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PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%−81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6–9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

PURPOSE/OBJECTIVE(S) Current treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields, 200 kHz). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. MATERIALS/METHODS This is a single arm pilot study. Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Total scalp was defined as 5 mm thickness from skin surface above the level of the foramen magnum. The scalp was used as an avoidance structure for planning, with the following dose constraints: mean < 20 Gy, 20 cc < 50 Gy, and 30 cc < 40 Gy. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. RESULTS A total of 30 patients were enrolled in the trial. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). Median follow-up was 8.9 months (range 1.6 to 21.4 months). Twenty (66.7%) patients had unmethylated MGMT promotor status and ten (33.3%) patients had methylated promoter status. Median time from surgery to radiation was 34 days (26 to 49 days). Scalp dose constraints were achieved for all patients, with the mean dose having a median value of 8.3 Gy (range 4.3 to 14.8 Gy), the D20cc median was 26.1 Gy (range 17.7 to 42.8 Gy), and the D30cc median was 23.5 Gy (range 14.8 to 35.4 Gy). Skin adverse events (AEs; erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). Nineteen patients (63.3%) had progression, with a median PFS of 7.6 months (range 1.6 to 12.7 months). Overall survival was not reached. CONCLUSION Concurrent TTFields (200 kHz) with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. AUTHOR DISCLOSURE R.C. Miller: None. A.J. Song: None. A. Ali: None. V. Bar-Ad: None. N. Martinez: None. J. Glass: None. I. Alnahhas: None. D.W. Andrews: None. K. Judy: None. J. Evans: None. C. Farrell: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. I. Chervoneva: None. M. Ly: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.H. Liu: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, BrainLab, Regeneron. Consultant; Varian, BrainLab, Zai lab.

PURPOSE/OBJECTIVE(S) To evaluate the clinical role of temozolomide rechallenge (TMZ) in patients with recurrent high-grade glioma (HGG) treated with re-irradiation (re-RT) regardless of surgical status. MATERIALS/METHODS Single-center retrospective review of patients with a primary diagnosis of World Health Organization (WHO) Grade III anaplastic astrocytoma or Grade IV GBM treated from 2008 to 2016 for disease recurrence with re-RT (35 Gy in 10 fractions) with and without temozolomide rechallenge. Baseline characteristics were analyzed with pairwise tests. OS/PFS were assessed with the Kaplan-Meier method and multivariable cox regression models for OS. RESULTS Two hundred and thirty patients were treated with re-irradiation (n = 67 with and n = 163 without concurrent TMZ), with a median follow-up of 13.4 months. Baseline characteristics were similar between the two groups. TMZ rechallenge did not improve OS (HR 0.81 [0.51-1.3] P = 0.39). Univariate regression analysis showed that higher KPS both at diagnosis and recurrence correlated with improved survival, whereas increasing histology grade of initial and recurrent disease and volume of recurrence were correlated with worse OS. Multivariate regression analysis showed primary tumor location to be a significant predictor of OS (P = 0.004) with occipital lobe lesions (P < 0.001) and in-field recurrence (P < 0.001) to be most favorably correlated with OS. CONCLUSION TMZ rechallenge in patients with recurrent HGG treated with re-irradiation offered no survival benefit. Our findings suggest that patient selection may be important in TMZ rechallenge. Further studies in identifying this group of patients are warranted. AUTHOR DISCLOSURE M.M. Basree: None. A. Ali: None. S. Garg: None. J. Glass: None. L. Kim: None. C. Farrell: None. J. Evans: None. K. Judy: None. D.W. Andrews: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, Brainlab, Regeneron. Consultant; Varian, Brainlab, Zai lab. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Purpose/Objective(s) Recent studies suggest improved local control (LC) of early-stage non-small cell lung cancer (NSCLC) treated with SBRT regimens with biologically equivalent dose (BED10) > 150 Gy. It is unclear if this association is histology dependent. Multiple groups have shown lower LC rates after SBRT for squamous cell carcinoma (SCC), compared to non-SCC NSCLC. We compared LC between BEDlow and BEDhigh SBRT schemes, stratified by histology. Materials/Methods As part of an IRB approved collaborative, we retrospectively analyzed 684 patients with cT1-2, cN0, cM0 NSCLC, treated with definitive SBRT to a minimum BED of 100 Gy at five international centers. Patients were grouped into SCC and non-SCC, then divided into BEDhigh (BED10 ≥150 Gy) or BEDlow (BED10 Results Of 684 eligible tumors, 457 were non-SCC and 227 SCC. Median follow-up was 30 months. Of non-SCC patients, 262 (57%) were BEDlow and 195 (43%) BEDhigh. Of SCC patients, 144 (63%) were BEDlow and 83 (37%) BEDhigh. BEDhigh SBRT included those treated with 54 Gy in 3 fractions (54/3). BEDlow included 60/5, 50/5, 48/4, or 60/8. Baseline characteristics, including T-stage and max tumor dimension, were similar between BED groups after matching. MVA including T-stage, tumor grade, and tumor location, showed BEDlow regimens were associated with higher rates of local failure for SCC (HR 9.8, 95% CI 1.9-25.1, P = 0.007), but not for non-SCC (HR 1.2, 95% CI 0.6-2.5, P = 0.6). Three-year LC rates for BEDlow and BEDhigh were 70% and 97%, respectively for SCC, and 91% and 92%, respectively, for non-SCC. Similarly, there were higher rates of failure with BEDlow PTVmean (3 yr LC 94 vs 69%, MVA HR 6.4, 95% CI 1.9-22.2, P = 0.003) and BEDlow GTVmean (3 yr LC 87 vs 68%, MVA HR 7.6, 95% CI 2.7-21.6, P = 0.001) in SCC patients. In non-SCC patients, LC was similar between BED groups for PTVmean (3 yr LC 92% vs 93%, MVA HR 1.1, 95% CI 0.5-2.8, P = 0.8) and GTVmean (3 yr LC 94 vs 90%, MVA HR 0.8, 95% CI 0.3-2.6, P = 0.8). There was a trend of worse survival in BEDlow SCC patients (MVA HR 1.3, 95% CI 0.9-1.9, P = 0.1), but survival was similar in non-SCC patients (MVA HR 1.02, 95% CI 0.8-1.3, P = 0.9). There were no differences in regional recurrence or distant metastases between BED groups in either histology. Conclusion This multi-institutional analysis shows improved LC in early-stage SCC NSCLC treated with SBRT regimens with BED10 > 150 Gy. No difference was observed in LC between BED groups for non-SCC patients. Our results suggest BEDhigh SBRT should be strongly considered for early-stage non-central SCC NSCLC.

Purpose/Objective(s) Radiation is an important treatment modality for patients with newly diagnosed gliomas. However, conventional radiation may cause microvascular changes resulting in loss of scalp thickness, elasticity and vascularization. This may increase the risk of wound complication and affect patients’ quality of life. Scalp-sparing VMAT can significantly reduce scalp radiation dose. We conducted a single-arm phase 2 trial evaluating scalp thickness, quality of life, and toxicities in patients treated on a scalp-sparing VMAT with concurrent chemotherapy. Materials/Methods This study is a single-arm phase 2 single-institution study. Adult patients (≥18 years old) with newly diagnosed grade II-IV gliomas, KPS ≥60, with an estimated survival ≥3 months, received surgical resection or biopsy, and require radiation treatment were eligible. Patients with any prior cranial radiation, intolerance to radiation, co-morbidities affecting wound-healing were excluded. Scalp-sparing intensity modulated radiation (20 cc of scalp overlying the bone plate received ≤50 Gy) were used. The primary endpoint is incidence of wound infection and/or wound dehiscence 90 days or later post-radiation treatment. Scalp thickness was measured prior to, 9 months and 18 months following treatment. Incidence of wound infection, adverse events and quality of life was recorded. Results Forty-six patients were enrolled. 41 patients completed evaluation at 30 days after first treatment, and 18 patients completed 9-month time point at the time of abstract submission. Median age at enrollment was 59.7 yo (22.2-82.6 yo). Twenty-seven patients had WHO grade IV, 12 patients with grade III, and 2 patients with grade II gliomas. Forty patients also received concurrent temozolomide. The median radiation dose is 60 Gy. Mean D20cc was 3001 cGy (1533-4408 cGy) and mean D30cc was 2378 cGy (594 – 3930 cGy). Scalp thickness decreased by an average of 10% (2-31%) and 19% (6-32%) at 9 and 18 months following CRT respectively. No patients had wound infections or dehiscence. This meets the preset benchmark of 5%. Twenty-one patients experienced grade 1 or 2 alopecia within 30 days of CRT completion. Eight patients experienced grade 1 dermatitis and one experienced grade 2 dermatitis all of which were during radiation treatment. The finds compared favorable to historical control. Conclusion Scalp-sparing VMAT is a feasible technique. The treatment is well tolerated with no significant scalp related complications. Further study is warranted to confirm the clinical benefits. Author Disclosure A. Ali: None. M.Z. Niazi: None. D.W. Andrews: None. J. Evans: None. K. Judy: None. C. Farrell: None. J. Glass: None. L. Kim: None. N. Martinez: None. I. Alnahhas: None. M. Werner-Wasik: Advisory Board; ASTRA Zeneca. Stock; Illumina. leading operations of the committee; NRG Oncology. V. Bar-Ad: None. B.E. Leiby: None. W. Shi: Independent Contractor; Wenyin Shi. Research Grant; Novocure, BrainLab, Regeneron. Consultant; Varian, BrainLab, Zai lab.

Purpose Fibrotic changes after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) are difficult to distinguish from local recurrences (LR), hampering proper patient selection for salvage therapy. This study validates previously reported high-risk computed tomography (CT) features (HRFs) for detection of LR in an independent patient cohort. Methods and Materials From a multicenter database, 13 patients with biopsy-proven LR were matched 1:2 to 26 non-LR control patients based on dose, planning target volume (PTV), follow-up time, and lung lobe. Tested HRFs were enlarging opacity, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, linear margin disappearance, loss of air bronchogram, and craniocaudal growth. Additionally, 2 new features were analyzed: the occurrence of new unilateral pleural effusion, and growth based on relative volume, assessed by manual delineation. Results All HRFs were significantly associated with LR except for loss of air bronchogram. The best performing HRFs were bulging margin, linear margin disappearance, and craniocaudal growth. Receiver operating characteristic analysis of the number of HRFs to detect LR had an area under the curve (AUC) of 0.97 (95% confidence interval [CI] 0.9-1.0), which was identical to the performance described in the original report. The best compromise (closest to 100% sensitivity and specificity) was found at ≥4 HRFs, with a sensitivity of 92% and a specificity of 85%. A model consisting of only 2 HRFs, bulging margin and craniocaudal growth, resulted in a sensitivity of 85% and a specificity of 100%, with an AUC of 0.96 (95% CI 0.9-1.0) (HRFs ≥2). Pleural effusion and relative growth did not significantly improve the model. Conclusion We successfully validated CT-based HRFs for detection of LR after SBRT for early-stage NSCLC. As an alternative to number of HRFs, we propose a simplified model with the combination of the 2 best HRFs: bulging margin and craniocaudal growth, although validation is warranted.

Radiation Therapy Oncology Group (RTOG) 0424 was a phase 2 study of a high-risk low-grade glioma (LGG) population who were treated with temozolomide (TMZ) and radiation therapy (RT), and outcomes were compared to those of historical controls. This study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months and a 20% improvement in 3-year overall survival (OS) rate from 54% to 65% at a 10% significance level (1-sided) and 96% power.Patients with LGGs with 3 or more risk factors for recurrence (age ≥40 years, astrocytoma histology, bihemispherical tumor, preoperative tumor diameter of ≥6 cm, or a preoperative neurological function status of1) were treated with RT (54 Gy in 30 fractions) and concurrent and adjuvant TMZ.From 2005 to 2009, 129 evaluable patients (75 males and 54 females) were accrued. Median age was 49 years; 91% had a Zubrod score of 0 or 1; and 69%, 25%, and 6% of patients had 3, 4, and 5 risk factors, respectively. Patients had median and minimum follow-up examinations of 4.1 years and 3 years, respectively. The 3-year OS rate was 73.1% (95% confidence interval: 65.3%-80.8%), which was significantly improved compared to that of prespecified historical control values (P.001). Median survival time has not yet been reached. Three-year progression-free survival was 59.2%. Grades 3 and 4 adverse events occurred in 43% and 10% of patients, respectively. One patient died of herpes encephalitis.The 3-year OS rate of 73.1% for RTOG 0424 high-risk LGG patients is higher than that reported for historical controls (P.001) and the study-hypothesized rate of 65%.

Purpose European data suggest that 8-fraction stereotactic body radiation therapy (SBRT) regimens may be similar in efficacy with less toxicity than ≤5-fraction SBRT for central lung lesions. However, under current Centers for Medicare and Medicaid Services guidelines, SBRT in the United States (US) is reimbursed for only ≤5 fractions, whereas there are no such restrictions for reimbursement in Canada. We hypothesize that US-specific SBRT reimbursement policies influence the use of ≥5-fraction SBRT in US academic centers in comparison with comparable Canadian centers. Methods and Materials A 15-question electronic survey was distributed to radiation oncologists at National Cancer Institute–designated cancer centers in the US and the 10 highest research-funded cancer centers in Canada. Fisher exact test or exact logistic regression if applicable was used, where P Results Of the 143 radiation oncologists from 60 US cancer centers and 6 Canadian cancer centers who completed the survey (17.6% response rate), 125 routinely prescribe SBRT. Fifty percent of US physicians versus 0% of Canadian physicians indicated that there are instances when they would like to prescribe >5-fraction SBRT but prescribe ≤5 fractions because of insurance reimbursement (P=.076 and P=.001, respectively). Seventy percent (P=.006) of US radiation oncologists versus 0% (P=.001) of Canadian radiation oncologists report that SBRT clinical investigation is constrained by the insurance reimbursement. The most common reported deterrent to prescribing >5-fraction SBRT in the US was insurance reimbursement (49.5%). Conclusions US radiation oncologists are more likely than those in Canada to report that SBRT clinical investigation and >5-fraction SBRT use may be negatively influenced by health insurance reimbursement; this perception was not held by physicians in Canada. Health care environment may significantly affect radiation therapy decision making and practice patterns.

Purpose: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool ( (brainmetgpa.com)) simplified GPA use. Results: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the numbermore » of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.« less

To assess the impact of prophylactic cranial irradiation (PCI) on self-reported cognitive functioning (SRCF), a functional scale on the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30).Radiation Therapy Oncology Group (RTOG) protocol 0214 randomized patients with locally advanced non-small cell lung cancer to PCI or observation; RTOG 0212 randomized patients with limited-disease small cell lung cancer to high- or standard-dose PCI. In both trials, Hopkins Verbal Learning Test (HVLT)-Recall and -Delayed Recall and SRCF were assessed at baseline (after locoregional therapy but before PCI or observation) and at 6 and 12 months. Patients developing brain relapse before follow-up evaluation were excluded. Decline was defined using the reliable change index method and correlated with receipt of PCI versus observation using logistic regression modeling. Fisher's exact test correlated decline in SRCF with HVLT decline.Of the eligible patients pooled from RTOG 0212 and RTOG 0214, 410 (93%) receiving PCI and 173 (96%) undergoing observation completed baseline HVLT or EORTC QLQ-C30 testing and were included in this analysis. Prophylactic cranial irradiation was associated with a higher risk of decline in SRCF at 6 months (odds ratio 3.60, 95% confidence interval 2.34-6.37, P.0001) and 12 months (odds ratio 3.44, 95% confidence interval 1.84-6.44, P.0001). Decline on HVLT-Recall at 6 and 12 months was also associated with PCI (P=.002 and P=.002, respectively) but was not closely correlated with decline in SRCF at the same time points (P=.05 and P=.86, respectively).In lung cancer patients who do not develop brain relapse, PCI is associated with decline in HVLT-tested and self-reported cognitive functioning. Decline in HVLT and decline in SRCF are not closely correlated, suggesting that they may represent distinct elements of the cognitive spectrum.

Purpose To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). Methods and Materials The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses. Results Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by −1.4% (95% confidence interval [CI], −3.4% to 0) and −7.6% (95% CI, −10.2% to −3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of −8.1% (95% CI, −13.3% to −5.3%) and −12.4% (95% CI, −15.5% to −6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship. Conclusions This study failed to demonstrate a significant dose-effect relationship for changes of pulmonary function after SBRT for early-stage non-small cell lung cancer.

Purpose Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. Methods and Materials This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m 2 ) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). Results Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. Conclusions Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Purpose We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Methods and Materials Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507 . Results The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. Conclusions Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

To determine the safety and efficacy of lung stereotactic body radiation therapy (SBRT) in octo- and nonagenarians and to compare their outcomes with those of younger patients.Patients with primary lung cancer treated with SBRT were identified from a multi-institutional (5 institutions) database of 1083 cases. Details of patient factors, treatment specifics, toxicity, and clinical outcomes were extracted from the database. All events were calculated from the end of radiation therapy. Estimates of local recurrence, regional recurrence, and distant metastases were calculated using the competing risk method. Cause-specific survival (CSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcomes were compared for those aged70, 70 to 79, and ≥80 years. Univariable and multivariable analyses were performed to determine associations with CSS and OS in patients aged ≥80 years.The median (range) follow-up was 1.7 (1-10) years, and median age was 75 (41-94) years. There were 305 patients aged70 years (28%), 448 aged 70 to 79 years (41%), and 330 aged ≥80 years (30%). There was no difference in 2-year local recurrence (4.2% vs 5.4% vs 3.7%, respectively, P=.7), regional recurrence (10.4% vs 7.8% vs 5.3%, P=.1), distant metastases (12.2% vs 7.7% vs 9.5%, P=.2), or CSS (90.6% vs 90.3% vs 90.4%, P=.6). Those aged ≥80 years had significantly lower 2-year OS (73.6% vs 67.2% vs 63.3%, P.01). The grade 3+ pneumonitis rate was 1.3% versus 1.6% versus 1.5% (P=1.0) in patients aged70, 70 to 79, and ≥80 years, respectively. The 90-day mortality rates for patients aged70, 70 to 79, and ≥80 years were 1.3%, 2.5%, and 2.4% (P=.01), respectively. In patients aged ≥80 years OS was associated with T category (hazard ratio 1.7; P.01).Stereotactic body radiation therapy is a safe treatment modality in elderly patients (aged ≥80 years). Despite larger tumor volumes, the tumor control outcomes were comparable to those in younger patients treated with SBRT. All patients with early-stage lung cancer, regardless of age, should be considered for treatment with SBRT.

To evaluate the accuracy and consistency of a gradient-based positron emission tomography (PET) segmentation method, GRADIENT, compared with manual (MANUAL) and constant threshold (THRESHOLD) methods.Contouring accuracy was evaluated with sphere phantoms and clinically realistic Monte Carlo PET phantoms of the thorax. The sphere phantoms were 10-37 mm in diameter and were acquired at five institutions emulating clinical conditions. One institution also acquired a sphere phantom with multiple source-to-background ratios of 2:1, 5:1, 10:1, 20:1, and 70:1. One observer segmented (contoured) each sphere with GRADIENT and THRESHOLD from 25% to 50% at 5% increments. Subsequently, seven physicians segmented 31 lesions (7-264 mL) from 25 digital thorax phantoms using GRADIENT, THRESHOLD, and MANUAL.For spheres20 mm in diameter, GRADIENT was the most accurate with a mean absolute % error in diameter of 8.15% (10.2% SD) compared with 49.2% (51.1% SD) for 45% THRESHOLD (p0.005). For larger spheres, the methods were statistically equivalent. For varying source-to-background ratios, GRADIENT was the most accurate for spheres20 mm (p0.065) and20 mm (p0.015). For digital thorax phantoms, GRADIENT was the most accurate (p0.01), with a mean absolute % error in volume of 10.99% (11.9% SD), followed by 25% THRESHOLD at 17.5% (29.4% SD), and MANUAL at 19.5% (17.2% SD). GRADIENT had the least systematic bias, with a mean % error in volume of -0.05% (16.2% SD) compared with 25% THRESHOLD at -2.1% (34.2% SD) and MANUAL at -16.3% (20.2% SD; p value0.01). Interobserver variability was reduced using GRADIENT compared with both 25% THRESHOLD and MANUAL (p value0.01, Levene's test).GRADIENT was the most accurate and consistent technique for target volume contouring. GRADIENT was also the most robust for varying imaging conditions. GRADIENT has the potential to play an important role for tumor delineation in radiation therapy planning and response assessment.

Purpose We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1–5 fractions of stereotactic body radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM). Methods and Materials Spinal cord dose–volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P max ), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/β = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy 2/2 ). Results The initial conventional radiotherapy nBED ranged from ∼30 to 50 Gy 2/2 (median ∼40 Gy 2/2 ). The SBRT reirradiation thecal sac mean P max nBED in the no-RM group was 20.0 Gy 2/2 (95% confidence interval [CI], 10.8–29.2), which was significantly lower than the corresponding 67.4 Gy 2/2 (95% CI, 51.0–83.9) in the RM group. The mean total P max nBED in the no-RM group was 62.3 Gy 2/2 (95% CI, 50.3–74.3), which was significantly lower than the corresponding 105.8 Gy 2/2 (95% CI, 84.3–127.4) in the RM group. The fraction of the total P max nBED accounted for by the SBRT P max nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53. Conclusions SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P max nBED of 20–25 Gy 2/2 appears to be safe provided the total P max nBED does not exceed approximately 70 Gy 2/2 , and the SBRT thecal sac P max nBED comprises no more than approximately 50% of the total nBED.

Purpose: Tumor response after nonoperative lung cancer therapy is traditionally evaluated by bidimensional measurement of maximum tumor diameters. The purpose of this analysis is to investigate whether tumor largest dimension (based on RECIST [Response Evaluation Criteria In Solid Tumors]), bidimensional tumor product, and volume correlate with each other in evaluating tumors of patients with locally advanced non-small-cell lung cancer (NSCLC). In addition, the pace of locally advanced NSCLC volumetric response over time, as well as the prognostic value of tumor size, was assessed in this report with software-assisted evaluation of sequential tumor measurement. Methods and Materials: Patients with locally advanced NSCLC treated with thoracic radiotherapy (RT) with or without chemotherapy were included, if the following were available: a pretreatment computed tomography (CT) simulation and at least two follow-up diagnostic thoracic CT scans taken at our institution after 1996 that were available in Dicom format for electronic transfer of images from diagnostic radiology to a computer terminal with commercial statistics software (AcQsim/CMS Focus). Primary lung tumor and grossly involved lymph nodes were contoured manually on pre-RT axial images and on all follow-up CT scans. Tumor/lymph node largest dimensions, bidimensional products (BP), and volumes were measured using the same software. Data were presented as percent change in volume or unidimensional and bidimensional measurements, with the CT simulation measurements serving as baseline. Results: A total of 22 patients were evaluated. The median thoracic RT dose was 62.4 Gy (range: 50.0–69.6), and all patients had a Karnofsky performance status ≥80. Chemotherapy (mostly carboplatin/paclitaxel) was given to 17 patients. Nineteen patients had Stage III NSCLC; 1 patient was in Stage I, 1 was in Stage IV, and 1 was recurrent. A total of 107 thoracic CT scans (22 pretreatment and 85 follow-up), averaging 4.9 scans per patient, were analyzed. Tumors reached the smallest volume at a median of 11.0 months from RT completion in all patients, 8.5 months in patients who subsequently failed locally ( n = 8), and 11.9 months in those who did not fail locally. Failure rates were as follows: in-field, 36% (8/22); intrathoracic (lung nodules, effusion, pleura), 55% (12/22); and distant, 50% (11/22). Eleven patients are still alive, 4 free of disease. Overall median survival time (MST) is 27.3 months. The median initial tumor volume was 88.0 cc (range: 3.8–218) for all patients; median BP was 33.0 cm 2 (range: 3.1–112.1), and median tumor largest dimension was 7.6 cm (range: 2.2–13.5). The MST of patients with initial tumor volume ≤63.0 cc ( n = 9) was >53.0 months and of those with tumor volume >63.0 cc was 17.3 months. The MST of patients ( n = 6) with initial bidimensional tumor product ≤16 cm 2 was >53.0 months and of those with tumor product >16 cm 2 was 17.3 months. The MST of patients with largest initial dimension ≤4 cm was >53.1 months and of those with largest dimension >4 cm was 25.0 months. At 24 months, 79% of patients with a tumor volume ≤124.0 cc ( n = 18) had locally controlled tumors, vs. 0% of patients with tumor volumes >124.0 cc. At the same time point, 93% of patients with BP ≤40 cm 2 were locally controlled, vs. 0% of those with BP >40 cm 2 ; 100% of patients with tumor dimensions ≤7.5 cm were locally controlled, vs. 40% of those with dimensions >7.5 cm. The partial responses in our series (assessed as the best response obtained during observation period) were as follows: 4 patients assessed based on either dimension only, product only, or volume only; 15 partial responses based on dimension or product; 16 partial responses based on volume alone; 3 cases of no tumor response, based on dimension or product; and 2 cases based on tumor volume alone. That represents good to excellent agreement among all three methods of measurement. Conclusions: ( 1 ) The response of locally advanced NSCLC to nonoperative therapy is a slow process, with tumor volumes reaching their nadir several months after treatment. ( 2 ) Smaller initial tumor size, as measured by largest tumor dimension, bidimensional product, or tumor volume, is associated with better local control and survival than larger initial measurements. ( 3 ) Any of the three tumor measurements (largest dimension, bidimensional product, or volume) can be used as a reliable tool in assessing lung cancer response to nonoperative therapy. This confirms further the validity of RECIST and does not suggest that tumor volume is significantly superior for response evaluation.

Background: Stereotactic radiosurgery (SRS) and, more recently, fractionated stereotactic radiotherapy (SRT) have been recognized as noninvasive alternatives to surgery for the treatment of acoustic schwannomas. We review our experience of acoustic tumor treatments at one institution using a gamma knife for SRS and the first commercial world installation of a dedicated linac for SRT. Methods: Patients were treated with SRS on the gamma knife or SRT on the linac from October 1994 through August 2000. Gamma knife technique involved a fixed-frame multiple shot/high conformality single treatment, whereas linac technique involved daily conventional fraction treatments involving a relocatable frame, fewer isocenters, and high conformality established by noncoplanar arc beam shaping and differential beam weighting. Results: Sixty-nine patients were treated on the gamma knife, and 56 patients were treated on the linac, with 1 NF-2 patient common to both units. Three patients were lost to follow-up, and in the remaining 122 patients, mean follow-up was 119 ± 67 weeks for SRS patients and 115 ± 96 weeks for SRT patients. Tumor control rates were high (≥97%) for sporadic tumors in both groups but lower for NF-2 tumors in the SRT group. Cranial nerve morbidities were comparably low in both groups, with the exception of functional hearing preservation, which was 2.5-fold higher in patients who received conventional fraction SRT. Conclusion: SRS and SRT represent comparable noninvasive treatments for acoustic schwannomas in both sporadic and NF-2 patient groups. At 1-year follow-up, a significantly higher rate of serviceable hearing preservation was achieved in SRT sporadic tumor patients and may therefore be preferable to alternatives including surgery, SRS, or possibly observation in patients with serviceable hearing.

Purpose: Survival of patients with locally-advanced non–small-cell lung cancer (LA-NSCLC) is predicted by the stage of the disease and other characteristics. This analysis was undertaken to identify these characteristics in a large cooperative group patient population, as well as to define subgroups of the population with differing outcomes. Patients and Methods: Analysis included 1,999 patients treated in 9 RTOG trials between 1983 and 1994 with thoracic irradiation (RT) with (n = 355) or without chemotherapy (CT). Results: In univariate analysis, the following characteristics were significantly associated with an improved survival: use of CT, CT delivered without major deviation, abnormal pulmonary function tests, normal hemoglobin, protein, LDH and BUN, presence of dyspnea, hemoptysis, cough or hoarseness, uninvolved lymph nodes, T1 or T2 stage, no malignant pleural effusion (PE), weight loss of < 8%, Karnofsky performance status (KPS) of at least 90, adenocarcinoma histology, female gender, and age less than 70 years. Recursive partitioning analysis (RPA) was subsequently applied to identify 5 patient subgroups with significantly different median survival times (MST): Group I, KPS of ≥ 90, who received chemotherapy (MST 16.2 months); Group II, KPS of ≥ 90, who received no CT, but had no PE (MST 11.9 months); Group III, KPS < 90, younger than 70 years, with non-large cell histology (MST 9.6 months); Group IV, KPS ≥ 90, but with PE, or KPS < 90, younger than 70 years, and with large cell histology, or older than 70 years, but without PE (MST 5.6–6.4 months); Group V, older than 70, with PE (MST 2.9 months). Conclusion: Cisplatinum-based CT improves survival, for excellent prognosis of LA-NSCLC patients, over RT alone. The presence of a malignant pleural effusion is a major negative prognostic factor for survival. The identification of RPA prognostic groups among patients with LA-NSCLC provides prognostic information and may serve as a basis of stratification in future trials.

Purpose: A phase I dose escalation of hypofractionated stereotactic radiotherapy (H-SRT) in recurrent or persistent malignant gliomas as a means of increasing the biologically effective dose and decreasing the high rate of reoperation due to toxicity associated with single-fraction stereotactic radiosurgery (SRS) and brachytherapy. Materials and Methods: From November 1994 to September 1996, 25 lesions in 20 patients with clinical and/or imaging evidence of malignant glioma persistence or recurrence received salvage H-SRT. Nineteen patients at the time of initial diagnosis had glioblastoma multiforme (GBM) and one patient had an anaplastic astrocytoma. All of these patients with tumor persistence or recurrence had received initial fractionated radiation therapy (RT) with a mean and median dose of 60 Gy (44.0–72.0 Gy). The median time from completion of initial RT to H-SRT was 3.1 months (0.7–45.5 months). Salvage H-SRT was delivered using daily 3.0–3.5 Gy fractions (fxs). Three different total dose levels were sequentially evaluated: 24.0 Gy/3.0 Gy fxs (five lesions), 30.0 Gy/3.0 Gy fxs (10 lesions), and 35.0 Gy/3.5 Gy fxs (nine lesions). Median treated tumor volume measured 12.66 cc (0.89–47.5 cc). The median ratio of prescription volume to tumor volume was 2.8 (1.4–5.0). Toxicity was judged by RTOG criteria. Response was determined by clinical neurologic improvement, a decrease in steroid dose without clinical deterioration, and/or radiologic imaging. Results: No grade 3 toxicities were observed and no reoperation due to toxicity was required. At the time of analysis, 13 of 20 patients had died. The median survival time from the completion of H-SRT is 10.5 months with a 1-year survival rate of 20%. Neurological improvement was found in 45% of patients. Decreased steroid requirements occurred in 60% of patients. Minor imaging response was noted in 22% of patients. Using Fisher's exact test, response of any kind correlated strongly to total dose ( p = 0.0056). None of six lesions treated with 21 Gy or 24 Gy responded, whereas there was a 79% response rate among the 19 lesions treated with 30 or 35 Gy. Tumor volumes ≤20 cc were associated with a higher likelihood of response ( p = 0.053). Conclusions: H-SRT used in this cohort of previously irradiated patients with malignant glioma was not associated with the need for reoperation due to toxicity or grade 3 toxicity. This low toxicity profile and encouraging H-SRT dose-related response outcome justifies further evaluation and dose escalation.

NRG Oncology/RTOG 0937: Randomized Phase 2 Study Comparing Prophylactic Cranial Irradiation (PCI) Alone to PCI and Consolidative Extracranial Irradiation for Extensive Disease Small Cell Lung Cancer (ED-SCLC) E.M. Gore, C. Hu, A. Sun, D. Grimm, S. Ramalingam, N.E. Dunlap, K.A. Higgins, M. Werner-Wasik, A.M. Allen, P. Iyengar, G.M. Videtic, R.K. Hales, R.C. McGarry, J.J. Urbanic, A.T. Pu, C. Johnstone, J.N. Atkins, and J.D. Bradley; Medical College of Wisconsin, Milwaukee, WI, NRG Oncology, Philadelphia, PA, Princess Margaret Hospital, Toronto, ON, Canada, Emory University, Atlanta, GA, United States, University of Louisville, Louisville, KY, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, Rabin Medical Center, Petah Tikva, Israel, University of Texas Southwestern Medical Center, DALLAS, TX, Cleveland Clinic, Cleveland, OH, Johns Hopkins University, Baltimore, MD, United States, University of Kentucky, Lexington, KY, University of California, San Diego, La Jolla, CA, Sutter Medical Group Radiological Associates of Sacramento, Sacramento, CA, Southeast Cancer Consortium-Upstate NCORP, Goldsboro, NC, Washington University School of Medicine, St. Louis, MO