0.01). Maximum skin surface dose (D0.1cc) had a higher mean of 49.6 Gy with HDR-BT compared to 31.4 Gy for VMAT (p < 0.01). Significantly smaller volumes of healthy tissue were irradiated with VMAT than with HDR-BT. This can be seen in brain volumes receiving 10, 20 and 30 Gy EQD2 and in extremities receiving 5 and 10 Gy. When close to the volume, the lens received significantly lower doses with VMAT (p < 0.01). CONCLUSION: In this small sample, VMAT gives equal coverage with lower OAR and skin surface doses than HDR-BT for both scalp and extremities. VMAT is a useful technique for treating large, superficial volumes with significant curvature in one or more planes.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer.

The aim of this study was to test the utility of AIMP3, an upstream regulator of DNA damage response following genotoxic stress, as a clinical biomarker in muscle-invasive bladder cancer (MIBC). AIMP3 was identified from a meta-analysis of a global gene-expression dataset. AIMP3 protein expression was determined by immunohistochemistry on a customised bladder cancer tissue-microarray (TMA). The mechanism of gene silencing was probed using methylation-specific PCR. The association between AIMP3 expression, Tp53 transactivity and genomic stability was analysed. In vitro AIMP3 translocation to the nucleus in response to ionising radiation was demonstrated using immunofluorescence. Radiosensitisation effects of siRNA-mediated AIMP3-knockdown were measured using colony forming assays. TMAs derived from patients enrolled in BCON, a Phase III multicentre radiotherapy trial in bladder cancer (ISRCTN45938399) were used to evaluate the association between AIMP3 expression and survival. The prognostic value of AIMP3 expression was determined in a TMA derived from patients treated by radical cystectomy. Loss of AIMP3 expression was frequent in MIBC and associated with impaired Tp53 transactivity and genomic instability. AIMP3-knockdown was associated with an increase in radioresistance. Loss of AIMP3 expression was associated with survival in MIBC patients following radiotherapy (HR = 0.53; 95% CI: 0.36 to 0.78, p = 0.002) but was not prognostic in the cystectomy set. In conclusion, AIMP3 expression is lost in a subset of bladder cancers and is significantly predictive of survival following radiotherapy in MIBC patients.

4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial.

BACKGROUND: Follicular lymphoma has been shown to be highly radiosensitive with responses to doses as low as 4 Gy in two fractions. This trial was designed to explore the dose response for follicular lymphoma comparing 4 Gy in two fractions with 24 Gy in 12 fractions METHODS: FORT is a prospective randomised, unblinded, phase 3 non-inferiority study comparing radiotherapy given as 4 Gy in two fractions with a standard dose of 24 Gy in 12 fractions. Entry criteria included all patients aged over 18 years, having local radiotherapy for radical or palliative local control, with follicular lymphoma or marginal zone lymphoma, who had received no previous treatment for at least 1 month before. The primary outcome was time to local progression analysed on an intention-to-treat basis. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Radiotherapy target sites were randomised (1:1) with minimisation stratified by histology (follicular lymphoma vs marginal zone lymphoma), treatment intent (palliative or curative) and centre. This trial is registered with ClinicalTrials.gov number, NCT00310167. FINDINGS: 299 sites were randomly assigned to 24 Gy and 315 sites to 4 Gy between April 7, 2006, and June 8, 2011, at 43 centres in the UK. After a median follow-up of 26 months (range 0·39-75·4), 91 local progressions had been recorded (21 in the 24 Gy group and 70 in the 4 Gy group). Time to local progression with 4 Gy was not non-inferior to 24 Gy (hazard ratio 3·42, 95% CI 2·09-5·55, p<0·0001). Eight (3%) of 282 patients in the 24 Gy group and four (1%) of 300 in the 4 Gy group had acute grade 3-4 toxic effects. Four (1%) patients in the 24 Gy group and four (1%) patients in the 4 Gy group had late toxic effects. Mucositis was the most common event in the 24 Gy group (two patients with acute mucositis and two with late mucositis; all grade 3) and was not reported in the 4 Gy group. The most common acute effect was pain at the site of irradiation (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3), and the most common late effect was fatigue (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3). INTERPRETATION: 24 Gy in 12 fractions is the more effective radiation schedule for indolent lymphoma and should be regarded as the standard of care. However, 4 Gy remains a useful alternative for palliative treatment. FUNDING: Cancer Research UK.

Re-irradiation practice and ESTRO/EORTC consensus recommendations: 2023 ASTRO education panel.

Indications for re-irradiation are increasing both for palliation and potentially curative attempts to achieve durable local control. This has been in part driven by the technological advances in the last decade including image-guided brachytherapy, volumetric-modulated arc therapy and stereotactic body radiotherapy. These enable high dose focal irradiation to be delivered to a limited target volume with minimal normal tissue re-irradiation. The European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) have collaboratively developed a comprehensive consensus on re-irradiation practices, aiming to standardise definitions, reporting, and clinical decision-making processes. The document introduces a universally applicable definition for reirradiation, categorised into two primary types based on the presence of geometric overlap of irradiated volumes and concerns for cumulative dose toxicity. It also identifies "repeat organ irradiation" and "repeat irradiation" for cases without such overlap, emphasising the need to consider toxicity risks associated with cumulative doses. Additionally, the document presents detailed reporting guidelines for re-irradiation studies, specifying essential patient and tumour characteristics, treatment planning and delivery details, and followup protocols. These guidelines are designed to improve the quality and reproducibility of clinical research, thus fostering a more robust evidence base for future re-irradiation practices. The consensus underscores the necessity of interdisciplinary collaboration and shared decision-making, highlighting performance status, patient survival estimates, and response to initial radiotherapy as critical factors in determining eligibility for re-irradiation. It advocates for a patient-centric approach, with transparent communication about treatment intent and potential risks. Radiobiological considerations, including the application of the linear-quadratic model, are recommended for assessing cumulative doses and guiding re-irradiation strategies. By providing these comprehensive recommendations, the ESTRO-EORTC consensus aims to enhance the safety, efficacy, and quality of life for patients undergoing re-irradiation, while paving the way for future research and refinement of treatment protocols in the field of oncology.

Quality-of-life outcomes in metastatic spinal cord compression: findings from the SCORAD trial.

PURPOSE: This article reports detailed quality-of-life data including preferred and actual place of care from SCORAD, the only large prospective randomized trial in metastatic spinal cord compression (MSCC). METHODS: SCORAD compared 2 doses of radiotherapy in patients with MSCC: 8 Gy single fraction and 20 Gy in 5 fractions. In total, 686 patients were randomized, of whom 590 had Health-Related Quality of Life (HRQoL) data collected at baseline and at least 1 later time point. HRQoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 supplemented with the QLU-C10D and data on place of care at weeks 1, 4, 8, and 12 postrandomization. Quality-of-Life Adjusted Survival was computed by multiplying Kaplan-Meier survival probabilities with the UK utility weights obtained from the QLU-C10D. RESULTS: Patients with a baseline physical functioning score of above 50 demonstrated a 28% reduction in the risk of death (hazard ratio [HR] = 0.72, 99% confidence interval [CI] = 0.54 to 0.95; P = .003). An increased risk of death was associated with fatigue (HR = 1.35, 99% CI = 1.03 to 1.76; P = .0040), dyspnea (HR = 1.61, 99% CI = 1.24 to 2.08; P < .001), and appetite loss (HR = 1.25, 99% CI = 0.99 to 1.59; P = .014). The preferred place of care for the majority was at home or with relatives (61%-74% across the 12 weeks) but achieved by only 53% at 8 weeks. CONCLUSIONS: Prolonged survival in patients with MSCC was associated with better HRQoL. More than 60% of patients preferred to be cared for at home or with relatives, but only half were able to achieve this. There was no difference in HRQoL between the multifraction and single-fraction groups. TRIAL REGISTRATION: ISRCTN97555949 and ISRCTN97108008.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Non-small cell lung cancer: histopathologic correlates for texture parameters at CT.

PURPOSE: To correlate computed tomographic (CT) texture in non-small cell lung cancer (NSCLC) with histopathologic markers for angiogenesis and hypoxia. MATERIALS AND METHODS: The study was institutional review board approved, and informed consent was obtained. Fourteen patients with NSCLC underwent CT prior to intravenous administration of pimonidazole (0.5 g/m(2)), a marker of hypoxia, 24 hours before surgery. Texture was assessed for unenhanced and contrast material-enhanced CT images by using a software algorithm that selectively filters and extracts texture at different anatomic scales (1.0 [fine detail] to 2.5 [coarse features]), with quantification of the standard deviation (SD) of all pixel values and the mean value of positive pixels (MPP) and uniformity of distribution of positive gray-level pixel values (UPP). After surgery, matched tumor sections were stained for angiogenesis (CD34 expression) and for markers of hypoxia (glucose transporter protein 1 [Glut-1] and pimonidazole). The percentage and average intensity of the tumor stained were assessed. A linear mixed-effects model was used to assess the correlations between CT texture and staining intensity. RESULTS: SD and MPP quantified from medium to coarse texture on contrast-enhanced CT images showed significant associations with the average intensity of tumor staining with pimonidazole (for SD: filter value, 2.5; slope = 0.003; P = .0003). UPP (medium to coarse texture) on unenhanced CT images showed a significant inverse association with tumor Glut-1 expression (filter value, 2.5; slope = -115.13; P = .0008). MPP quantified from medium to coarse texture on both unenhanced and contrast-enhanced CT images showed significant inverse associations with tumor CD34 expression (unenhanced CT: filter value, 1.8; slope = -0.0008; P = .003; contrast-enhanced CT: filter value, 1.8; slope = -0.0006; P = .004). CONCLUSION: Texture parameters derived from CT images of NSCLC have the potential to act as imaging correlates for tumor hypoxia and angiogenesis. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112428/-/DC1.

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

Operable non-small cell lung cancer: correlation of volumetric helical dynamic contrast-enhanced CT parameters with immunohistochemical markers of tumor hypoxia.

PURPOSE: To assess the relationship between helical dynamic contrast material-enhanced (DCE) computed tomographic (CT) parameters and immunohistochemical markers of hypoxia in patients with operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: After institutional review board approval was obtained, 20 prospective patients who were suspected of having NSCLC underwent whole-tumor DCE CT with kinetic modeling (Patlak analysis) 24 hours before scheduled surgery. Flow-extraction product (in milliliters per 100 milliliters per minute) and blood volume (in milliliters per 100 milliliters) were derived. After surgery, matched whole-tumor sections were stained for exogenous and endogenous markers of hypoxia (pimonidazole infused intravenously 24 hours before surgery, immediately after DCE CT; glucose transporter protein). Correlation between DCE CT parameters and immunohistochemical markers was assessed by using the Spearman rank correlation. DCE CT parameters and immunohistochemical markers were also compared according to pathologic subtype, grade, stage, and nodal status by using the Mann-Whitney test. P values less than .05 indicated a statistically significant difference. RESULT: Fourteen patients with confirmed primary NSCLC underwent resection. There were negative correlations between blood volume and pimonidazole staining (r = -0.48, P = .004), and between flow-extraction product and glucose transporter protein expression (r = -0.50, P = .002). Flow-extraction product was significantly higher in adenocarcinomas than in squamous cell tumors (17.73 vs 11.46; P = .043). Glucose transporter protein expression was significantly lower for adenocarcinomas than for squamous tumors (14.07 vs 33.03; P < .001) and in node negative than in node positive tumors (15.63 vs 23.85; P = .005). CONCLUSION: Blood volume and flow-extraction product derived at DCE CT correlated negatively with pimonidazole and glucose transporter protein expression, indicating the potential of these CT parameters as imaging biomarkers of hypoxia.

Radiotherapy-induced toxicity in prostate cancer patients with hip prostheses.

INTRODUCTION: Acute and late toxicity was analysed for prostate cancer patients with bilateral hip prostheses, who received fixed field intensity modulated radiotherapy (IMRT). The aims were (1) to establish whether toxicity rates differed from those of a control group with normal hips, (2) to develop a volumetric modulated arc therapy (VMAT) approach for patients with prostheses and (3) to compare doses to bladder and rectum for the control group, prostheses group and VMAT replans for the prostheses group. METHODS: Genitourinary (GU) and gastrointestinal (GI) toxicity was scored using Common Terminology Criteria for Adverse Events version 5.0. The incidence of grade 2 or worse (G2+) toxicity was compared using Fisher's exact test. Dose volume histograms (DVHs) and mean doses to organs at risk (OARs) were compared using signed rank tests. RESULTS: There were 17 patients in the prostheses group and 50 in the control group. Acute and late GU toxicity was similar. G2+ late GI toxicity incidence was 31% for the prostheses group and 14% for the control group (p = 0.14). Significant differences (p < 0.05) were seen between the OAR DVHs of the prostheses group who had IMRT and the control group for a range of intermediate doses. The rectum mean dose was significantly different (p < 0.001), but no difference was seen for the bladder mean dose (p = 0.08). CONCLUSIONS: No significant differences were seen in GU and GI toxicity incidence between patients with bilateral hip prostheses and a control group. The DVHs for bladder and rectum were significantly higher for patients with prostheses planned with IMRT. Replanning using a VMAT technique significantly reduced doses to the OARs, whilst maintaining good planning target volume coverage.

Comparison of multiple gene expression platforms for measuring a bladder cancer hypoxia signature.

Tumour hypoxia status provides prognostic information and predicts response to hypoxia­modifying treatments. A previous study by our group derived a 24­gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to compare platforms for generating signature scores, identify cut­off values for prospective studies, assess intra­tumour heterogeneity and confirm hypoxia relevance. Briefly, RNA was extracted from prospectively collected diagnostic biopsies of muscle invasive bladder cancer (51 patients), and gene expression was measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Cross­platform transferability of the gene signature was assessed using regression and concordance analysis. The cut­off values were the cohort median expression values. Intra­ and inter­tumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks (2­18) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24 h), and extracted RNA was run on custom TLDA cards. Hypoxia scores (HS) values showed good agreement between platforms: Clariom S vs. TLDA (r=0.72, P<0.0001; concordance 73%); Clariom S vs. NanoString (r=0.84, P<0.0001; 78%); TLDA vs. NanoString (r=0.80, P<0.0001; 78%). Cut­off values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (Clariom S). Intra­tumour heterogeneity in gene expression and HS (coefficient of variation 3.9%) was less than inter­tumour (7.9%) variability. HS values were higher in bladder cancer cells exposed to hypoxia compared with normoxia (P<0.02). In conclusion, the present study revealed that application of the 24­gene bladder cancer hypoxia signature was platform agnostic, cut­off values determined prospectively can be used in a clinical trial, intra­tumour heterogeneity was low and the signature was sensitive to changes in oxygen levels in vitro.

Prognostic factors for survival and ambulatory status at 8 weeks with metastatic spinal cord compression in the SCORAD randomised trial.

BACKGROUND: Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival. PATIENTS AND METHOD: SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348). RESULTS: The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p < 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p < 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set. CONCLUSIONS: Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.

Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results.

BACKGROUND AND PURPOSE: A randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma. Previous analysis, at median follow up of 85 months, demonstrated improved relapse free survival (RFS) with EBRT + HDR-BTb. This data has now been updated with a median follow up of 131 months. MATERIALS AND METHODS: From December 1997 to August 2005, patients were assigned either to EBRT alone delivering 55 Gy in 20 fractions over 4 weeks or EBRT followed by a temporary high-dose-rate implant delivering 2 × 8·5 Gy over 24 h. The primary endpoint was RFS defined by a PSA rise ≥2.0 µg/l above nadir, clinical progression or death. Actuarial survival rates and Hazard Ratios (HRs) were calculated using the Kaplan-Meier method and Cox's Proportional Hazard Model, respectively. Secondary endpoints were overall survival (OS), urinary and bowel toxicity. RESULTS: One hundred and six patients received EBRT alone and 110 EBRT + HDR-BTb. Median time to relapse was 137 months in the HDR-BTb arm compared to 82 months for EBRT alone (p = 0·01). A 27% risk of recurrence with EBRT alone was observed (p = 0·001), resulting in a 21% improvement in RFS at 12 years with EBRT + HDR-BTb. In multivariate analysis treatment arm, risk category and no androgen deprivation therapy were significant covariates for risk of relapse. Differences in overall survival were not significant. CONCLUSION: At 12 years there remains a significant improvement in RFS after EBRT + HDR-BTb; both treatments were equitoxic for severe late urinary and bowel events and urethral strictures.

Advances in radiotherapy in bone metastases in the context of new target therapies and ablative alternatives: A critical review.

In patients with bone metastases (BM), radiotherapy (RT) is used to alleviate symptoms, reduce the risk of fracture, and improve quality of life (QoL). However, with the emergence of concepts like oligometastases, minimal invasive surgery, ablative therapies such as stereotactic ablative RT (SABR), radiosurgery (SRS), thermal ablation, and new systemic anticancer therapies, there have been a paradigm shift in the multidisciplinary approach to BM with the aim of preserving mobility and function survival. Despite guidelines on using single-dose RT in uncomplicated BM, its use remains relatively low. In uncomplicated BM, single-fraction RT produces similar overall and complete response rates to RT with multiple fractions, although it is associated with a higher retreatment rate of 20% versus 8%. Complicated BM can be characterised as the presence of impending or existing pathologic fracture, a major soft tissue component, existing spinal cord or cauda equina compression and neuropathic pain. The rate of complicated BM is around 35%. Unfortunately, there is a lack of prospective trials on RT in complicated BM and the best dose/fractionation regimen is not yet established. There are contradictory outcomes in studies reporting BM pain control rates and time to pain reduction when comparing SABR with Conventional RT. While some studies showed that SABR produces a faster reduction in pain and higher pain control rates than conventional RT, other studies did not show differences. Moreover, the local control rate for BM treated with SABR is higher than 80% in most studies, and the rate of grade 3 or 4 toxicity is very low. The use of SABR may be preferred in three circumstances: reirradiation, oligometastatic disease, and radioresistant tumours. Local ablative therapies like SABR can delay change or use of systemic therapy, preserve patients' Qol, and improve disease-free survival, progression-free survival and overall survival. Moreover, despite the potential benefit of SABR in oligometastatic disease, there is a need to establish the optial indication, RT dose fractionation, prognostic factors and optimal timing in combination with systemic therapies for SABR. This review evaluates the role of RT in BM considering these recent treatment advances. We consider the definition of complicated BM, use of single and multiple fractions RT for both complicated and uncomplicated BM, reirradiation, new treatment paradigms including local ablative treatments, oligometastatic disease, systemic therapy, physical activity and rehabilitation.