The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG).

PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

Australian & New Zealand Faculty of Radiation Oncology Genito-Urinary Group: 2011 consensus guidelines for curative radiotherapy for urothelial carcinoma of the bladder.

Curative radiotherapy, with or without concurrent chemotherapy, is recognized as a standard treatment option for muscle-invasive bladder cancer. It is commonly used for two distinct groups of patients: either for those medically unfit for surgery, or as part of a 'bladder preserving' management plan incorporating the possibility of salvage cystectomy. However, in both situations, the approach to radiotherapy varies widely around the world. The Australian and New Zealand Faculty of Radiation Oncology Genito-Urinary Group recognised a need to develop consistent, evidence-based guidelines for patient selection and radiotherapy technique in the delivery of curative radiotherapy. Following a workshop convened in May 2009, a working party collated opinions and conducted a wide literature appraisal linking each recommendation with the best available evidence. This process was subject to ongoing re-presentation to the Faculty of Radiation Oncology Genito-Urinary Group members prior to final endorsement. These Guidelines include patient selection, radiation target delineation, dose and fractionation schedules, normal tissue constraints and investigational techniques. Particular emphasis is given to the rationale for the target volumes described. These Guidelines provide a consensus-based framework for the delivery of curative radiotherapy for muscle-invasive bladder cancer. Widespread input from radiation oncologists treating bladder cancer ensures that these techniques are feasible in practice. We recommend these Guidelines be adopted widely in order to encourage a uniformly high standard of radiotherapy in this setting, and to allow for better comparison of outcomes.

Prolonged survival in a patient with choroidal metastases from urothelial bladder cancer.

Choroidal metastases secondary to urothelial carcinoma are extremely rare and are usually associated with an extremely poor prognosis. We present a case of an 88-year-old man with newly diagnosed urothelial carcinoma of the bladder who presented with acute loss of vision before commencing definitive concurrent chemoradiotherapy to the bladder. Ophthalmological examination demonstrated bilateral choroidal metastases. He received palliative radiotherapy to the orbits and completed his planned radiotherapy to the bladder. He remained disease-free at last follow-up 4 years after the completion of treatment. We review the literature particularly with regard to diagnosis and management of choroidal metastases. Choroidal metastases should be considered in a patient with a history of urothelial cancer presenting with new onset of eye symptoms.

Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach.

BACKGROUND: We retrospectively reviewed outcomes in patients treated with radiotherapy (RT) for cutaneous head and neck carcinoma with perineural invasion (PNI), with the aim of developing risk-adapted treatment guidelines. METHODS: A total of 118 patients were treated with RT between April 1992 and July 2000. Ninety-seven patients had PNI discovered through histology (pPNI) and 21 patients had symptoms/signs of PNI (cPNI). All received RT (median dose, 55 Gy; range, 17-74): 114 postoperatively and 4 definitively. Median follow-up was 84 months (range, 4-201). RESULTS: The 5-year local control (LC) rates were 90% with pPNI and 57% with cPNI (p < .0001). The pPNI and cPNI groups also differed in relapse-free survival (76% vs 46%, p = .003), disease-specific survival (90% vs 76%, p = .002), and overall survival (69% vs 57%, p = .03). pPNI patients with BCC histology (n = 42) had better LC (97% vs 84%, p = .02) than pPNI SCC (n = 55). CONCLUSION: Surgery plus RT provides a high rate of LC in patients with pPNI, particularly those with BCC. Therapeutic improvements are needed for patients with cPNI.

Post-prostatectomy radiation therapy: consensus guidelines of the Australian and New Zealand Radiation Oncology Genito-Urinary Group.

BACKGROUND AND PURPOSE: Three randomised trials have demonstrated the benefit of adjuvant post-prostatectomy radiotherapy (PPRT) for high risk patients. Data also documents the effectiveness of salvage radiotherapy following a biochemical relapse post-prostatectomy. The Radiation Oncology Genito-Urinary Group recognised the need to develop consensus guidelines on to whom, when and how to deliver PPRT. MATERIALS AND METHODS: Draft guidelines were developed and refined at a consensus conference in June 2006 attended by 63 delegates where urological, radiotherapy and diagnostic imaging experts spoke on aspects of PPRT. Unresolved issues were further developed by working parties and redistributed until consensus was reached. RESULTS: Central to the recommendations is that patients with positive surgical margins, seminal vesicle invasion and/or extracapsular extension have a high risk of residual local disease and should be informed of the options of either immediate adjuvant radiotherapy or active surveillance with early salvage in the event of biochemical recurrence. Salvage radiotherapy should be instituted at the earliest confirmation of biochemical recurrence. Detailed contouring guidelines have been developed, defining the regions at risk of residual microscopic disease which should be included in the clinical target volume. The recommended doses are 60-64Gy for adjuvant, and 60-66Gy for salvage radiotherapy. The role of hormone therapy in conjunction with PPRT is yet to be defined. CONCLUSIONS: These consensus guidelines have been developed to give clinical and technical guidance to radiation oncologists and urologists in the management of high risk post-prostatectomy patients.

Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy.

PURPOSE: We sought to derive and validate an interdisciplinary consensus definition for the anatomic boundaries of the postoperative clinical target volume (CTV, prostate bed). METHODS AND MATERIALS: Thirty one patients who had planned for radiotherapy after radical prostatectomy were enrolled and underwent computed tomography and magnetic resonance imaging (MRI) simulation prior to radiotherapy. Through an iterative process of consultation and discussion, an interdisciplinary consensus definition was derived based on a review of published data, patterns of local failure, surgical practice, and radiologic anatomy. In validation, we analyzed the distribution of surgical clips in reference to the consensus CTV and measured spatial uncertainties in delineating the CTV and vesicourethral anastomosis. Clinical radiotherapy plans were retrospectively evaluated against the consensus CTV (prostate bed). RESULTS: Anatomic boundaries of the consensus CTV (prostate bed) are described. Surgical clips (n = 339) were well distributed throughout the CTV. The vesicourethral anastomosis was accurately localized using central sagittal computed tomography reconstruction, with a mean +/- standard deviation uncertainty of 1.8 +/- 2.5 mm. Delineation uncertainties were small for both MRI and computed tomography (mean reproducibility, 0-3.8 mm; standard deviation, 1.0-2.3); they were most pronounced in the anteroposterior and superoinferior dimensions and at the superior/posterior-most aspect of the CTV. Retrospectively, the mean +/- standard deviation CTV (prostate bed) percentage of volume receiving 100% of prescribed dose was only 77% +/- 26%. CONCLUSIONS: We propose anatomic boundaries for the CTV (prostate bed) and present evidence supporting its validity. In the absence of gross recurrence, the role of MRI in delineating the CTV remains to be confirmed. The CTV is larger than historically practiced at our institution and should be encompassed by a microscopic tumoricidal dose.

Comparison of localization performance with implanted fiducial markers and cone-beam computed tomography for on-line image-guided radiotherapy of the prostate.

PURPOSE: The aim of this work was to assess the accuracy of kilovoltage (kV) cone-beam computed tomography (CBCT)-based setup corrections as compared with orthogonal megavoltage (MV) portal image-based corrections for patients undergoing external-beam radiotherapy of the prostate. METHODS AND MATERIALS: Daily cone-beam CT volumetric images were acquired after setup for patients with three intraprostatic fiducial markers. The estimated couch shifts were compared retrospectively to patient adjustments based on two orthogonal MV portal images (the current clinical standard of care in our institution). The CBCT soft-tissue based shifts were also estimated by digitally removing the gold markers in each projection to suppress the artifacts in the reconstructed volumes. A total of 256 volumetric images for 15 patients were analyzed. RESULTS: The Pearson coefficient of correlation for the patient position shifts using fiducial markers in MV vs. kV was (R2 = 0.95, 0.84, 0.81) in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The correlation using soft-tissue matching was as follows: R2 = 0.90, 0.49, 0.51 in the LR, AP and SI directions. A Bland-Altman analysis showed no significant trends in the data. The percentage of shifts within a +/-3-mm tolerance (the clinical action level) was 99.7%, 95.5%, 91.3% for fiducial marker matching and 99.5%, 70.3%, 78.4% for soft-tissue matching. CONCLUSIONS: Cone-beam CT is an accurate and precise tool for image guidance. It provides an equivalent means of patient setup correction for prostate patients with implanted gold fiducial markers. Use of the additional information provided by the visualization of soft-tissue structures is an active area of research.

Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival.

PURPOSE: Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken. The primary endpoints were acute toxicity and pathologic complete response rate (pCR). Secondary endpoints were local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). METHODS AND MATERIALS: A total of 134 patients with adenocarcinoma of the rectum (clinical T3/T4 or N1/N2) were treated. The initial cohort received 40 Gy in 20 fractions, the second 46 Gy in 23 fractions, and the third 50 Gy in 25 fractions. 5FU (225 mg/m2/day) was given continuously throughout radiotherapy. A total of 121 patients underwent surgical resection. RESULTS: Treatment was well tolerated. Grade 3/4 acute toxicity was observed in 13%, 4%, and 14% of patients in the 40 Gy, 46 Gy, and 50 Gy cohorts, respectively (p = 0.20). pCR was documented in 15%, 23%, and 33% of patients, respectively (p = 0.07). The 2-year actuarial LRFS was 72%, 90%, and 89% (p = 0.02); DFS was 62%, 84%, and 78% (p = 0.02); and OS was 72%, 94%, and 92%, respectively (p = 0.03). CONCLUSIONS: All treatment schedules were well tolerated. There was a trend toward increased pCR with higher doses. A statistically significant increase in LRFS, DFS, and OS was seen with radiation doses of 46 Gy and greater, but there was no difference between 46 Gy and 50 Gy.