Anand Swaminath

The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy.

AIMS The Canadian Association of Radiation Oncology-Stereotactic Body Radiotherapy (CARO-SBRT) Task Force was established in 2010. The aim was to define the scope of practice guidelines for the profession to ensure safe practice specific for the most common sites of lung, liver and spine SBRT. MATERIALS AND METHODS A group of Canadian SBRT experts were charged by our national radiation oncology organisation (CARO) to define the basic principles and technologies for SBRT practice, to propose the minimum technological requirements for safe practice with a focus on simulation and image guidance and to outline procedural considerations for radiation oncology departments to consider when establishing an SBRT programme. RESULTS We recognised that SBRT should be considered as a specific programme within a radiation department, and we provide a definition of SBRT according to a Canadian consensus. We outlined the basic requirements for safe simulation as they pertain to spine, lung and liver tumours, and the fundamentals of image guidance. The roles of the radiation oncologist, medical physicist and dosimetrist have been detailed such that we strongly recommend the development of SBRT-specific teams. Quality assurance is a key programmatic aspect for safe SBRT practice, and we outline the basic principles of appropriate quality assurance specific to SBRT. CONCLUSION This CARO scope of practice guideline for SBRT is specific to liver, lung and spine tumours. The task force recommendations are designed to assist departments in establishing safe and robust SBRT programmes.

Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis

In stage III non-small cell lung cancer (NSCLC), the standard of care in young patients is chemoradiotherapy, but this standard is not as clearly established for older patients. We aimed to determine the efficacy and harm associated with chemoradiotherapy versus radiotherapy alone in elderly (≥70 years), stage III NSCLC patients through a systematic review. We conducted a systematic search of MEDLINE, EMBASE, CENTRAL, Scopus, Web of Science and conference proceedings. Two reviewers independently identified randomized trials (RCT) and extracted trial-level data. Risk of bias was assessed and meta-analysis was conducted looking at survival and safety outcomes. We included three trials and subgroup data from one systematic review. The three RCTs had high risk of bias due primarily to lack of blinding and the systematic review scored 4/11 using the AMSTAR tool. Overall survival (HR 0.66, 95% CI 0.53-0.82; I2 0%; 3 trials; 407 patients) and progression-free survival (HR 0.67, 95% CI 0.53-0.85; I2 0%; 2 trials; 327 patients) both favored chemoradiotherapy. Risk of treatment-related death and grade 3+ pneumonitis were not significantly different between groups. In conclusion, treatment of stage III NSCLC patients 70 years or older with chemotherapy and radiotherapy is associated with improved overall survival compared to radiotherapy alone. With the exception of increased hematological toxicity, CRT appears to be tolerable in fit elderly patients and represents a reasonable standard of clinical care.

Accuracy of Robotic Radiosurgical Liver Treatment Throughout the Respiratory Cycle

PURPOSE To quantify random uncertainties in robotic radiosurgical treatment of liver lesions with real-time respiratory motion management. METHODS AND MATERIALS We conducted a retrospective analysis of 27 liver cancer patients treated with robotic radiosurgery over 118 fractions. The robotic radiosurgical system uses orthogonal x-ray images to determine internal target position and correlates this position with an external surrogate to provide robotic corrections of linear accelerator positioning. Verification and update of this internal-external correlation model was achieved using periodic x-ray images collected throughout treatment. To quantify random uncertainties in targeting, we analyzed logged tracking information and isolated x-ray images collected immediately before beam delivery. For translational correlation errors, we quantified the difference between correlation model-estimated target position and actual position determined by periodic x-ray imaging. To quantify prediction errors, we computed the mean absolute difference between the predicted coordinates and actual modeled position calculated 115 milliseconds later. We estimated overall random uncertainty by quadratically summing correlation, prediction, and end-to-end targeting errors. We also investigated relationships between tracking errors and motion amplitude using linear regression. RESULTS The 95th percentile absolute correlation errors in each direction were 2.1 mm left-right, 1.8 mm anterior-posterior, 3.3 mm cranio-caudal, and 3.9 mm 3-dimensional radial, whereas 95th percentile absolute radial prediction errors were 0.5 mm. Overall 95th percentile random uncertainty was 4 mm in the radial direction. Prediction errors were strongly correlated with modeled target amplitude (r=0.53-0.66, P<.001), whereas only weak correlations existed for correlation errors. CONCLUSIONS Study results demonstrate that model correlation errors are the primary random source of uncertainty in Cyberknife liver treatment and, unlike prediction errors, are not strongly correlated with target motion amplitude. Aggregate 3-dimensional radial position errors presented here suggest the target will be within 4 mm of the target volume for 95% of the beam delivery.

Metformin for chemo-radio-sensitization of NSCLC.

http://dx.doi.org/10.1016/j.radonc.2016.06.018 0167-8140/ 2016 Elsevier Ireland Ltd. All rights reserved. To the Editor Wewould like to congratulate the team of Wink et al. (2016) [1] for their retrospective study suggesting that metformin is associated with improved progression free survival (PFS) and distant metastasis free survival (DMFS) in diabetic patients with locally advanced (LA) non-small cell lung cancer (NSCLC). Many retrospective analyses have examined the potential benefits of metformin in cancer [2–7] but very few studies focused on patients with LA-NSCLC receiving curative concurrent chemo-radiotherapy (CCRT). The results of this study are consistent with observations made by our group and others that metformin inhibits proliferation and radio-sensitizes NSCLC through activation of AMPK [8], a heterotrimeric enzyme that acts as a sensor of metabolic and genotoxic stress [9]. Metformin blocks complex I of mitochondria oxidative phosphorylation chain. This is believed to raise cellular AMP/ADP levels leading to direct activation of AMPK through its energy sensing c-subunit [10]. However, we and others observed that metformin also activates the genotoxic stress sensor Ataxia Telangiectasia Mutated (ATM) [8,11,12]. While the mechanism of this activation remains unclear, it may involve generation of Reactive Oxygen Species (ROS), secondary to the metabolic stress induced by metformin, which would lead to activation of DNA repair pathways [13]. Collectively, the available pre-clinical data suggest that metformin chronically activates in cells and tumors an ATM-AMPK-p53/p21 axis and suppresses Akt-mTOR activity [8,9]. Apart from inhibition of cell cycle, survival and growth, this activity may also include improved genomic stability [13] that could contribute to improved clinical outcomes. By default, retrospective studies on metformin investigate diabetic patients. As such, cancer control results of the agent in this setting are confounded by the metabolic benefits of the drug in improving glycemia. Similarly, in the study by Wink et al., it is not possible to distinguish the activity in diabetics not treated with metformin from non-diabetics, as diabetics not on metformin appear to have been included in the control group. Hence, to fully understand the anti-tumor activity of metformin, the drug must be investigated in prospective studies with non-diabetic patients. In the past 2 years, two randomized phase II studies opened to investigate metformin in LA-NSCLC treated with CCRT: (i) NRG-LU001 (NCT02186847) investigates the chemo-radiosensitizing action of metformin in stage III NSCLC in patients receiving CCRT followed by consolidation chemotherapy, with metformin administered only concurrent with cytotoxic therapy; and (ii) the Ontario-Clinical-Oncology-Group (OCOG)–ALMERA (NCT02115464) trial which examines the ability of metformin to offer both chemo-radio-sensitization as well as consolidative therapy in stage III patients, with metformin delivered through cisplatin-based CCRT and beyond for a total of 12 months. The primary outcome in both trials is improvement in twelve month PFS. An additional randomized placebo-controlled phase II study at M.D. Anderson Cancer Center (NCT02285855), investigates metformin in combination with stereotactic radiotherapy in early stage NSCLC patients. These studies will provide much anticipated results on the concept of targeting metabolism to improve clinical outcomes in NSCLC patients treated with cytotoxic therapy. If positive, the results of NRG-LU001 and OCOG-ALMERA will help determine the design of subsequent phase III trials with metformin in NSCLC.

A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy

Lung stereotactic-body radiotherapy (SBRT) places additional requirements on targeting accuracy over standard approaches. In treatment planning, a tumour volume is geometrically expanded and the resulting planning target volume (PTV) is covered with the prescribed dose. This ensures full dose delivery despite various uncertainties encountered during treatment. We developed a retrospective technique for optimizing the PTV expansion for a patient population. The method relies on deformable image registration (DIR) of the planning CT to a treatment cone-beam CT (CBCT). The resulting transformation is used to map the planned target onto the treatment geometry, allowing the computation of the achieved target/PTV overlap. Basic validation of the method was performed using an anthropomorphic respiratory motion phantom. A self-validation technique was also implemented to allow estimation of the DIR error for the data being analyzed. Our workflow was used to retrospectively optimize PTV margin for 25 patients treated over 93 fractions. Targets for these patients were contoured on 4D CT images. SBRT delivery followed CBCT acquisition and a couch correction. A post-treatment CBCT was also acquired in some cases. Our basic validation demonstrated that the DIR-based technique is capable of transforming target volumes from planning CTs to treatment CBCTs with sub-mm accuracy. Our clinical analysis showed that the minimum percentages of target volumes covered for 3, 4, and 5 mm PTV margins were 92.1, 97.6, and 99.2, respectively. Analyzing data acquired before and just after treatment demonstrated that margins exceeding 5 mm did not significantly improve coverage. Finally, a 5 mm PTV margin achieved  ⩾95% target volume coverage with  ⩾95% probability. Our technique is accurate, automated, self-validating, and incorporates complex ITV shapes/deformations to allow PTV margin optimization. The analysis of clinical data indicates a 5 mm PTV margin is optimal for our process. This approach is generalizable to other disease sites and treatment strategies.