Fred Hsu

Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for 1-3 brain metastases: a feasibility study using volumetric modulated arc therapy.

PURPOSE To evaluate the feasibility of using volumetric modulated arc therapy (VMAT) to deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) for one to three brain metastases. METHODS AND MATERIALS Ten patients previously treated with stereotactic radiosurgery for one to three brain metastases underwent repeat planning using VMAT. The whole brain prescription dose was 32.25 Gy in 15 fractions, and SIB doses to brain metastases were 63 Gy to lesions >or=2.0 cm and 70.8 Gy to lesions <2.0 cm in diameter. The mean dose to the hippocampus was kept at <6 Gy(2). Plans were optimized for conformity and target coverage while minimizing hippocampal and ocular doses. Plans were evaluated on target coverage, prescription isodose to target volume ratio, conformity number, homogeneity index, and maximum dose to prescription dose ratio. RESULTS Ten patients had 18 metastases. Mean values for the brain metastases were as follows: conformity number = 0.73 +/- 0.10, target coverage = 0.98 +/- 0.01, prescription isodose to target volume = 1.34 +/- 0.19, maximum dose to prescription dose ratio = 1.09 +/- 0.02, and homogeneity index = 0.07 +/- 0.02. For the whole brain, the mean target coverage and homogeneity index were 0.960 +/- 0.002 and 0.39 +/- 0.06, respectively. The mean hippocampal dose was 5.23 +/- 0.39 Gy(2). The mean treatment delivery time was 3.6 min (range, 3.3-4.1 min). CONCLUSIONS VMAT was able to achieve adequate whole brain coverage with conformal hippocampal avoidance and radiosurgical quality dose distributions for one to three brain metastases. The mean delivery time was under 4 min.

EGFR mutation status on brain metastases from non-small cell lung cancer.

OBJECTIVES The purpose of this study was to examine the impact of EGFR mutations on the incidence of brain metastases in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS A retrospective, population-based study was conducted using a provincial cancer registry to identify patients with metastatic NSCLC. Patients with diagnostic EGFR mutation testing were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts. The primary endpoint was the incidence of brain metastases. Cumulative incidence curves were estimated using the competing risk method. The secondary endpoint was overall survival. RESULTS For 543 patients there were 121 EGFR+ and 422 EGFR WT. The cumulative incidence of brain metastases was 39.2% for EGFR+ patients compared to 28.2% for EGFR WT (p=0.038; HR 1.4). In multivariate analysis, younger age and EGFR+ status were significant factors for developing brain metastases. The median survival for the EGFR+ and EGFR WT cohorts were 22.4 and 7.9 months (p<0.001), respectively. In multivariate analysis, poor performance status and brain metastases were factors significant for worse survival. CONCLUSIONS There is a higher incidence of brain metastases for patients with EGFR+ metastatic NSCLC, even when adjusted for differences in survival, compared to EGFR WT. For patients with and without brain metastases, survival prognosis with stage IV NSCLC is much longer with EGFR+ disease.

High-Grade Glioma Radiation Therapy Target Volumes and Patterns of Failure Obtained From Magnetic Resonance Imaging and 18F-FDOPA Positron Emission Tomography Delineations From Multiple Observers

PURPOSE The objective of this study was to compare recurrent tumor locations after radiation therapy with pretreatment delineations of high-grade gliomas from magnetic resonance imaging (MRI) and 3,4-dihydroxy-6-[(18)F]fluoro-L-phenylalanine ((18)F-FDOPA) positron emission tomography (PET) using contours delineated by multiple observers. METHODS AND MATERIALS Nineteen patients with newly diagnosed high-grade gliomas underwent computed tomography (CT), gadolinium contrast-enhanced MRI, and (18)F-FDOPA PET/CT. The image sets (CT, MRI, and PET/CT) were registered, and 5 observers contoured gross tumor volumes (GTVs) using MRI and PET. Consensus contours were obtained by simultaneous truth and performance level estimation (STAPLE). Interobserver variability was quantified by the percentage of volume overlap. Recurrent tumor locations after radiation therapy were contoured by each observer using CT or MRI. Consensus recurrence contours were obtained with STAPLE. RESULTS The mean interobserver volume overlap for PET GTVs (42% ± 22%) and MRI GTVs (41% ± 22%) was not significantly different (P=.67). The mean consensus volume was significantly larger for PET GTVs (58.6 ± 52.4 cm(3)) than for MRI GTVs (30.8 ± 26.0 cm(3), P=.003). More than 95% of the consensus recurrence volume was within the 95% isodose surface for 11 of 12 (92%) cases with recurrent tumor imaging. Ten (91%) of these cases extended beyond the PET GTV, and 9 (82%) were contained within a 2-cm margin on the MRI GTV. One recurrence (8%) was located outside the 95% isodose surface. CONCLUSIONS High-grade glioma contours obtained with (18)F-FDOPA PET had similar interobserver agreement to volumes obtained with MRI. Although PET-based consensus target volumes were larger than MRI-based volumes, treatment planning using PET-based volumes may not have yielded better treatment outcomes, given that all but 1 recurrence extended beyond the PET GTV and most were contained by a 2-cm margin on the MRI GTV.

Population-based outcomes of boost versus salvage radiosurgery for brain metastases after whole brain radiotherapy☆

PURPOSE We conducted a retrospective population-based study to examine the survival outcomes in patients with brain metastases treated with salvage stereotactic radiosurgery (SRS), compared to boost SRS, after previous whole brain radiotherapy (WBRT). METHODS AND MATERIALS From January 2000 to June 2011, 191 patients treated with WBRT and SRS for brain metastases in British Columbia were studied. Patients were divided into a boost cohort and a salvage cohort. The criteria used to determine eligibility for SRS were: 1-3 metastases, ≤4cm size, Karnofsky performance status ≥ 70, and control of extracranial disease. RESULTS Diagnosis by primary site was 84 lung, 47 breast, 15 melanoma, 12 renal, 9 colorectal, and 24 other. There were 113 patients (59%) in the boost cohort and 78 patients (41%) in the salvage cohort. The median overall survival from WBRT for the whole population was 17.7months: 12.1 months for the boost cohort and 22.7 months for the salvage cohort. There was no difference in median survival after SRS for the boost and salvage cohorts (11.2 vs. 11.2 months, p=0.78). CONCLUSIONS In selected patients with brain metastases treated with WBRT, survival following salvage SRS is as good as survival after WBRT + boost SRS.

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study

PURPOSE Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.

Factors predictive of obliteration after arteriovenous malformation radiosurgery.

OBJECTIVE To investigate predictive factors of complete obliteration following treatment with linac-based stereotactic radiosurgery for intracerebral arteriovenous malformations. METHODS Archived plans for 48 patients treated at the British Columbia Cancer Agency and who underwent post-treatment digital subtraction angiography to assess obliteration were studied. Actuarial estimates of obliteration were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of incidence of obliteration. Log-rank test was used to search for parameters associated with obliteration. RESULTS Complete nidus obliteration was achieved in 38/48 patients (79.2%). Actuarial rate of obliteration was 75.9% at 4 years (95% confidence interval 63.1%-88.6%). On univariate analysis, prescribed dose to the margin (p=0.002) and dose to isocentre (p=0.022) showed statistical significance. No parameters were significant in a multivariate model. According to the log-rank test, prescribed dose to the margin of >20 Gy (p=0.004) and dose to the isocentre of >25 Gy (p=0.004) were associated with obliteration. CONCLUSION Reported series in the literature suggest a number of different factors are predictive of complete obliteration of arteriovenous malformations following radiosurgery. However, differing definitions of volume and complete obliteration makes direct comparison between series difficult. This study demonstrates that complete obliteration of the nidus following linear accelerator-based stereotactic radiosurgery for arteriovenous malformations appears to be most closely related to the prescribed marginal dose. In particular, a marginal dose of >20 Gy is strongly associated with obtaining complete obliteration of the nidus.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations

BACKGROUND In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. RESULTS Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. CONCLUSIONS Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

Stereotactic Radiosurgery for Metastases in Eloquent Central Brain Locations.

BACKGROUND To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. METHODS We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size ≤4 cm, and Karnofsky performance status ≥70. Local progression-free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). CONCLUSIONS Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications.

Population-based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases: SABR-5

BackgroundOligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1–3 or 1–5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates.MethodsThis is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity.DiscussionSABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials.Trial RegistrationRegistered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

Miliary metastases are associated with epidermal growth factor receptor mutations in non-small cell lung cancer: a population-based study

Abstract Background: Miliary metastases are characterized by metastatic nodules that are diffuse, innumerable and small. The purpose of this study was to examine the incidence, prognostic significance and impact of epidermal growth factor receptor (EGFR) mutations for miliary metastases from non-small cell lung cancer (NSCLC). Material and methods: Patients were identified from a Provincial cancer registry (British Columbia, Canada) for the period 2010–2012. Inclusion criteria were stage IV NSCLC at presentation and conclusive EGFR mutation testing. Miliary metastases were defined by subjective and objective radiographic criteria. The primary endpoint was the incidence of miliary lung, brain and liver metastases. Secondary endpoints were survival and the prognostic implication for each site of miliary metastases. Results: For 543 patients, the total number of brain, lung and liver metastases were 165 (30.4%), 290 (53.4%) and 67 (12.3%), respectively. The EGFR mutation positive (EGFR+) subgroup had a significantly higher 3-year cumulative incidence of miliary brain (4.1 vs. 0.5%, p = .015) and miliary lung (11.6 vs. 3.3%, p < .001) metastases compared to EGFR wild type (WT). A greater proportion of metastases from EGFR + cancers were miliary for brain (8.5 vs. 1.7%, p = .035) and lung (18.9 vs. 6.9%, p = .003) sites. Only non-miliary brain (HR = 1.45) and liver (HR = 1.70) metastases predicted for poor overall survival. Conclusions: Mutations in EGFR were associated with a higher rate of miliary brain and lung metastases. The presence of miliary metastases did not predict for poor overall survival.