Phase 3 trials are typically designed to account for baseline patient characteristics and other factors that may influence treatment outcomes, but stratification factors are inconsistently employed across trials and the impact of commonly used variables is not well defined in the contemporary treatment of limited-stage small cell lung cancer. Better refinement of prognostic baseline characteristics may allow for reduced complexity of clinical trial design. Analysis includes 638 patients enrolled on CALGB 30610/RTOG 0538 randomized to either 45 Gy twice-daily radiotherapy or 70 Gy once-daily radiotherapy concurrent with 4 cycles of chemotherapy. Stratification factors for randomization included gender, ECOG performance status (PS), weight loss > 5% prior to study entry, timing of initiating radiotherapy (chemotherapy cycle 1 vs cycle 2), radiotherapy planning technique (3D conformal vs intensity modulated), and carboplatin or cisplatin-based chemotherapy. The only variable significantly associated with improved survival was female gender (HR 0.79, p = 0.021), while a trend toward improved survival was observed with the use of cisplatin vs. carboplatin (HR 0.81, P = 0.121). There was also a trend toward better survival for ECOG PS 1 vs. ECOG PS 2 (HR =0.78, p =0.15), but not for ECOG 0 vs. ECOG 1 (HR=1.05, p=0.59). Weight loss, timing of initiating radiotherapy, and radiotherapy technique did not appear to impact survival. A similar impact of each factor was observed regardless of treatment arm. These data may help simplify trial design and selection of stratification factors for future prospective trials. In particular, outcomes were virtually indistinguishable for ECOG PS = 0 and ECOG PS = 1 patients, suggesting these groups may be combined in future studies.

Purpose/Objective(s)Pulmonary toxicity, and in particular radiation pneumonitis, remains a major limitation in the radiotherapy treatment of lung cancer patients. Functional avoidance radiotherapy proposes to use functional imaging to reduce pulmonary toxicity by designing radiotherapy treatment plans that reduce doses to functional regions of the lung. A novel form of lung functional imaging has been proposed that uses 4DCT imaging to calculating 4DCT-based lung ventilation (4DCT-ventilation) maps. A phase II, multi-center, prospective study was initiated to evaluate 4DCT-ventilaiton functional avoidance radiotherapy. The study hypothesis was that functional avoidance radiotherapy could reduce the rate of ≥ grade 2 radiation pneumonitis to 12% compared to a 25% ≥ grade 2 historical pneumonitis rate. Based on a binomial, one-sided 95% confidence interval (CI), the trial would be positive if ≤ 11 of 67 patients (16.4%) experienced ≥ grade 2 radiation pneumonitis.Materials/MethodsLung cancer patients receiving curative intent radiotherapy (prescription doses of 45-75 Gy) and planned curative intent chemotherapy were accrued from 2 institutions. Patient 4DCTs along with image processing techniques were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose and respecting tolerances of organs-at-risk. Functional doses were reduced by selecting favorable arc geometry and employing optimization techniques. Patients were evaluated for pneumonitis at 3, 6, and 12 months after completing radiotherapy.ResultsSixty-seven evaluable patients were accrued between April 2015 and December 2019. Median Karnofsky performance status was 90 and 76% of patient's had stage III disease. The median prescription dose was 60 Gy (range 45–66 Gy) delivered in 30 fractions (range 15–33 fractions). Eleven patients (16%) underwent surgery as part of their treatment, 88% of patients received concurrent chemotherapy, and 25% of patients were treated with immunotherapy while they were on study. Median follow-up was 312 days. The crude rate of ≥ grade 2 radiation pneumonitis was 14.9% (10/67 patients, upper 95% CI of 24.0%), meeting the phase II criteria.ConclusionBecause 4DCTs are a standard part of the treatment planning process for lung cancer patients, 4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra imaging procedure necessary. Our study reports on the first multi-center, prospective study of 4DCT-ventilation functional avoidance radiotherapy. The study met phase II criteria demonstrating reduced pneumonitis rates and provides favorable evidence for 4DCT-ventilation functional avoidance to be investigated in a phase III study. Future work will report on secondary objective including pulmonary function, patient-reported outcomes, and imaging-based end-points.

Outcomes are similar to the contemporaneous CONVERT trial, and compare favorably to the prior phase II trial examining 61.2 Gy CB TRT (RTOG 0239) in LSCLC, despite the allowance of early stage (N0) disease in those studies. The improvement in OS compared with RTOG 0239 is likely attributed to improved staging and advances in radiotherapy planning and delivery, though additional factors may have contributed. Support: U10CA180821, U10CA180882; U10CA180868 (NRG), U10CA180888 (SWOG); https://acknowledgments.alliancefound.org Clinicaltrials.gov Id: NCT00632853.

The importance of the heart has been emphasized in recent thoracic chemo-radiation (CRT) literature. A lung cancer dose escalation study (RTOG 0617) noted that heart doses were significantly associated with overall survival (OS). The purpose of this study was to characterize pre-to-post treatment cardiac metabolic changes using FDG-PET scans and to evaluate whether PET-based cardiac imaging changes predicted for OS. Lung cancer patients enrolled on a multi-institutional, prospective clinical trial for functional avoidance thoracic radiotherapy were analyzed. 39 patients who had undergone pre and post chemo-radiation FDG-PET imaging were studied. Post-CRT PET scans were acquired at a median time of 97 days (range 11 to 477 days) after treatment. Patients on the study were treated with definitive CRT with radiation doses ranging from 45-60 Gy in 15-30 fractions. For each patient, the pre-treatment PET-CT and post-treatment PET-CT were rigidly registered to the planning CT, dose, and structure set. PET-based dose-response was assessed by comparing pre-treatment to post-treatment Standardized Uptake Values (SUV) in the heart contour. A dose-response curve was generated by binning each voxel in the heart contour into 10 Gy dose-bins and analyzing the average SUV changes in each dose-bin. Patients on the study were followed for OS for up to 14 months after completing chemo-radiation. We evaluated whether the pre-to-post treatment changes in the average or maximum SUV were predictive of OS. The OS analysis was performed by comparing mean SUV changes for patients that were alive or had died at last follow-up and by using a univariate cox proportional hazard model to assess whether pre-to-post treatment SUV changes were a significant predictor of OS. The cardiac SUV dose-response curve revealed increasing changes in SUV as a function of dose with relative SUV increases of 11.4%, 9.8%, 9.4%, 12.2%, 14.2%, and 20.1% in the 10, 20, 30, 40, 50, and 60 Gy dose-bins, respectively. The SUV dose-response curve demonstrated an average increase of 1.7% for every 10 Gy. Median follow-up was 410 days (range 181 to 541) with 30/39 patients alive at last follow-up. Patients that were alive at follow up had an average increase of +17.2% in cardiac SUV while patients that did not survive had a decrease in SUV of -13.5% (p=0.048). Both the mean and maximum pre to post-treatment SUV changes were significant predictors (p<0.03) of OS. Functional imaging has been used for target delineation and evaluating normal lung function in thoracic CRT but has yet to be used for cardiac treatment response assessment. In our dataset, post-treatment changes in cardiac PET were significant indicators of dose-response and potential predictors of OS. Pre and post-treatment PET imaging is frequently obtained for lung cancer patients and if validated by multivariate analysis, our data show the potential for PET cardiac changes to be an early predictor for cardiac death, allowing for intervention.

Lung cancer remains the leading cause of cancer related death in men and women in the US. The US Preventive Service Task Force recommends annual screening for lung cancer with low-dose computed tomography in high risk individuals in order to detect lung cancer at earlier stages and reduce rates of lung-cancer mortality. This study assesses factors associated with early mortality (30 days from initial diagnosis) in non-small cell lung cancer (NSCLC) during the last decade. The National Cancer Database was queried for patients ≥ 18 years with NSCLC treated from 2006-2015. Patients included had known follow up at 30 days from diagnosis. Survival interval was calculated from the date of diagnosis to the date of death. Two categories were selected: patients who died within 30 days of diagnosis and those who lived longer than 30 days. Univariate and multivariate logistic regression was used to assess variables associated with early mortality. Variables included: age, sex, race, insurance, facility type, region of country, population density, income, education level, comorbidity score, year of diagnosis, and AJCC overall clinical stage. A total of 974,732 patients were included; 70,167 (7.2%) died within 30 days of their diagnosis. Under multivariate logistic regression comparing those who died within 30 days to those who lived longer than 30 days, older age (odds ratio [OR] 1.03; p<0.001), higher Charlson comorbidity score (OR 1.42; p<0.001), patients with Medicare (OR 1.10; p<0.001), Medicaid/other government insurance (OR 1.25; p<0.001), or no insurance (OR 2.02; p<0.001) were all significant predictors for early mortality. Higher overall clinical stage also predicted for early mortality: stage II (OR 2.01), III (OR 3.31), IV (OR 7.87), not staged (OR 5.95) vs. I (all p<0.001). Of those who died within 30 days from diagnosis, 45,861 (65%) presented with stage IV disease (p<0.001). Factors associated with a lower odds of 30 day mortality included diagnosis in more recent years and receipt of care at comprehensive community cancer programs (OR 0.93), academic (OR 0.77), and integrated network cancer programs (OR 0.89) when compared to community programs (all p<0.001). Female patients (OR 0.82; p<0.001), those in higher income counties (ORs 0.86-0.93; all p<0.001), and patients living in areas with higher high-school graduation rates (OR 0.92, p<0.001) were also less likely to die within 30 days of their diagnosis. Approximately 7% of newly diagnosed NSCLC patients have died within 30 days of their diagnosis over the past decade. The majority of these individuals (65%) present with stage IV disease. Increasing awareness about lung cancer screening programs, improvements in access to care, and better medical optimization especially for elderly patients with multiple comorbidities may help further reduce the rates of early mortality in NSCLC.

We previously observed that LCT improves progression free survival (PFS) in patients with oligometastatic NSCLC after front-line systemic therapy without progression (Gomez et al, Lancet Oncol 2016). Here we report the final analysis of this trial, including the mature secondary endpoint of OS.

The comparative effectiveness of stereotactic body radiotherapy (SBRT) versus surgery for early-stage non-small cell lung cancer (esNSCLC) continues to be debated. Perioperative surgical mortality may give SBRT patients an early survival advantage. We endeavored to compare near-term mortality in a large esNSCLC population between patients undergoing surgery or SBRT in an analysis of the National Cancer Database (NCDB). NCDB was queried for patients with T1-T2a N0 M0 NSCLC diagnosed from 2004 to 2013 undergoing either SBRT or surgery. Thirty-day and 90-day post-treatment mortality was calculated by subtracting the time from diagnosis to treatment initiation from duration of follow-up and compared between SBRT and various surgical approaches. Patients were segmented into similarly sized age quartiles. Multivariate logistic regression (MVA) was performed to determine associations between odds of mortality and demographic, facility-specific, and clinical factors. Propensity-score matching (PSM) was also performed to derive a 3:1 (surgery:SBRT) matched cohort in order to compare odds of mortality between surgery and SBRT by univariate logistic regression. We identified 76,623 surgery patients, of whom 77.7% received lobectomy, and 8,216 SBRT patients, who received a median dose of 51 Gy. Surgical patients experienced increased mortality as compared to those undergoing SBRT at both 30 days (2.1% vs 0.7%) and 90 days (3.6% vs 2.9%), differences most pronounced among patients older than 75 (Table 1). On MVA, each surgical modality was associated with increased mortality versus SBRT at 30 days (odds ratio [OR] for sublobar resection 2.76, 95% CI 2.08-3.68; OR for lobectomy 3.52, 95% CI 2.70-4.60; OR for pneumonectomy 14.1, 95% CI 10.1-19.8; all P < 0.001) and at 90 days (OR for sublobar resection 1.36, 95% CI 1.16-1.61; OR for lobectomy 1.58, 95% CI 1.37-1.83; OR for pneumonectomy 5.59, 95% CI 4.46-7.01; all P < 0.001). Among a PSM cohort of 28,248 patients, surgical patients continued to experience increased mortality at both 30 days (2.5% vs 0.7%; OR 3.43, 95% CI 2.57-4.56; P < 0.001) and 90 days (4.2% vs 2.8%; OR 1.53, 95% CI 1.31-1.79; P < 0.001). We identified greater mortality in the near-term post-treatment period in a modern cohort of esNSCLC patients undergoing surgery versus SBRT. These findings may guide management of esNSCLC, particularly for older patients and those at greatest risk of perioperative morbidity, and underscore the importance of multidisciplinary evaluation.Abstract 1154; Table 1Age QuartileSublobar ResectionLobectomyPneumonectomyAll SurgerySBRT30-Day Mortality Rates (%)<620.70.85.31.00.762-681.31.47.21.50.469-751.72.410.92.40.8>752.93.913.83.70.890-Day Mortality Rates (%)<621.31.48.11.62.762-682.32.411.02.61.969-753.24.216.04.22.7>755.46.521.36.43.5 Open table in a new tab

Studien zur Verbesserung der Tumorkontrolle beim Glioblastoma multiforme (GBM) durch Erhöhung der Bestrahlungsdosis mit konventioneller Fraktionierung haben zu keinem verbesserten Behandlungsergebnis geführt. Über die hypofraktionierte Bestrahlung kann die biologisch effektive Strahlendosis gesteigert werden. Deswegen verglichen Carlson und Kollegen die Ergebnisse von 2 konsekutiven Phase II-Studien, in denen die Patienten jeweils mit hypofraktionierter intensitätsmodulierter Bestrahlungstherapie (Hypo-IMRT) und Temozolomid (TMZ) behandelt wurden, mit oder ohne zusätzliches Bevacizumab (BEV).

The phase I results of NRG/RTOG 0813 trial were reported at ASTRO 2015. We hereby report the phase II results - efficacy and toxicity beyond year 1. Medically inoperable patients (pts) with biopsy proven, PET staged T1-2 (<5 cm) N0M0 centrally located NSCLC (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura) were successively accrued onto a dose-escalating 5 fraction SBRT schedule ranging from 10-12 Gy/fraction (fr) delivered over 1.5-2 weeks. Phase I data analysis revealed that maximum tolerated dose was the highest dose level allowed on the study, 12 Gy/fr x 5 fractions. Thirty-three eligible pts were treated with 12 Gy/fx, and another 38 pts were treated on the preceding dose level of 11.5 Gy/fr; this is the report of efficacy based on patients in those two cohorts. Patients were elderly, and the majority had performance status 0-1. T1 cancers were treated in 58% of pts in the 11.5 Gy/fr cohort and 70% in 12 Gy/fr cohort. Median PTV volumes were 43cc (range 14.85 - 155.05 cc) and 32 cc (7.48 - 117.25) respectively. Organs closest to PTV/most at risk were main bronchus (45% and 39%, respectively) and large vessels (53% and 21%). Median follow-up was 33 months (mo) for the 11.5 Gy/fr cohort and 29.8 mo for the 12 Gy/fr cohort (49 and 31.8 mo for the surviving pts, respectively). Late toxicities grade 3 or greater (G3+) attributed to SBRT were 2 G5 toxicities in the 11.5 Gy/fr cohort, and in the 12 Gy/fr cohort 3 G3 (2 respiratory, 1 cardiac), 1 G4 (esophageal perforation), and 1 G5 (pulmonary hemorrhage) toxicities. The Table details the incidence of attributed G3+ toxicity, observed failure patterns, and outcomes.Tabled 1Abstract 16; Table 1Dose level11.5 Gy x 5fr12 Gy x 5frNumber (n) of eligible patients3833Pts w Toxicity G3+ (at any time)67Pts w Early Toxicity G3+ (within 1st yr)54Pts with Late Toxicity G3+ (beyond 1st yr)25Pts with primary tumor failure46Pts with involved lobe failure22Pts with regional (lymph node) failure24Pts with distant failure652-year local control89.4% (81.6-97.4%)*87.7% (78.3-97%)*2-yr progression free survival52.2% (35.3-66.6%)*54.5% (36.3-69.6%)*2-year overall survival (OS)70.2% (52.6-82.3%)*72.7% (54.1-84.8%)**90% confidence interval. Open table in a new tab *90% confidence interval. Observed local control at 2 yrs in 71 pts treated with the two highest doses levels (11.5-12 Gy/fr x 5 fr) in this multicenter trial was high, and G3+ toxicity rates were acceptable. Two-year OS rates of 70% in this medically inoperable group of elderly pts with comorbidities were comparable to pts with peripheral early stage tumors. This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U10CA37422 (CCOP), and CA81647 (ATC) from the National Cancer Institute (NCI).

Brain metastases (BM) are frequently observed in patients with melanoma and remain a significant cause of cancer-related morbidity and death. We previously demonstrated that the survival of patients (pts) with BM varies widely by diagnosis (Dx) and Dx-specific prognostic factors as defined by the Dx-Specific Graded Prognostic Assessment (DS-GPA). The melanoma cohort in our original study (1985-2005, n = 481, JCO 2012:30; 419-425) had a median survival (MS) of 6.7 months from the time of initial BM treatment. The purpose of the current study was to assess the effect of gene mutations on survival, time from primary diagnosis to BM (TPDBM) and cause of death in melanoma pts. We created a multi-institutional IRB-approved retrospective database of pts with melanoma and newly diagnosed BM between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, CKIT, and NRAS), and treatment were recorded and correlated with survival (measured from time of initiation of treatment for BM) and cause of death. The Log Rank Test and Wilcoxon Rank Sum Test were used for MS and TPDBM P value computation. Of 771 evaluable pts, 543 (70%) had known gene alteration status. Mutation status, MS, TPDBM, and interquartile ranges (IQR) in months (mo) were:Abstract 1034; Table 1MelanomaNMS (mo)IQR (mo)P-valueTPDBM (mo)IQR (mo)P-valueOverall771104-253314-65BRAF status unknown228 (30%)83-163615-76BRAF status known543 (70%)115-300.00043314-600.32BRAF negative271 (50%)94-243224-55BRAF positive272 (50%)136-330.033614-670.17 Open table in a new tab Among BRAF-positive pts, 194/272 (71%) received BRAF and/or MEK targeted drugs and 156/272 (57%) received some combination of BRAF and/or MEK targeted drugs with either immunotherapy or chemotherapy. CKIT and NRAS mutations were present in 26/272 (10%) and 61/269 (23%) of pts, respectively and there was no significant difference (NSD) in survival for pts with and without CKIT or NRAS mutations. Correlation of mutation status and survival with age, race, gender, type, and timing of radiation and drug treatment, KPS, number of BM, GPA, extracranial metastases, and cause of death will be presented. This is the largest reported series of melanoma pts with BM and shows pts with BRAF-positive melanoma survive longer after initial BM treatment than BRAF-negative pts and twice as long in this era (2006-2015) compared to our prior report (1985-2005). There was NSD in TPDBM between pts with and without BRAF mutations. CKIT and NRAS mutations did not affect survival. Transition to a DSmol-GPA incorporating molecular variables will aid clinical decision-making and stratification of future clinical trials. Further research is needed to better define the effect of BRAF and/or MEK targeted drugs and immunotherapy in pts with melanoma and BM.

Glioblastoma multiforme (GBM) is a nearly uniformly fatal brain tumor with a median recurrence rate of 8 months and survival of 14 months after multimodality treatment. We sought to evaluate outcomes based on the presence or absence of symptoms at the time of recurrence. We retrospectively analyzed 60 patients with GBM treated from 2007-2014 at our institution. All patients received radiation therapy with concurrent temozolomide. All patients had a documented symptomatic or radiographic recurrence. Symptomatic recurrence was defined as development of new or recurring symptoms prior to evidence of radiographic recurrence; those in this group had follow-up imaging confirming recurrence. Radiographic recurrence was defined as unequivocal evidence of recurrence on MRI; these individuals did not have symptoms at the time of recurrence. All cases were reviewed and confirmed as recurrences at multidisciplinary tumor board review. Overall survival (OS) was defined as time from the completion of initial radiation therapy to death, while post-relapse survival was defined as the time from recurrence to death. Median age for the symptomatic and radiographic group was 58 and 57 years respectively. The symptomatic group consisted of more male patients (63%) compared to the radiographic cohort (50%). Recursive partitioning analysis (RPA) classes were similar between both groups. MGMT and IDH-1 status were unknown in the majority of patients. Median tumor size (greatest diameter) was larger in the symptomatic group, 46 mm vs 40 mm. The median time to recurrence was 9.5 mos (range 3-49 mo). Forty relapses (66.7%) were symptomatic; 20 (33.3%) were radiographic. Median OS for the symptomatic and radiographic cohort were 15.5 mo and 20 mo respectively, a relative difference of 4.5 mo (p = 0.090). Post-relapse survival was 3 months in patients who recurred symptomatically and 10 mo for those that recurred by imaging (p= 0.005). Among the radiographic recurrence cohort, those who later went on to develop symptoms also had a median survival from symptom onset of 3 mos, equivalent to the symptomatic recurrence group. OS is worse in GBM patients who present with symptoms at the time of recurrence. The development of clinical symptoms is also significantly predictive of post-relapse survival, though a component of this may be due to lead time bias. While median OS only trended toward significance between cohorts, this difference in survival between symptomatic and asymptomatic recurrences is relatively large and should be validated in larger patient cohorts. If this difference is confirmed, we would suggest that future studies evaluating treatment options in the recurrent setting may need to stratify patients based on presence of symptoms at the time of enrollment.

The publication of RTOG 8815 established hyperfractionated, twice-daily thoracic radiation therapy (BID RT) with concurrent platinum-etoposide (PE) as the standard of care in limited-stage small cell lung cancer (LS-SCLC). However, many patients with this aggressive, often debilitating malignancy find BID RT intolerable due to both physical and logistical limitations. As an alternative, patients unable to receive BID RT are treated with daily 3Gy fractions (QD RT) to a total dose of 45Gy at our institution. We hypothesized that hypofractionated QD RT in the setting of concurrent PE would be as safe and effective as BID RT. We conducted a retrospective review of patients with LS-SCLC treated with curative intent. Patients received 45Gy either QD (3Gy) or BID (1.5Gy) with concurrent PE. Covariables reviewed include age, gender, race, insurance status, year of diagnosis, 3D vs IMRT planning, PTV volume, chemotherapy agents and cycles, RT dose and fractionation, incidence of Grade ≥2 radiation pneumonitis and subsequent delivery of prophylactic cranial irradiation (PCI). Chi-square and logistic regression analyses were utilized to compare the characteristics of treatment groups for dichotomous and continuous variables, respectively. Kaplan-Meier progression-free (PFS) and overall survival (OS) estimates were generated, with accompanying univariate (UVA) log-rank and multivariate (MVA) Cox proportional hazards regression analyses. Thirty-six patients were evaluable, with a median follow-up of 13 months for the entire cohort (range 3-79), and a median follow-up of 18.5 months for survivors (range 7-73). 88% of patients were deceased at last follow-up. For the entire cohort, median age was 63 years (range 54-81). 24 (67%) patients received BID RT; 12 (33%) received QD RT. BID and QD groups were balanced with respect to age, race, sex, insurance status, PTV volume, and 3D vs IMRT planning. One patient in each group was treated with corticosteroids for radiation pneumonitis. No significant differences were observed for PFS or OS outcomes. 2-year PFS was 13.4% (BID) vs 16.7% (QD) (HR 0.81; 95% CI 0.73-1.67; p<.61) and 2-year OS was 34.5% (BID) vs 31.7% (QD) (HR 0.72; 95% CI 0.28-1.86; p<.51). Neither the incidence of Grade ≥2 radiation pneumonitis (p=0.61) nor utilization of PCI (BID 58% vs 50% QD, p=0.64) differed between the two groups. In this single-institution study, hypofractionated QD RT to 45Gy delivered with concurrent PE was associated with toxicity and outcomes comparable to BID RT with concurrent PE. Further validation with a larger, prospective dataset is warranted. Daily hypofractionated thoracic RT with concurrent chemotherapy represents a reasonable alternative for patients who cannot be treated twice daily.

Lung cancer is the most common cause of brain metastases (BM) which remain a common cause of death. We have previously demonstrated that the survival of patients (pts) with BM varies widely by diagnosis (Dx) and Dx-specific prognostic factors as defined by Dx-Specific Graded Prognostic Assessment (DS-GPA) (JCO 2012:30; 419–425). The purpose of this study was to assess the effect of biological heterogeneity, specifically gene mutations (with or without the use of targeted therapies) on survival in pts with lung adenocarcinoma and BM. A multi-institutional IRB-approved retrospective database of pts with lung cancer and newly diagnosed BM between 2006 and 2014 was created. Clinical parameters, gene mutation/translocation status (EGFR, ALK, and KRAS), and treatment were recorded and correlated with survival, measured from time of initiation of first treatment for BM. Of 2,482 pts in the database, 2,103 had sufficient data for evaluation and 800 of the 1328 pts with adenocarcinoma had known mutation status (largest reported series). Their mutation status, median survival time (MS) and interquartile range (IQR) in months (mo) were as in Table 1.Oral Scientific Abstracts 83; Table 1.NMS (mo)95% CIIQR (mo)P-valueAdenocarcinoma132815.213.9 – 16.46 – 32Mutation status: known800 (60%)18.015.5 – 19.86 – 37< 0.01Mutation status: unknown528 (40%)12.010.2 – 14.25 – 24EGFR positive197 (26%)25.120.0 – 29.911 – 47< 0.01EGFR negative555 (74%)15.513.0 – 18.56 – 35ALK positive83 (16%)33.227.3 – 50.319 – 62< 0.01ALK negative449 (84%)15.613.2 – 19.06 – 34KRAS positive179 (31%)11.78.4 – 15.95 – 320.01KRAS negative397 (69%)20.017.4 – 22.78 – 40 Open table in a new tab Most (89%) pts with EGFR or ALK mutations received targeted drug therapy. There was no significant difference in MS between EGFR positive pts treated (n = 175, MS = 25.1 mo, IQR = 12–47) versus not treated (n = 19, MS = 45.9 mo, IQR = 2–51, P = .56) or between ALK positive pts treated (n = 72, MS = 37.4 mo, IQR = 19–62) versus not treated (n = 10, MST-NA, IQR = 8-NA, P = .81) with targeted drug therapies, although the number of untreated patients was small. A comparison to historical controls and correlation of mutation status and survival with age, race, gender, smoking history, TNM stage, treatment, KPS, extracranial metastases, GPA, BM characteristics (number, volume, and location), timing of targeted drug therapy, time from primary Dx to BM and cause of death will be presented. Analogous to HER2+ breast cancer BM patients, gene mutations profoundly influence survival (positively for EGFR and ALK, negatively for KRAS) in pts with lung adenocarcinoma and BM. Compared to prior reports, MS in this cohort was substantially longer. Transition to a DSmol-GPA incorporating molecular variables will aid clinical decision making and stratification of future clinical trials.

The brain is a common site of metastasis for patients with non-small cell lung cancer (NSCLC) and brain metastases (Br-Mets) in these patients is associated with a poor prognosis. It is unknown if the time from diagnosis of NSCLC to development of Br-Mets is prognostic for survival. The purpose of this study is to characterize the survival impact of synchronous versus metachronous diagnosis of Br-Mets from NSCLC. A retrospective single institution review of patients with NSCLC and Br-Mets diagnosed between 2007 and 2014 was performed. Overall survival (OS) from the time of brain metastases diagnosis was estimated using the Kaplan-Meier method. The survival impact of synchronous (<2 months from primary to Br-Met diagnosis) vs metachronous Br-Mets, Karnofsky-Performance Status (KPS), number of cranial metastases, presence of extracranial metastases (ECM), and EGFR/ALK mutation status were evaluated with univariate (UVA) and multivariate (MVA) analyses using log-rank tests and Cox proportional hazards regressions. We identified 327 patients that met inclusion criteria. The median follow up was 8.7 months and the median OS after diagnosis of Br-Mets was 10 months. Increased time from initial lung cancer diagnosis to diagnosis of Br-Mets was associated with prolonged OS. On UVA, increased time in months from NSCLC diagnosis to Br-Mets development was associated with significantly improved OS as a continuous variable (p=0.030) and as a categorical variable (synchronous brain mets [N=186] vs metachronous 2-24 months [N=83] vs metachronous 24+ months [N=58]) with a median OS of 8.5 vs 9.7 vs 15.8, respectively (p=0.016 and 0.0006). Other factors significant for improved survival on UVA were age (<50yo vs 50-60yo and >60yo), KPS (70 vs 70-80 vs 90-100) and absence of ECM. On MVA, months from NSCLC diagnosis to Br-Mets development remained independently associated with improved OS as a continuous variable (p=0.035) and as a categorical variable for patients with a 24+ month interval from NSCLC diagnosis to Br-Mets development (HR 0.67; 95% CI 0.45-1.00; p=0.05) EGFR and ALK mutation status was available for 109 patients and after accounting for mutation status on MVA, metachronous diagnosis of Br-Mets after 24 months was no longer significant for OS (p=0.386). In this retrospective analysis, metachronous development of Br-Mets >24 months from the diagnosis of NSCLC was associated with improved survival measured from the time of brain metastases diagnosis. On subset analysis accounting for EGFR and ALK mutations, this benefit was no longer seen.

A new and exciting form of functional imaging has been proposed using 4DCT data to create functional lung ventilation maps. 4DCT-ventilation provides functional information without the added dosimetric or monetary cost to the patient. Development of clinical trials is underway to use 4DCT-ventilation for thoracic functional avoidance with the idea that preferential radiation (RT) sparing of functional regions may decrease pulmonary toxicity. Prior to proceeding with clinical trials, studies are needed that assess and determine patient eligibly criteria for functional avoidance. For patients with homogenous lung function, there is no basis to preferentially spare any regions. Conversely, in patients with regionally variant lung ventilation, avoiding radiation to functional lung can be of benefit. The purpose of our work was to assess the percentage of stage III lung cancer patients that may be eligible for functional avoidance and develop clinical and quantitative inclusion criteria for clinical trials. From two institutions, 96 stage III lung cancer patients who underwent thoracic RT were retrospectively reviewed. 4DCT data sets, spatial registration, and a density-change based model were used to compute 4DCT ventilation maps. To assess eligibility, 3 investigators reviewed each 4DCT-ventilation map to reach a consensus on clinical defect presence. Quantitative metrics were developed to reflect the degree of ventilation obstruction and heterogeneity including an algorithm using the regional ventilation in each lung third and the ratio of ipsilateral to contralateral ventilation (I/C). The ability of the quantitative metrics to predict for observer defined defects was assessed using logistic regression and area under the curve (AUC). Investigator-determined clinical ventilation defects were present in 66 patients (69%). AUCs were 0.83 (p<0.01) and 0.72 (p<0.01) for the regional ventilation and I/C respectively, suggesting that regional ventilation is the optimal quantitative method to assess ventilation defects. With a sensitivity of 85%, the regional ventilation algorithm identified 56 patients (59%) suitable for functional avoidance RT. 4DCT-ventilation functional avoidance clinical trials have great potential to reduce radiation toxicity. Our data suggest that ∼70% of stage III lung cancer patients have significant ventilation defects and ∼60% are suitable for 4DCT-ventilation functional avoidance. The development of clinical and quantitative inclusion criteria is essential to functional avoidance clinical trials. We present the first study to use 4DCT-ventilation to define patient eligibility for functional avoidance and develop metrics that will help guide patient inclusion criteria.

We performed two consecutive prospective Phase 2 trials evaluating hypo-IMRT with TMZ for the treatment of newly diagnosed GBM. In the second trial we added concurrent and adjuvant BEV. We compare results from these 2 trials to determine whether the addition of BEV affects overall survival (OS) or progression-free survival (PFS). Patients with newly diagnosed GBM after biopsy or resection were enrolled on a clinical trial with hypo-IMRT and TMZ (TMZ alone) from 2008-2010, or the second protocol with the same hypo-IMRT and TMZ plus BEV (TMZ/BEV) from 2010-2013. All patients received postoperative hypo-IMRT to the surgical cavity and residual tumor as seen on T1-weighted brain MRI to a total dose of 60 Gy in 10 fractions and to the T2 abnormality to a dose of 30 Gy in 10 fractions. Concurrent TMZ (75 mg/m2/day) was given to all patients for 28 consecutive days followed by adjuvant TMZ (150-200 mg/m2/day). Patients enrolled on the TMZ/BEV trial received concurrent and adjuvant BEV (10 mg/kg) on days 1 and 15 of each 28-day cycle. Hazard ratios of OS and PFS were compared between trials in a Cox proportional hazard model. Twenty-six patients were enrolled on the TMZ alone trial and 30 patients on the TMZ/BEV trial. No differences were seen between patient populations with respect to age, gender, RPA class, and surgery type. Patients enrolled on the TMZ/BEV trial had a significantly higher KPS and significantly larger planning tumor volume (PTV) (83% vs 77.7%; p = 0.025 and 128 cc vs 100 cc; p = 0.029, respectively). Median follow-up for TMZ alone and TMZ/BEV was 13.9 mos and 14.2 mos, respectively. Median OS was 16.3 months for both TMZ/BEV and TMZ alone. Median PFS was 3.2 months longer with TMZ/BEV but this difference was not significant (12.8 mos vs 9.4 mos, p = 0.39). Six month PFS was also not different with TMZ/BEV vs BEV (80% vs 84%; p = 0.702). An exploratory analysis evaluating the difference in clinically significant radiation necrosis between trials found a higher rate with TMZ/BEV (47% vs 15%; OR = 4.88; CI 1.17, 20.4; p = 0.024); however, after controlling for tumor size and performance status the difference was reduced and no longer significant (OR = 4.52; CI 0.95; 21.7). The addition of BEV to TMZ and hypo-IMRT does not improve OS for patients with GBM; PFS was longer in the cohort treated with BEV, but not statistically significant, probably due to small patient number. The OS from these 2 hypo-IMRT trials are comparable to outcomes with current standard of care therapy, with radiation delivery time reduced to 2 weeks.

PURPOSE:To better define patterns of practice for patients with non-small cell lung cancer (NSCLC) in the United States. METHODS AND MATERIALS:A survey of 36 questions was designed to collect information regarding practice patterns of radiation oncologists for the management of patients with NSCLC. All American Society for Radiation Oncology members were invited to respond. RESULTS:Four hundred twenty-four responses from radiation oncologists in the United States were received. The response rate for the survey was approximately 20%. Substantial discrepancies were seen in the use of stereotactic body radiation therapy (SBRT) for patients with peripherally and centrally located early-stage tumors and in the recommended SBRT dose. There was a near consensus opinion regarding the use of concurrent chemotherapy and the radiation dose for patients with inoperable stage II and III NSCLC with a good performance status; however, in patients with a poor performance status or in patients with stage IV disease treatment recommendations differed remarkably. Additionally, the use of elective nodal irradiation and the assessment of tumor motion during simulation were highly variable. Thoracic radiation oncologists were more likely to prescribe higher doses, omit elective nodal irradiation, and use advanced technologies (P < .001). CONCLUSIONS:Substantial variations were seen in the management of patients with stage I and IV NSCLC in addition to the incorporation of new technology. This information can be used to help design meaningful clinical trials.

BACKGROUND: Primary gliosarocoma (GSM) is a rare central nervous system tumor with limited experience reported in the literature.The author presents clinical experience and outcome for primary GSM patients in one medical center.METHOD: Patients with primary GSM were selected using a retrospective review (1990 2011).A meticulous chart review was performed and clinical, pathologic data were taken into analysis.RESULTS: Eleven patients were diagnosed with primary GSM.It was 1.6% that of glioblastoma in the same period.The overall median survival was 12 months.Patients who underwent maximal safe resection were found to have a prolonged median survival compared with patients who only underwent biopsy of the tumor (12 vs 6 months, p ¼ 0.288).All patients received adjuvant postoperative radiotherapy and 7 of 11 patients received chemotherapy with temozolomide.Four patients received gamma-knife radiosurgery for local recurrence.However, gamma-knife radiosurgery did not affect the survival.Patients who received re-explorative surgery for resectable recurred tumor had a prolonged median survival compared to patients who non-resectable recurred tumor (14 vs 6 months, p ¼ 0.0082).CONCLUSION: Primary GSM, like glioblastoma, is a highly malignant tumor of the central nervous system.However, due to its rarity, our experience is limited.According to the guidance for glioblastoma treatment, the standard treatment for primary GSM is maximal safe resection, postoperative radiotherapy, and chemotherapy with temozolomide.Despite an aggressive treatment, the life expectancy of patients diagnosed with GSM is very short.Still, standard treatment is not well established on primary GSM.Accordingly, we need a larger and comprehensive clinical investigation in the future.

Bev combined with chemotherapy has improved survival in the treatment of advanced NSCLC. Pre-clinical data suggest that Bev has radiosensitizing properties in solid tumor models. The specific aim of this analysis is to describe the results of incorporating Bev into the standard SWOG CRT regimen in LA-NSCLC. Pts with unresectable stage III NSCLC, PS 0-1, adequate organ function were accrued in two strata, low and high risk (squamous histology, hemoptysis, tumor cavitation and/or near a major vessel). Pts were treated with CDDP 50 mg/m2 (D1, 8), Etoposide 50 mg/m2 (D1-5) for 2 cycles concurrent with TRT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation Docetaxel 75 mg/m2 and Bev 15 mg/kg for 3 cycles (Cohort 1). If safety was established then accrual would continue with Bev administered on D1-5, 37, 57 of concurrent chemoradiation therapy (Cohort 2) followed by advancing Bev to Day 1, 22, 43 (Cohort 3). Three-dimensional treatment planning (CT or PET-CT) and delivery, including tissue heterogeneity corrections, was mandated. QARC approved 3D benchmarks were required. IMRT was not allowed. V20 limit (total lung volume -GTV) ≤35%. Twenty-nine pts (17 Low, 12 High) were registered, all to Cohort 1. Twenty-six pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) were evaluable, including 10 high-risk, 16 low-risk cases. Twenty-two pts reached a total dose of 64.8 Gy (with an unscheduled RT break in a single pt). Of 9 high-risk pts with RT data available, median V20 = 30%, range: 23%-35%; of 14 low-risk pts with RT data available, median V20 = 35%, range: 21%-48%. In 12 pts V20 was near or > 35%: 34% in 2 pts, 35% in 5 pts, 45% in 2 pts, and 48% in 2 pts. Grade 3-4 toxicities during CRT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, febrile neutropenia 3, esophagitis 2, and pneumonitis 1. Two episodes of fatal hemoptysis in the high risk group, occurring during consolidation therapy, resulting in closure of this stratum. The low risk stratum, in which no hemoptysis occurred, subsequently closed because of poor accrual. Median overall survival was 23 mos for low risk pts and 17 mos for the high risk stratum. Bev could not be successfully integrated into CRT for LA-NSCLC as designed in this trial due to unacceptable hemoptysis. Trials with bevacizumab in this setting should not be pursued.