A Phase I Study of Dasatinib with Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer

Objectives: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. Methods: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m2/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. Results: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. Conclusion: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases

PURPOSE: To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. MATERIALS AND METHODS: Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky performance status \u3e /=70, and life expectancy \u3e /=3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with \u3e /=1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. RESULTS: Median survival for all patients was 11 months. Among patients with \u3e /=1-year WBRT-free survival, median survival was 33 months (12-107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p \u3c 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden ( \u3c /=5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. CONCLUSION: A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone

Prescription dose evaluation for APBI with noninvasive image-guided breast brachytherapy using equivalent uniform dose

ABSTRACT PURPOSE: Noninvasive image-guided breast brachytherapy (NIBB) is an attractive novel approach to deliver accelerated partial breast irradiation (APBI). Calculations of equivalent uniform dose (EUD) were performed to identify the appropriate APBI dose for this technique. METHODS AND MATERIALS: APBI plans were developed for 15 patients: five with threedimensional conformal APBI (3D-CRT), five with multi-lumen intracavitary balloons (m-IBB), and five simulating NIBB treatment. Prescription doses of 34.0 and 38.5 Gy were delivered in 10 fractions for m-IBB and 3D-CRT, respectively. Prescription doses ranging from 34.0 to 38.5 Gy were considered for NIBB. Dose-volume histogram data from all 3D-CRT, m-IBB, and NIBB plans were used to calculate the biologically effective EUD and corresponding EUD to the PTV_eval using the following equation: ). An a/b value of 4.6 Gy was assumed for breast tumor. EUD for varying NIBB prescription doses were compared with EUD values for the other APBI techniques. RESULTS: Mean PTV_eval volume was largest for 3D-CRT (372.9 cm 3 ) and was similar for NIBB and m-IBB (88.7 and 87.2 cm 3 , respectively). The EUD value obtained by prescribing 38.5 Gy with 3D-CRT APBI was 38.6 Gy. The EUD value of 34.0 Gy prescribed with m-IBB was 34.4 Gy. EUD values for NIBB ranged from 33.9 to 38.2 Gy for prescription doses ranging from 34.0 to 38.5 Gy. CONCLUSIONS: Using EUD calculations to compare APBI techniques and treatment doses, a prescription dose of 36.0 Gy in 10 fractions using NIBB has a comparable biologic equivalent dose to other established brachytherapy techniques.

Thirty- and ninety-day outcomes after sublobar resection with and without brachytherapy for non–small cell lung cancer: Results from a multicenter phase III study

ObjectiveSublobar resection (SR) is commonly used for patients considered high risk for lobectomy. Nonoperative therapies are increasingly being reported for patients with similar risk because of perceived lower morbidity. We report 30- and 90-day adverse events (AEs) from American College of Surgeons Oncology Group Z4032, a multicenter phase III study for high-risk patients with stage I non–small cell lung cancer.MethodsData from 222 evaluable patients randomized to SR (n = 114) or SR with brachytherapy (n = 108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0, at 30 and 90 days after surgery. Risk factors (age, percent baseline carbon monoxide diffusion in the lung [DLCO%], percent forced expiratory volume in 1 second [FEV1%], upper lobe vs lower lobe resections, performance status, surgery approach, video-assisted thoracic surgery vs open and extent, and wedge vs segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of grade 3 or higher (G3+) AEs. Respiratory AEs were also specifically analyzed.ResultsMedian age, FEV1%, and DLCO% were similar in the 2 treatment groups. There was no difference in the location of resection (upper vs lower lobe) or the use of segmental or wedge resections. There were no differences between the groups with respect to “respiratory” G3+ AEs (30 days: 14.9% vs 19.4%, P = .35; 0–90 days: 19.3% vs 25%, P = .31) and “any” G3+ AEs (30 days: 25.4% vs 30.6%, P = .37; 0–90 days: 29.8% vs 37%, P = .25). Further analysis combined the 2 groups. Mortality occurred in 3 patients (1.4%) by 30 days and in 6 patients (2.7%) by 90 days. Four of the 6 deaths were thought to be due to surgery. When considered as continuous variables, FEV1% was associated with “any” G3+ AE at days 0 to 30 (P = .03; odds ratio [OR] = 0.98) and days 0 to 90 (P = .05; OR = 0.98), and DLCO% was associated with “respiratory” G3+ AE at days 0 to 30 (P = .03; OR = 0.97) and days 0 to 90 (P = .05; OR = 0.98). Segmental resection was associated with a higher incidence of any G3+ AE compared with wedge resection at days 0 to 30 (40.3% vs 22.7%; OR = 2.56; P < .01) and days 0 to 90 (41.5% vs 29.7%; OR = 1.96; P = .04). The median FEV1% was 50%, and the median DLCO% was 46%. By using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of “respiratory” and “any” G3+ AE for days 0 to 30 and 0 to 90.ConclusionsIn a multicenter setting, SR with brachytherapy was not associated with increased morbidity compared with SR alone. SR/SR with brachytherapy can be performed safely in high-risk patients with non–small cell lung cancer with low 30- and 90-day mortality and acceptable morbidity. Segmental resection was associated with increased “any” G3+ AE, and DLCO% less than 46% was associated with “any” G3+ AE and “respiratory” G3+ AE at both 30 and 90 days

Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice

The millions of common DNA variations that occur in the human population, or among inbred strains of mice and rats, perturb the expression (transcript levels) of a large fraction of the genes expressed in a particular tissue. The hundreds or thousands of common cis-acting variations that occur in the population may in turn affect the expression of thousands of other genes by affecting transcription factors, signaling molecules, RNA processing, and other processes that act in trans. The levels of transcripts are conveniently quantitated using expression arrays, and the cis- and trans-acting loci can be mapped using quantitative trait locus (QTL) analysis, in the same manner as loci for physiologic or clinical traits. Thousands of such expression QTL (eQTL) have been mapped in various crosses in mice, as well as other experimental organisms, and less detailed maps have been produced in studies of cells from human pedigrees. Such an integrative genetics approach (sometimes referred to as “genetical genomics”) is proving useful for identifying genes and pathways that contribute to complex clinical traits. The coincidence of clinical trait QTL and eQTL can help in the prioritization of positional candidate genes. More importantly, mathematical modeling of correlations between levels of transcripts and clinical traits in genetic crosses can allow prediction of causal interactions and the identification of “key driver” genes. An important objective of such studies will be to model biological networks in physiologic processes. When combined with high-density single nucleotide polymorphism (SNP) mapping, it should be feasible to identify genes that contribute to transcript levels using association analysis in outbred populations. In this review we discuss the basic concepts and applications of this integrative genomic approach to cardiovascular and metabolic diseases

Incidence, treatment, and survival patterns for sacral chordoma in the United States, 1974-2011

IntroductionSacral chordomas represent one half of all chordomas, a rare neoplasm of notochordal remnants. Current NCCN guidelines recommend surgical resection with or without adjuvant radiotherapy, or definitive radiation for unresectable cases. Recent advances in radiation for chordomas include conformal photon and proton beam radiation. We investigated incidence, treatment, and survival outcomes to observe any trends in response to improvements in surgical and radiation techniques over a near 40 year time period.Materials and Methods345 microscopically confirmed cases of sacral chordoma were identified between 1974 and 2011 from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Cases were divided into three cohorts by calendar year, 1974-1989, 1990-1999, and 2000-2011, as well as into two groups by age less than or equal to 65 versus greater than 65 to investigate trends over time and age via Chi-square analysis. Kaplan-Meier analyses were performed to determine effects of treatment on survival. Multivariate Cox regression analysis was performed to determine predictors of overall survival.Results5-year overall survival for the entire cohort was 60.0%. Overall survival correlated significantly with treatment modality, with 44% surviving at 5 years with no treatment, 52% with radiation alone, 82% surgery alone, and 78% surgery and radiation (p<.001). Age greater than 65 was significantly associated with non-surgical management with radiation alone or no treatment (p<.001). Relatively fewer patients received radiation between 2000 and 2011 compared to prior time periods (p=.03) versus surgery, for which rates which did not vary significantly over time (p=.55). However, 5-year overall survival was not significantly different by time period. Age group and treatment modality were predictive for overall survival on multivariate analysis (p<.001). ConclusionSurgery remains an important component in the treatment of sacral chordomas in current practice. Fewer patients were treated with radiation more recently despite advances in photon and proton beam radiation. Overall survival remains unchanged. Additional analyses of margin status, radiation modality, and local control in current practice are warranted

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases

Purpose: To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. Material and Methods: Patients with brain metastases treated with SRS from 2001-2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1-4 brain metastases, Karnofsky Performance Status ≥70, and life expectancy ≥3 mo. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with ≥1-yr WBRT-free survival (N=104), and those who died or required salvage WBRT within 3 mo of SRS (N=56). Differences between these groups were assessed by univariate and multivariate analyses.Results: Median survival for all patients was 11 mo. Among patients with ≥1-yr WBRT-free survival, median survival was 33 mo [12-107 mo] with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p<0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (≤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival.Conclusions: A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone