Brian Yaremko

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

BackgroundStereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.MethodsAfter stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.DiscussionThis study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study.Trial registrationClinicaltrials.gov identifier: NCT01446744

Inter-observer and intra-observer reliability for lung cancer target volume delineation in the 4D-CT era

BACKGROUND AND PURPOSE To investigate inter-observer and intra-observer target volume delineation (TVD) error in 4D-CT imaging of thoracic tumours. MATERIALS AND METHODS Primary and nodal gross tumour volumes (GTV) of 10 lung tumours on the 10 respiratory phases of a 4D-CT scan were contoured by six radiation oncologist observers. Inter-observer and intra-observer variability were assessed by the coefficient of variation (COV) and the volume overlap index (VOI). ANOVA was performed to assess differences in inter-observer and intra-observer variability based on patient case difficulty, respiratory phase, physician seniority, and physician observer. RESULTS VOI analysis determined that inter-observer was a more significant source of error than intra-observer variability. VOI improved with the use of 4D-CT as compared to conventional CT. ANOVA analysis for COVs found case difficulty (easy versus difficult) to be significant for inter-observer primary tumour and intra-observer nodal disease delineation. Physician seniority, respiratory phase, and individual physician were not found to be significant for TVD error. CONCLUSION Variability in TVD is a major source of error in 4D-CT treatment planning. Development of measures to reduce inter-observer and intra-observer TVD variability are necessary in order to deliver high quality radiotherapy.

Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): Patient outcomes and prognostic factors

OBJECTIVES Metastatic non-small cell lung carcinoma (NSCLC) generally carries a poor prognosis, and systemic therapy is the mainstay of treatment. However, extended survival has been reported in patients presenting with a limited number of metastases, termed oligometastatic disease. We retrospectively reviewed the outcomes of such patients treated at two centers. MATERIALS AND METHODS From September 1999-July 2012, a total of 61 patients with 1-3 synchronous metastases, who were treated with radical intent to all sites of disease, were identified from records of two cancer centers. Treatment was considered radical if it involved surgical resection and/or delivery of radiation doses ≥13 × 3 Gy. RESULTS Besides the primary tumor, 50 patients had a solitary metastasis, 9 had two metastases, and 2 had three metastases. Locations of metastases included the brain (n = 36), bone (n = 11), adrenal (n = 4), contralateral lung (n = 4), extra-thoracic lymph nodes (n = 4), skin (n = 2) and colon (n = 1). Only one patient had metastases in two different organs. Median follow-up was 26.1 months (m), median overall survival (OS) was 13.5m, median progression free survival (PFS) was 6.6m and median survival after first progression (SAFP) was 8.3m. The 1- and 2-year OS were, 54% and 38%, respectively. Significant predictors of improved OS were: smaller radiotherapy planning target volume (PTV) (p = 0.004) and surgery for the primary lung tumor (p < 0.001). Factors associated with improved SAFP included surgery for the primary lung tumor, presence of brain metastases, and absence of bone metastases. No significant differences in outcomes were observed between the two centers. CONCLUSION Radical treatment of selected NSCLC patients presenting with 1-3 synchronous metastases can result in favorable 2-year survivals. Favorable outcomes were associated with intra-thoracic disease status: patients with small radiotherapy treatment volumes or resected disease had the best OS. Future prospective clinical trials, ideally randomized, should evaluate radical treatment strategies in such patients.

A Phase II Study of Bevacizumab in Combination With Definitive Radiotherapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma: Preliminary Results of RTOG 0417

PURPOSE Concurrent cisplatin-based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer. RTOG 0417 was a Phase II study exploring the safety and efficacy of the addition of bevacizumab to standard CRT. METHODS AND MATERIALS Eligible patients with bulky tumors (Stage IB-IIIB) were treated with once-weekly cisplatin (40 mg/m(2)) chemotherapy and standard pelvic radiotherapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for three cycles. Treatment-related serious adverse event (SAE) and other adverse event (AE) rates within the first 90 days from treatment start were determined. Treatment-related SAEs were defined as any Grade ≥ 4 vaginal bleeding or thrombotic event or Grade ≥ 3 arterial event, gastrointestinal (GI) bleeding, or bowel/bladder perforation, or any Grade 5 treatment-related death. Treatment-related AEs included all SAEs and Grade 3 or 4 GI toxicity persisting for >2 weeks despite medical intervention, Grade 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia, Grade 3 or 4 other hematologic toxicity, and Grade 3 or 4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs. All AEs were scored using the National Cancer Institute Common Terminology Criteria (CTCAE) v 3.0 (MedDRA version 6.0). RESULTS A total of 60 patients from 28 institutions were enrolled between 2006 and 2009, and of these, 49 patients were evaluable. The median follow-up was 12.4 months (range, 4.6-31.4 months).The median age was 45 years (range, 22-80 years). Most patients had FIGO Stage IIB (63%) and were of Zubrod performance status of 0 (67%). 80% of cases were squamous. There were no treatment-related SAEs. There were 15 (31%) protocol-specified treatment-related AEs within 90 days of treatment start; the most common were hematologic (12/15; 80%). 18 (37%) occurred during treatment or follow-up at any time. 37 of the 49 patients (76%) had cisplatin and bevacizumab administered per protocol, and 46 of the 49 (94%) had both external beam and brachytherapy administered per protocol or with acceptable variation. CONCLUSION Bevacizumab in addition to standard pelvic chemoradiotherapy for locally advanced cervical cancer is feasible and safe with respect to the protocol-specified treatment-related SAEs and AEs.

Thresholding in PET images of static and moving targets

Continued therapeutic gain in the treatment of non-small-cell lung cancer (NSCLC) will depend upon our ability to escalate the dose to the primary tumour while minimizing normal tissue toxicity. Both these objectives are facilitated by the accurate definition of a target volume that is as small as possible. To this end, both tumour immobilizations via deep inspiratory breath-hold, along with positron emission tomography (PET), have emerged as two promising approaches. Though PET is an excellent means of defining the general location of a tumour focus, its ability to define exactly the geometric extent of such a focus strongly depends upon selection of an appropriate image threshold. However, in clinical practice, the image threshold is typically not chosen according to consistent, well-established criteria. This study explores the relationship between image threshold and the resultant PET-defined volume using a series of F-18 radiotracer-filled hollow spheres of known internal volumes, both static and under oscillatory motion. The effects of both image threshold and tumour motion on the resultant PET image are examined. Imaging data are further collected from a series of simulated gated PET acquisitions in order to test the feasibility of a patient-controlled gating mechanism during deep inspiratory breath-hold. This study illustrates quantitatively considerable variability in resultant PET-defined tumour volumes depending upon numerous factors, including image threshold, size of the lesion, the presence of tumour motion and the scanning protocol. In this regard, when using PET in treatment planning for NSCLC, the radiation oncologist must select the image threshold very carefully to avoid either under-dosing the tumour or overdosing normal tissues.

RTOG 0417: Efficacy of Bevacizumab in Combination With Definitive Radiation Therapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma

PURPOSE Radiation Therapy Oncology Group 0417 was a phase II study that explored the safety and efficacy of the addition of bevacizumab to chemoradiation therapy. The safety results have been previously reported. Herein we report the secondary efficacy endpoints of overall survival (OS), locoregional failure (LRF), para-aortic nodal failure (PAF), distant failure (DF), and disease-free survival (DFS). METHODS AND MATERIALS Eligible patients with bulky Stage IB-IIIB disease were treated with once-weekly cisplatin (40 mg/m2) chemotherapy and standard pelvic radiation therapy and brachytherapy. Bevacizumab was administered at 10 mg/kg intravenously every 2 weeks for 3 cycles during chemoradiation. For OS, failure was defined as death of any cause and was measured from study entry to date of death. LRF was defined as any failure in the pelvis. PAF was defined as any para-aortic nodal failure. DF was analyzed both including and excluding PAF. DFS was measured from study entry to date of first LRF. DF was measured with or without PAF or death. OS and DFS were estimated by the Kaplan-Meier method, and LRF and DF rates were estimated by the cumulative incidence method. RESULTS 49 eligible patients from 28 institutions were enrolled between 2006 and 2009. The median follow-up time was 3.8 years (range, 0.8-6.0 years). The surviving patients had a median follow-up time of 3.9 years (range, 2.1-6.0 years). Most patients had tumors of International Federation of Gynecology and Obstetrics Stage IIB (63%), and 80% were squamous. The 3-year OS, DFS, and LRF were 81.3% (95% confidence interval [CI], 67.2%-89.8%), 68.7% (95% CI, 53.5%-79.8%), and 23.2% (95% CI, 11%-35.4%), respectively. The PAF, DF without PAF, and DF with PAF at 3 years were 8.4% (95% CI, 0.4%-16.3%), 14.7% (95% CI, 4.5%-24.9%), and 23.1% (95% CI 11.0%-35.2%), respectively. CONCLUSION In this study, bevacizumab in combination with standard pelvic chemoradiation therapy for locally advanced cervical cancer showed efficacy results that are promising and may warrant further investigation.

Management and Prognosis in Synchronous Solitary Resected Brain Metastasis from Non–Small-Cell Lung Cancer

BACKGROUND Reports in the medical literature have described cases of extended survival of patients with non-small-cell lung cancer (NSCLC) with solitary metastatic disease who have received aggressive treatment both to the brain metastasis and to the local/regional disease. The objective of this research is to analyze prognostic factors that predict for outcome in this unique patient population. PATIENTS AND METHODS A single-institution, retrospective chart review was performed on 35 patients with NSCLC and a synchronous solitary brain metastasis (SSBM) treated with craniotomy and whole-brain radiation therapy. Eight patients (22.9%) had chest surgery, 24 (68.6%) had chemotherapy, and 14 (40%) had thoracic radiation as part of their local management. Fourteen had stage I/II disease (42.9%), and 20 had stage III disease (57.1%). Mean age at diagnosis was 58.5 years. Eighteen patients (56.25%) had a brain metastasis < 3 cm, and 14 patients (43.75%) had a metastasis > 3 cm. RESULTS Median survival was 7.8 months, and at last follow-up, 3 patients (8.6%) were alive and well, 6 patients (17.1%) were alive and with disease, 24 patients (68.6%) had died of disease, and 2 patients (5.7%) had died of other causes. Univariate analysis demonstrated that lung surgery (P = .0033), primary lung treatment > 8 weeks after brain surgery (P = .0128), and stage I/II disease (P = .0467) were predictive of overall survival. CONCLUSION Survival remains poor for patients with NSCLC with an SSBM. However, patients with thoracic disease amenable to local resection should be considered for such therapy because a survival advantage could exist compared with patients with more locally advanced disease.

An evaluation of an automated 4D-CT contour propagation tool to define an internal gross tumour volume for lung cancer radiotherapy

BACKGROUND AND PURPOSE To evaluate an automated 4D-CT contouring propagation tool by its impact on the inter- and intra-physician variability in lung tumour delineation. MATERIALS AND METHODS In a previous study, six radiation oncologists contoured the gross tumour volume (GTV) and nodes on 10 phases of the 4D-CT dataset of 10 lung cancer patients to examine the intra- and inter-physician variability. In this study, a model-based deformable image registration algorithm was used to propagate the GTV and nodes on each phase of the same 4D-CT datasets. A blind review of the contours was performed by each physician and edited. Inter- and intra-physician variability for both the manual and automated methods was assessed by calculating the centroid motion of the GTV using the Pearson correlation coefficient and the variability in the internal gross tumour volume (IGTV) overlap using the Dice similarity coefficient (DSC). RESULTS The time for manual delineation was (42.7±18.6)min versus (17.7±5.4)min when the propagation tool was used. A significant improvement in the mean Pearson correlation coefficient was also observed. There was a significant decrease in mean DSC in only 1 out of 10 primary IGTVs and 2 out of 10 nodal IGTVs. Intra-physician variability was not significantly impacted (DSC>0.742). CONCLUSIONS Automated 4D-CT propagation tools can significantly decrease the IGTV delineation time without significantly decreasing the inter- and intra-physician variability.

Threshold modification for tumour imaging in non-small-cell lung cancer using positron emission tomography.

AimPositron emission tomography (PET) has been used increasingly in the staging and radiotherapy treatment planning of non-small-cell lung cancer (NSCLC). This study investigates the factors that affect the resultant size of a given image on PET. MethodsPET was used to assess the geometric characteristics of a series of radioisotope-filled, stationary spheres of known volume, surrounded by positron-emitting radioactive tracer of variable activity. The resultant PET-derived spherical volumes were then referenced to the known spherical volumes in order to illustrate quantitatively the potential influence of image threshold, tumour size and background concentration. This influence was further illustrated by clinical examples. ResultsConsidering the diameter of the spheres used in this study (10–48 mm), higher image thresholds were required for accurate rendering of the smallest spherical volumes. This inverse relationship was most consistently illustrated at the lowest background intensity ratios. ConclusionPET-derived volumes of NSCLC must be interpreted with caution. The data presented in this study may be used to guide the selection of appropriate image thresholds for potential clinical application.

SPECT‐based functional lung imaging for the prediction of radiation pneumonitis: A clinical and dosimetric correlation

When we irradiate lung cancer, the radiation dose that can be delivered safely is limited by the risk of radiation pneumonitis (RP) in the surrounding normal lung. This risk is dose‐dependent and is commonly predicted using metrics such as the V20, which are usually formulated assuming homogeneous pulmonary function. Because in vivo pulmonary function is not homogeneous, if highly functioning lung can be identified beforehand and preferentially avoided during treatment, it might be possible to reduce the risk of RP, suggesting the utility of function‐based prediction metrics.