Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

First clinical experience with real-time portal imaging-based breath-hold monitoring in tangential breast radiotherapy.

Background and purpose: Real-time treatment monitoring with the electronic portal imaging device (EPID) can conceptually provide a more accurate assessment of the quality of deep inspiration breath-hold (DIBH) and patient movement during tangential breast radiotherapy (RT). A system was developed to measure two geometrical parameters, the lung depth (LD) and the irradiated width (named here skin distance, SD), along three user-selected lines in MV EPID images of breast tangents. The purpose of this study was to test the system during tangential breast RT with DIBH. Materials and methods: Measurements of LDs and SDs were carried out in real time. DIBH was guided with a commercial system using a marker block. Results from 17 patients were assessed. Mean midline LDs, , per tangent were compared to the planned mLDs; differences between the largest and smallest observed () per tangent were calculated. Results: For 56% (162/288) of the tangents tested, were outside the tolerance window. All but one patient had at least one fraction showing this behaviour. The largest difference found between an and its planned mLD was -16.9 mm. The accuracy of patient positioning and the quality of marker-block-based DIBH guidance contributed to the differences. Fractions with patient position verification using a single EPID image taken before treatment showed a lower rate (34%), suggesting reassessment of setup procedures. Conclusions: Real-time treatment monitoring of the internal anatomy during DIBH delivery of tangential breast RT is feasible and useful. The new system requires no additional radiation for the patient.

Implementation of the Australian Computer-Assisted Theragnostics (AusCAT) network for radiation oncology data extraction, reporting and distributed learning.

INTRODUCTION: There is significant potential to analyse and model routinely collected data for radiotherapy patients to provide evidence to support clinical decisions, particularly where clinical trials evidence is limited or non-existent. However, in practice there are administrative, ethical, technical, logistical and legislative barriers to having coordinated data analysis platforms across radiation oncology centres. METHODS: A distributed learning network of computer systems is presented, with software tools to extract and report on oncology data and to enable statistical model development. A distributed or federated learning approach keeps data in the local centre, but models are developed from the entire cohort. RESULTS: The feasibility of this approach is demonstrated across six Australian oncology centres, using routinely collected lung cancer data from oncology information systems. The infrastructure was used to validate and develop machine learning for model-based clinical decision support and for one centre to assess patient eligibility criteria for two major lung cancer radiotherapy clinical trials (RTOG-9410, RTOG-0617). External validation of a 2-year overall survival model for non-small cell lung cancer (NSCLC) gave an AUC of 0.65 and C-index of 0.62 across the network. For one centre, 65% of Stage III NSCLC patients did not meet eligibility criteria for either of the two practice-changing clinical trials, and these patients had poorer survival than eligible patients (10.6 m vs. 15.8 m, P = 0.024). CONCLUSION: Population-based studies on routine data are possible using a distributed learning approach. This has the potential for decision support models for patients for whom supporting clinical trial evidence is not applicable.

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast.

PURPOSE: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. RESULTS: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). CONCLUSIONS: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

Audiovisual biofeedback improves the correlation between internal/external surrogate motion and lung tumor motion.

PURPOSE: Breathing management can reduce breath-to-breath (intrafraction) and day-by-day (interfraction) variability in breathing motion while utilizing the respiratory motion of internal and external surrogates for respiratory guidance. Audiovisual (AV) biofeedback, an interactive personalized breathing motion management system, has been developed to improve reproducibility of intra- and interfraction breathing motion. However, the assumption of the correlation of respiratory motion between surrogates and tumors is not always verified during medical imaging and radiation treatment. Therefore, the aim of the study was to test the hypothesis that the correlation of respiratory motion between surrogates and tumors is the same under free breathing without guidance (FB) and with AV biofeedback guidance for voluntary motion management. METHODS: For 13 lung cancer patients receiving radiotherapy, 2D coronal and sagittal cine-MR images were acquired across two MRI sessions (pre- and mid-treatment) with two breathing conditions: (a) FB and (b) AV biofeedback, totaling 88 patient measurements. Simultaneously, the external respiratory motion of the abdomen was measured. The internal respiratory motion of the diaphragm and lung tumor was retrospectively measured from 2D coronal and sagittal cine-MR images. The correlation of respiratory motion between surrogates and tumors was calculated using Pearson's correlation coefficient for: (a) abdomen to tumor (abdomen-tumor) and (b) diaphragm to tumor (diaphragm-tumor). The correlations were compared between FB and AV biofeedback using several metrics: abdomen-tumor and diaphragm-tumor correlations with/without ≥5 mm tumor motion range and with/without adjusting for phase shifts between the signals. RESULTS: Compared to FB, AV biofeedback improved abdomen-tumor correlation by 11% (p = 0.12) from 0.53 to 0.59 and diaphragm-tumor correlation by 13% (p = 0.02) from 0.55 to 0.62. Compared to FB, AV biofeedback improved abdomen-tumor correlation by 17% (p = 0.01) and diaphragm-tumor correlation by 15% (p < 0.01) while correcting 0.3 s (p = 0.54) and 0.2 s (p = 0.19) phase shifts, respectively. In addition, AV biofeedback with ≥5 mm tumor motion range, compared to FB improved abdomen-tumor correlation by 14% (p = 0.18) and diaphragm-tumor correlation by 17% (p = 0.01). The highest abdomen-tumor and diaphragm-tumor correlations were found using ≥5 mm tumor motion range and phase shifts, resulting in a 12% improvement in AV biofeedback. CONCLUSIONS: Our results demonstrated that AV biofeedback improves the correlation of respiratory motion between surrogates and the tumor. This suggests a need for AV biofeedback for respiratory guidance utilizing respiratory surrogates during image-guided and MRI-guided radiotherapy in thoracic regions.

Fostering a culture of research within a clinical radiation oncology department.

INTRODUCTION: Support and investment in increasing a research-active culture in clinical practice needs to be translated at the department and hospital levels as well as regional, state and national levels. We aimed to improve the research culture of our department, to enable more clinical staff to become more research competent and research active. METHODS: We describe and discuss the appointment of a Director of Research and a Research Coordinator into our already-research-active department and the interactions at the research-clinical interface. By identifying barriers and instituting enablers which ameliorate their effect, we explore how a clinical department can utilize the resources already available with the goal of developing a more confident and competent clinician-researcher culture as measured by a range of research metrics. RESULTS: We observed an improved research culture within our department. Our department's improved research culture was reflected by increased numbers of peer-reviewed publications (of 30%), research students/supervisions (of 60%) and engagement of external speakers. We also observed double the number of first-authored peer-reviewed articles and a growth in conference presentations, posters and speaker invitations/awards. In the majority of the research performance metrics tracked, there was a steady improvement noted over the four years monitored. CONCLUSIONS: By responding to the barriers of staff (such as time, expertise and ideas) with structural and personal enablers, as well as funded resources, it is possible to develop research capacity and confidence in a clinical setting.

Audiovisual biofeedback guided breath-hold improves lung tumor position reproducibility and volume consistency.

PURPOSE: Respiratory variation can increase the variability of tumor position and volume, accounting for larger treatment margins and longer treatment times. Audiovisual biofeedback as a breath-hold technique could be used to improve the reproducibility of lung tumor positions at inhalation and exhalation for the radiation therapy of mobile lung tumors. This study aimed to assess the impact of audiovisual biofeedback breath-hold (AVBH) on interfraction lung tumor position reproducibility and volume consistency for respiratory-gated lung cancer radiation therapy. METHODS: Lung tumor position and volume were investigated in 9 patients with lung cancer who underwent a breath-hold training session with AVBH before 2 magnetic resonance imaging (MRI) sessions. During the first MRI session (before treatment), inhalation and exhalation breath-hold 3-dimensional MRI scans with conventional breath-hold (CBH) using audio instructions alone and AVBH were acquired. The second MRI session (midtreatment) was repeated within 6 weeks after the first session. Gross tumor volumes (GTVs) were contoured on each dataset. CBH and AVBH were compared in terms of tumor position reproducibility as assessed by GTV centroid position and position range (defined as the distance of GTV centroid position between inhalation and exhalation) and tumor volume consistency as assessed by GTV between inhalation and exhalation. RESULTS: Compared with CBH, AVBH improved the reproducibility of interfraction GTV centroid position by 46% (P = .009) from 8.8 mm to 4.8 mm and GTV position range by 69% (P = .052) from 7.4 mm to 2.3 mm. Compared with CBH, AVBH also improved the consistency of intrafraction GTVs by 70% (P = .023) from 7.8 cm3 to 2.5 cm3. CONCLUSIONS: This study demonstrated that audiovisual biofeedback can be used to improve the reproducibility and consistency of breath-hold lung tumor position and volume, respectively. These results may provide a pathway to achieve more accurate lung cancer radiation treatment in addition to improving various medical imaging and treatments by using breath-hold procedures.

Audiovisual Biofeedback Improves Cine-Magnetic Resonance Imaging Measured Lung Tumor Motion Consistency.

PURPOSE: To assess the impact of an audiovisual (AV) biofeedback on intra- and interfraction tumor motion for lung cancer patients. METHODS AND MATERIALS: Lung tumor motion was investigated in 9 lung cancer patients who underwent a breathing training session with AV biofeedback before 2 3T magnetic resonance imaging (MRI) sessions. The breathing training session was performed to allow patients to become familiar with AV biofeedback, which uses a guiding wave customized for each patient according to a reference breathing pattern. In the first MRI session (pretreatment), 2-dimensional cine-MR images with (1) free breathing (FB) and (2) AV biofeedback were obtained, and the second MRI session was repeated within 3-6 weeks (mid-treatment). Lung tumors were directly measured from cine-MR images using an auto-segmentation technique; the centroid and outlier motions of the lung tumors were measured from the segmented tumors. Free breathing and AV biofeedback were compared using several metrics: intra- and interfraction tumor motion consistency in displacement and period, and the outlier motion ratio. RESULTS: Compared with FB, AV biofeedback improved intrafraction tumor motion consistency by 34% in displacement (P=.019) and by 73% in period (P<.001). Compared with FB, AV biofeedback improved interfraction tumor motion consistency by 42% in displacement (P<.046) and by 74% in period (P=.005). Compared with FB, AV biofeedback reduced the outlier motion ratio by 21% (P<.001). CONCLUSIONS: These results demonstrated that AV biofeedback significantly improved intra- and interfraction lung tumor motion consistency for lung cancer patients. These results demonstrate that AV biofeedback can facilitate consistent tumor motion, which is advantageous toward achieving more accurate medical imaging and radiation therapy procedures.

Correction of systematic setup errors in prostate radiation therapy: how many images to perform?

The purpose of this study was to develop an evidence-based off-line setup correction protocol for systematic errors in prostate radiation therapy. Daily orthogonal electronic portal images were acquired from 30 patients. Field displacements were measured in the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions for each treatment fraction. The off-line protocol corrects the mean field displacement found from n consecutive images, starting at a particular fraction of treatment, with a fixed tolerance level. Simulations were performed with the measured data to determine (1) how many images (n) should be averaged to determine the systematic error; (2) on which treatment fraction should the protocol be initiated; and (3) what tolerance level should be applied to determine whether the patient position should be corrected. Uncorrected systematic errors in the ML, SI, and AP directions were (mean position +/- 1 standard deviation [SD]): -0.7 +/- 2.2 mm, -1.5 +/- 1.3 mm, and 1.4 +/- 2.6 mm, respectively. Random errors (1 SD and range) were 1.9 mm (1.3 - 3.3), 1.5 mm (0. - 4.1), and 1.8 mm (1.0-2.6), respectively. A correction based on a single image taken on the first fraction actually increased the systematic errors in the ML and SI directions compared with no correction. More accurate correction of systematic errors was achieved with increasing number of images averaged, with only small benefit after 5 images. With fewer images averaged, delaying the start of the protocol resulted in more accurate correction because of the influence of unrepresentative positions at early fractions. The number of corrections made on patients with small (< 2 mm) systematic errors was minimized for tolerance values of 2 mm and n > or = 5 images averaged. The optimal off-line setup correction protocol would be to shift the patient by the mean displacement of the first 5 portal images of a radical course of radiation therapy. A small tolerance level should be utilized with 2 mm giving good accuracy with minimal unnecessary shifts.

Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? a community-based population analysis.

PURPOSE: The effects of age and comorbidity on treatment and outcomes for patients with limited stage small-cell lung cancer (L-SCLC) are unclear. This study analyzes relapse and survival in a community-based population with L-SCLC according to age and comorbidity. METHODS: A retrospective review was performed on 174 patients with L-SCLC referred to the British Columbia Cancer Agency, Vancouver Island Centre, between January 1991 and December 1999. Patient and treatment characteristics, disease response, relapse, and survival were compared among three age cohorts: <65 years (n = 55, 32%), 65-74 years (n = 76, 44%), and > or =75 years (n = 43, 25%); and according to Charlson comorbidity scores 0, 1, and > or =2. Multivariate analysis was performed to identify independent prognostic factors associated with treatment response and survival. RESULTS: Patient factors that significantly differed with age were functional status classified by Eastern Cooperative Oncology Group performance status and number of comorbidities. Increasing age was significantly associated with fewer diagnostic scans. Combined modality chemoradiotherapy (CRT) was given in 86%, 66%, and 40% of patients ages <65, 65-74, and > or =75 years, respectively, (p <0.0001). Thoracic irradiation use was comparable among the age cohorts (p >0.05), but chemotherapy use varied significantly with less intensive regimens, fewer cycles, and lower total doses with advancing age (p <0.05). Prophylactic cranial irradiation (PCI) was used in 41 patients, only 3 of whom were age >70 years. Overall response rates to primary treatment significantly decreased with advancing age: 91%, 79%, and 74% in patients ages <65, 65-74, and > or =75 years, respectively (p = 0.014). Treatment toxicity and relapse patterns were similar across the age cohorts. Overall 2-year survival rates were significantly lower with advancing age: 37%, 22%, and 19% (p = 0.003), with corresponding median survivals of 17, 12, and 7 months among patients ages <65, 65-74, and > or =75 years, respectively. On multivariate analysis, age and Charlson comorbidity scores were not significantly associated with treatment response and survival. Independent prognostic factors favorably associated with survival were good performance status, normal lactate dehydrogenase, absence of pleural effusion, and > or =four cycles of chemotherapy. CONCLUSION: Increasing age was associated with decreased performance status and increased comorbidity. Older patients with L-SCLC were less likely to be treated with CRT, intensive chemotherapy, and PCI. Treatment response and survival rates were lower with advancing age, but this may be attributed to poor performance status and suboptimal treatment rather than age.