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Highlights • EGFR mutation status is not an independent predictor of response to palliative lung radiotherapy. • TKIs remain important in local thoracic management even in patients who receive radiation. • Acquired resistance to TKIs may be associated with cross-resistance to palliative radiotherapy., Purpose To examine the impact of epidermal growth factor receptor (EGFR) mutations on objective response to palliative lung radiotherapy in patients with metastatic non-small cell lung cancer (NSCLC). Materials and Methods A multicentre retrospective study was conducted of patients with metastatic NSCLC diagnosed between March 2010 and June 2012 who received palliative radiotherapy to the chest. Patients included for study had baseline imaging and follow-up imaging 1–3 months after radiotherapy. The primary endpoint was 1–3 month local objective imaging response by the Response Evaluation Criteria in Solid Tumours (RECIST). Patients were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts for analysis. Results There were 121 patients for study inclusion: 89 (74%) were EGFR WT and 32 (26%) were EGFR+. The response rate between EGFR WT and EGFR+ cohorts was not significantly different (49 vs. 63%, p = 0.21). On multivariate analysis, initiation of a tyrosine kinase inhibitor (TKI) after radiotherapy was associated with a higher rate of response (OR: 5.07, 95%CI: 1.08–23.69, p = 0.039) but EGFR mutation status was not. For the EGFR+ cohort, patients with disease progression after initial management on a TKI had a worse response rate compared to patients who were TKI-naïve before starting radiotherapy (30 vs. 77%, p = 0.018). Local control was not statistically different between the EGFR cohorts. Conclusion The EGFR mutation status alone was not an independent predictor of objective radiographic response to palliative thoracic radiotherapy. Acquired resistance to TKI therapy may be associated with disease cross-resistance to palliative radiotherapy.

After palliative radiotherapy for bone metastases from NSCLC, up to 30% of patients may derive no symptomatic benefit, and there are a lack of biological predictors for this. The purpose was to investigate whetherPatients were identified from a prospectively collected patient-reported outcomes database for all patients with lung cancer treated with conventional palliative radiotherapy for bone metastases from 2013 to 2016 in the province of British Columbia. Patients were divided on the basis of mutational status into the following:The final cohort consisted of 388 treatment courses for 329 unique patients. For the WT, EGFR+, and ALK+ groups, there were 180, 63, and nine treatment courses, respectively. There were 92 patients with noThere was an association between EGFR+ and ALK+ tumors and increased rates of partial pain response to palliative radiotherapy.

Glioma is the most common type of tumor in the central nervous system (CNS). Diagnosis is through history, physical examination, radiology, histology and molecular profiles. Magnetic resonance imaging is a standard workup for all CNS tumors. Multidisciplinary team management is strongly recommended. The management of low-grade gliomas is still controversial with regards to early surgery, radiotherapy, chemotherapy, or watchful waiting watchful waiting. Patients with suspected high-grade gliomas should undergo an assessment by neurosurgeons for the consideration of maximum safe resection to achieve optimal tumor debulking, and to provide adequate tissue for histologic and molecular diagnosis. Post-operative radiotherapy and/or chemotherapy are given depending on disease grade and patient performance. Glioblastoma are mostly considered incurable. Treatment approaches in the elderly, pediatric population and recurrent gliomas are discussed with the latest updates in the literature. Treatment considerations include performance status, neurocognitive functioning, and co-morbidities. Important genetic mutations, clinical trials and guidelines are summarized in this review.

Background and purpose To examine the incidence and outcomes of patients with brain metastases from extra-pulmonary small cell carcinoma (EPSCC) and assess the indication for prophylactic cranial irradiation (PCI). Materials and methods A Provincial cancer registry was used to conduct a retrospective, population-based study of patients diagnosed with EPSCC between January 1997 and December 2011. The primary end point was the incidence of brain metastases. The secondary endpoint was overall survival. A "PCI Eligible" cohort was defined to provide an estimation of the incidence of brain metastases in clinically relevant patients. Results In 287 patients, the primary sites were 21% gastrointestinal, 34% genito-urinary, 14% gynecologic, 5% head/neck and 25% unknown primary. Thirty-five (12.5%) patients had brain metastases: 12 (4.2%) at initial diagnosis and 23 (8%) later in the disease course. In PCI Eligible patients, the 3-year cumulative incidence of new brain metastases was 5.5% for M0 stage disease and 26.3% for M1 disease. There was no significant difference in the incidence of brain metastases between primary sites. Conclusions The incidence of brain metastases in patients with EPSCC is comparatively low, even in a cohort of patients that were suitable for PCI. Based on our analysis, we cannot recommend PCI for patients with EPSCC.

Background Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). Methods This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. Discussion This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT. Trial registration Clinicaltrials.gov identifier: NCT03694015. Date of registration: October 3, 2018.

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).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.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 (p0.001), respectively. In multivariate analysis, poor performance status and brain metastases were factors significant for worse survival.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.

Epidermal growth factor receptor (EGFR) exon 20 mutations are seldom tested for in part because they are less common than other EGFR driver mutations and are not associated with sensitivity to EGFR tyrosine kinase inhibitors. We report two cases of lung adenocarcinoma with EGFR exon 20 mutations and a presentation of diffuse, tiny, innumerable lung and brain nodules resembling miliary metastases. Clinicians should be aware of this pattern of presentation in patients with primary resistance EGFR exon 20 mutations.

Background: Oligometastases 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. Methods: This 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

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.

Stereotactic radiosurgery (SRS) can be used as a salvage treatment in selected patients with recurrent brain metastases after previous brain radiation. We report the case of a patient with metastatic lung adenocarcinoma who experienced recurrence numerous times in the brain and was successfully treated each time with SRS. For this patient, brain imaging surveillance helped identify metastases early for salvage SRS. We have also included a discussion of published literature regarding the neurocognitive toxicity of repeated courses of SRS.

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. 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. 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. 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.

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).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.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.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.

BACKGROUND The clinical advantage of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with brain metastases and poor prognosis is controversial. To investigate the feasibility of a phase III clinical trial in a population of patients with poor prognosis, we conducted a randomized feasibility study of WBRT versus SRS. METHODS Patients with Karnofsky performance status (KPS) ≥ 70, life expectancy of 3–6 months, based on both Diagnosis-Specific Graded Prognostic Assessments and attending oncologist opinion, and 1– 10 brain metastases with a diameter ≤ 4 cm were enrolled at six Canadian cancer centers. Patients were randomly assigned to WBRT (20 Gy in 5 fractions) or SRS (15 Gy in 1 fraction). The primary endpoint was the rate of accrual. A secondary endpoint was the ratio of screened subjects to accrued subjects. This trial is registered with ClinicalTrials.gov (NCT02220491). RESULTS Between January 2015 and November 2017, 210 were screened to enroll 22 patients (9.5 screened/participant) and 20 patients were randomized. The accrual rate was 0.63 patients / month. The most common reasons for exclusion were: estimated median survival outside 3–6 months (n = 40), baseline KPS below 70 (n = 28), and > 10 brain metastases (n = 28). The median survival was 7.0 months. The overall survival was 9.5 months (n = 11) for patients who had subsequent systemic therapy, compared to 3.7 months (n = 9) in patients who had none. In both arms, the cumulative incidence of retreatment with brain radiotherapy was 40%. CONCLUSIONS Accrual was slow and the median survival was longer than expected, but a randomized trial evaluating WBRT vs SRS in patients with poor prognosis would likely be feasible by enrolling only patients with no remaining systemic therapy options.

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.

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: 12.1months for the boost cohort and 22.7months for the salvage cohort. There was no difference in median survival after SRS for the boost and salvage cohorts (11.2 vs. 11.2months, 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.

To investigate predictive factors in the development of symptomatic radiation injury after treatment with linear accelerator-based stereotactic radiosurgery for intracerebral arteriovenous malformations and relate the findings to the conclusions drawn by Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).Archived plans for 73 patients who were treated at the British Columbia Cancer Agency were studied. Actuarial estimates of freedom from radiation injury were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used for analysis of incidence of radiation injury. Log-rank test was used to search for dosimetric parameters associated with freedom from radiation injury.Symptomatic radiation injury was exhibited by 14 of 73 patients (19.2%). Actuarial rate of symptomatic radiation injury was 23.0% at 4 years. Most patients (78.5%) had mild to moderate deficits according to Common Terminology Criteria for Adverse Events, version 4.0. On univariate analysis, lesion volume and diameter, dose to isocenter, and a V(x) for doses ≥8 Gy showed statistical significance. Only lesion diameter showed statistical significance (p 0.05) in a multivariate model. According to the log-rank test, AVM volumes5 cm(3) and diameters30 mm were significantly associated with the risk of radiation injury (p0.01). The V(12) also showed strong association with the incidence of radiation injury. Actuarial incidence of radiation injury was 16.8% if V(12) was28 cm(3) and 53.2% if28 cm(3) (log-rank test, p = 0.001).This study confirms that the risk of developing symptomatic radiation injury after radiosurgery is related to lesion diameter and volume and irradiated volume. Results suggest a higher tolerance than proposed by QUANTEC. The widely differing findings reported in the literature, however, raise considerable uncertainties.

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.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 lesionsor=2.0 cm and 70.8 Gy to lesions2.0 cm in diameter. The mean dose to the hippocampus was kept at6 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.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).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.

Single-stranded-DNA-binding proteins (SSBs) are required for numerous genetic processes ranging from DNA synthesis to the repair of DNA damage, each of which requires binding with high affinity to ssDNA of variable base composition. To gain insight into the mechanism of sequence-nonspecific binding of ssDNA, NMR chemical shift and (15)N relaxation experiments were performed on an isolated ssDNA-binding domain (RPA70A) from the human SSB replication protein A. The backbone (13)C, (15)N, and (1)H resonances of RPA70A were assigned for the free protein and the d-CTTCA complex. The binding-induced changes in backbone chemical shifts were used to map out the ssDNA-binding site. Comparison to results obtained for the complex with d-C(5) showed that the basic mode of binding is independent of the ssDNA sequence, but that there are differences in the binding surfaces. Amide nitrogen relaxation rates (R(1) and R(2)) and (1)H-(15)N NOE values were measured for RPA70A in the absence and presence of d-CTTCA. Analysis of the data using the Model-Free formalism and spectral density mapping approaches showed that the structural changes in the binding site are accompanied by some significant changes in flexibility of the primary DNA-binding loops on multiple timescales. On the basis of these results and comparisons to related proteins, we propose that the mechanism of sequence-nonspecific binding of ssDNA involves dynamic remodeling of the binding surface.

2078 Background: Local control of brain metastases reduces risk of death from intracranial progression and improves survival in selected patients. Volumetric modulated arc therapy can deliver a fra...

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 >20Gy is strongly associated with obtaining complete obliteration of the nidus.