James J. Urbanic

Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis

OBJECT As a strategy to delay or avoid whole-brain radiotherapy (WBRT) after resection of a brain metastasis, the authors used high-resolution MR imaging and cavity-directed radiosurgery for the detection and treatment of further metastases. METHODS Between April 2001 and October 2009, 112 resection cavities in 106 patients with no prior WBRT were treated using radiosurgery directed to the tumor cavity and for any synchronous brain metastases detected on high-resolution MR imaging at the time of radiosurgical planning. A median dose of 17 Gy to the 50% isodose line was prescribed to the gross tumor volume, defined as the rim of enhancement around the resection cavity. Patients were followed up via serial imaging, and new brain metastases were generally treated using additional radiosurgery, with salvage WBRT typically reserved for local treatment failure at a resection cavity, numerous failures, or failures occurring at short time intervals. Local and distant treatment failures were determined based on imaging results. Kaplan-Meier curves were generated to estimate local and distant treatment failure rates, overall survival, neurological cause-specific survival, and time delay to salvage WBRT. RESULTS Radiosurgery was delivered to the resection cavity alone in 57.5% of patients, whereas 24.5% of patients also received treatment for 1 synchronous metastasis, 11.3% also received treatment for 2 synchronous metastases, and 6.6% also received treatment for 3-10 additional lesions. The median overall survival was 10.9 months. Overall survival at 1 year was 46.8%. The local tumor control rate at 1 year was 80.3%. The disease control rate in distant regions of the brain at 1 year was 35.4%, with a median time of 6.9 months to distant failure. Thirty-nine of 106 patients eventually received salvage WBRT, and the median time to salvage WBRT was 12.6 months. Kaplan-Meier estimates showed that the rate of requisite WBRT at 1 year was 45.9%. Neurological cause-specific survival at 1 year was 50.1%. Leptomeningeal failure occurred in 8 patients. One patient had treatment failure within the resection tract. Seven patients required reoperation: 2 for resection cavity recurrence, 3 for radiation necrosis, 1 for hydrocephalus, and 1 for a CSF cutaneous fistula. On multivariate analysis, a preoperative tumor diameter > 3 cm was predictive of local treatment failure. CONCLUSIONS Cavity-directed radiosurgery combined with high-resolution MR imaging detection and radiosurgical treatment of synchronous brain metastases is an effective strategy for delaying and even foregoing WBRT in most patients. This technique provides acceptable local disease control, although distant treatment failure remains significant.

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial

BACKGROUND Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis. METHODS In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774. FINDINGS Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1-18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45-5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86-3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35-0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference -33·6% [95% CI -45·3 to -21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7-16·0, 69 deaths) for SRS and 11·6 months (9·9-18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76-1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths. INTERPRETATION Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population. FUNDING National Cancer Institute.

A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927)

PURPOSE To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year. METHODS AND MATERIALS Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm. RESULTS Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2. CONCLUSIONS 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.

The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery

OBJECT Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS. METHODS Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13-24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival. RESULTS Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume. CONCLUSIONS Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

Trends in the outcomes for patients with limited stage small cell lung cancer : An analysis of the Surveillance, Epidemiology, and End Results database

We used the Surveillance, Epidemiology, and End Results (SEER) database to examine the outcomes of patients with limited stage small cell lung cancer (LS-SCLC) over time and to determine if any trends were present with respect to the publication of significant clinical trials. We assembled a cohort of 6271 patients aged 21 years and older with LS-SCLC diagnosed from 1983 to 1998 and followed through 2005. Potential covariates included patient age at diagnosis, sex, race, year of diagnosis, laterality, tumor size, and location (upper lobe, middle lobe, lower lobe, or main bronchus). In multivariate analysis, older age, male sex, African American race, and main bronchus location were all associated with a statistically significant increase in the mortality hazard. When compared to patients diagnosed in 1983-1987 who did not receive radiotherapy, the hazard for mortality was significantly reduced for patients diagnosed in 1988-1992 regardless of whether they received radiotherapy (HR=0.59; CI 0.52-0.65; p<0.0001) or not (HR=0.67; CI 0.60-0.75; p<0.0001). Patients who were diagnosed in 1993-1998 and received radiotherapy had similarly improved survival (HR=0.53; CI 0.47-0.58; p<0.0001), which was better than patients from the same time era who did not receive radiotherapy (HR=0.77; CI 0.69-0.85; p<0.0001). In conclusion, the survival for patients with LS-SCLC has improved over time. Many factors are likely involved, however we believe that part of this improvement was the result of clinical trials which investigated and subsequently defined chemoradiotherapy as the standard of care. In order to continue to improve clinical outcomes, clinical trials investigating new treatment paradigms are needed.

A nomogram for predicting distant brain failure in patients treated with gamma knife stereotactic radiosurgery without whole brain radiotherapy

BACKGROUND We review our single institution experience to determine predictive factors for early and delayed distant brain failure (DBF) after radiosurgery without whole brain radiotherapy (WBRT) for brain metastases. MATERIALS AND METHODS Between January 2000 and December 2010, a total of 464 patients were treated with Gamma Knife stereotactic radiosurgery (SRS) without WBRT for primary management of newly diagnosed brain metastases. Histology, systemic disease, RPA class, and number of metastases were evaluated as possible predictors of DBF rate. DBF rates were determined by serial MRI. Kaplan-Meier method was used to estimate rate of DBF. Multivariate analysis was performed using Cox Proportional Hazard regression. RESULTS Median number of lesions treated was 1 (range 1-13). Median time to DBF was 4.9 months. Twenty-seven percent of patients ultimately required WBRT with median time to WBRT of 5.6 months. Progressive systemic disease (χ(2)= 16.748, P < .001), number of metastases at SRS (χ(2) = 27.216, P < .001), discovery of new metastases at time of SRS (χ(2) = 9.197, P < .01), and histology (χ(2) = 12.819, P < .07) were factors that predicted for earlier time to distant failure. High risk histologic subtypes (melanoma, her2 negative breast, χ(2) = 11.020, P < .001) and low risk subtypes (her2 + breast, χ(2) = 11.343, P < .001) were identified. Progressive systemic disease (χ(2) = 9.549, P < .01), number of brain metastases (χ(2) = 16.953, P < .001), minimum SRS dose (χ(2) = 21.609, P < .001), and widespread metastatic disease (χ(2) = 29.396, P < .001) were predictive of shorter time to WBRT. CONCLUSION Systemic disease, number of metastases, and histology are factors that predict distant failure rate after primary radiosurgical management of brain metastases.

Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment

BACKGROUND AND PURPOSE Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. MATERIALS AND METHODS Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. RESULTS Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. CONCLUSION Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity.

Tumor histology predicts patterns of failure and survival in patients with brain metastases from lung cancer treated with gamma knife radiosurgery.

BACKGROUND We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS). OBJECTIVE To determine whether tumor histology predicts patient outcomes. METHODS Between July 1, 2000, and December 31, 2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. Included in our study were 44 squamous cell carcinoma (SCC), 31 small cell carcinoma (SCLC), and 138 adenocarcinoma (ACA) patients; 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole-brain radiation therapy (WBRT) before their GKRS, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of 2 lesions were treated per patient with median marginal dose of 20 Gy. RESULTS Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC patients (P = .008). The 1-year local control rates were 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (P = .027). The 1-year distant failure rates were 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (P = .057). The likelihood of dying of neurological death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (P = .027). The median time to WBRT was 11 months for SCC and 24 months for ACA patients (P = .04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (hazard ratio [HR]: 6.46, P = .025) and distant failure (HR: 3.32, P = .0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR: 2.552, P = .01) and worsened overall survival (HR: 1.77, P < .0121). CONCLUSION Histological subtype of lung cancer appears to predict outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.

A Pooled Analysis of Limited-Stage Small-Cell Lung Cancer Patients Treated with Induction Chemotherapy Followed by Concurrent Platinum-Based Chemotherapy and 70 Gy Daily Radiotherapy: CALGB 30904

Introduction: Standard therapy for limited-stage small-cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy (RT) followed by prophylactic cranial radiotherapy. Although many consider the standard RT regimen to be 45 Gy in 1.5 Gy twice-daily fractions, this has failed to gain widespread acceptance. We pooled data of patients assigned to receive daily RT of 70 Gy from three, consecutive prospective Cancer and Leukemia Group B L-SCLC cancer trials and report the results here. Methods: All patients from consecutive Cancer and Leukemia Group B L-SCLC trials (39808, 30002, and 30206) using high-dosage daily RT with concurrent chemotherapy were included, and analyzed for toxicity, disease control, and survival. Overall survival (OS) and progression-free survival (PFS) were modeled using Cox proportional hazards models. Prognostic variables for OS-rate and PFS-rate were assessed using logistic regression model. Results: Two hundred patients were included. The median follow-up was 78 months. Grade 3 or greater esophagitis was 23%. The median OS for pooled population was 19.9 months (95% confidence interval [CI]: 16.7–22.3), and 5-year OS rate was 20% (95% CI: 16–27%). The 2-year PFS was 26% (95% CI: 21–32%). Multivariate analysis found younger age (p = 0.02; hazard ratio [HR]: 1.023; 95% CI: 21-32), and female sex (p = 0.02; HR:0.69; 95% CI: 0.50-0.94) independently associated with improved overall survival. Conclusion: Two-Gy daily RT to a total dosage of 70 Gy was well tolerated with similar survival to 45 Gy (1.5 Gy twice-daily). This experience may aid practitioners decide whether high-dosage daily RT with platinum-based chemotherapy is appropriate outside of a clinical trial.

Prophylactic cranial irradiation in elderly patients with small cell lung cancer: Findings from a North Central Cancer Treatment Group pooled analysis

OBJECTIVES To examine the efficacy of prophylactic cranial irradiation (PCI) in elderly patients with small cell lung cancer (SCLC) (≥70 years of age) from a pooled analysis of four prospective trials. MATERIALS & METHODS One hundred fifty-five patients with SCLC (limited stage, LSCLC, and extensive stage, ESCLC) participated in four phase II or III trials. Ninety-one patients received PCI (30 Gy/15 or 25 Gy/10) and 64 patients did not receive PCI. Survival was compared in a landmark analysis that included only patients who had stable disease or better in response to primary therapy. RESULTS Patients who received PCI had better survival than patients who did not receive PCI (median survival 12.0 months vs. 7.6 months, 3-year overall survival 13.2% vs. 3.1%, HR = 0.53 [95% CI 0.36-0.78], p = 0.001). On multivariate analysis of the entire cohort, the only factor that remained significant for survival was stage (ESCLC vs. LSCLC, p = 0.0072). In contrast, the multivariate analysis of patients who had ESCLC revealed that PCI was the sole factor associated with a survival advantage (HR = 0.47 [95% CI 0.24-0.93], p = 0.03). Grade 3 or higher adverse events (AEs) were significantly greater in patients who received PCI (71.4% vs. 47.5%, p = 0.0031), with non-neuro and non-heme being the specific AE categories most strongly correlated with PCI delivery. CONCLUSIONS PCI was associated with a significant improvement in survival for our entire elderly SCLC patient cohort on univariate analysis. Multivariate analysis suggested that the survival advantage remained significant in patients with ESCLC. PCI was also associated with a modest increase in grade 3 or higher AEs.