Tim Lautenschlaeger

MicroRNAs in non-small cell lung cancer invasion and metastasis: from the perspective of the radiation oncologist.

ABSTRACT Introduction: MicroRNAs (miRs), small sequences of RNA regulating various cellular processes, are implicated to play major roles in cancer. Herein, we discuss the association of several miRs with non-small cell lung cancer (NSCLC), specifically relating to tumor invasion and metastasis to lymphatics and/or distant organs, which can often be correlated with overall prognosis.Areas covered: There exists strong evidence that presence of several miR combinations correlates with prognosis in both early- and advanced-stage NSCLCs. Principally, miR alterations could be useful in enhancing current imaging-based methods to more accurately estimate the extent of invasion/metastases.Expert Commentary: Despite the immature nature of this subject, its large ramifications on clinical oncology are clearly evident. Based on miR signature-related stratification, radiotherapy could be potentially personalized beyond current treatment standards.

International Medical Graduates in Radiation Oncology: Historical Trends and Comparison With Other Medical Specialties

PURPOSE This is the first National Resident Matching Program analysis evaluating historical patterns of international medical graduates (IMGs) in radiation oncology (RO) and providing comparison with American (MD) medical graduates (AMGs), osteopathic students (DOs), unfilled positions, and other specialties. METHODS AND MATERIALS National Resident Matching Program data for IMGs were available from 2003 to 2015, with limited data for other specialty matches. The following RO-specific figures were obtained per year: total positions available; total matched positions; number of unfilled positions; and number of IMG, AMG, and DO matches. In addition, the number of IMG matches and total matched positions were obtained for 19 other specialties. Fisher exact tests and χ(2) tests were considered significant at α <.05. RESULTS From 2010 to 2015, 0.8% of RO matches were IMGs, a decline from 2.4% in 2003 to 2009 (P=.006). Proportions of DO matches during these intervals increased by 40% (from 1.0% to 1.4%), significantly lower than IMGs for 2003 to 2009 (P=.03) but not 2010 to 2015 (P=.26). From 2003 to 2015, the percentage of IMG matches, at 1.5%, was significantly lower than the percentage of unfilled seats, at 3.5% (P<.001). In comparison with other specialties (2003-2015), RO had the fewest IMG matches (1.5%), followed by otolaryngology (1.9%) and orthopedics (2.2%); specialties with the highest IMG proportions were internal medicine (37.1%), family medicine (35.7%), and neurology (31.1%). CONCLUSIONS Presently, IMGs represent <1% of RO matches, the lowest among major specialties. There are several speculative factors associated with this low proportion. There are significantly more unfilled positions than those filled by IMGs; programs at risk of not matching could weigh the advantages and disadvantages of interviewing IMGs.

Concurrent brain radiotherapy and EGFR-TKI may improve intracranial metastases control in non-small cell lung cancer and have survival benefit in patients with low DS-GPA score

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has intracranial activity in EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). The optimal timing of brain radiotherapy (RT) and appropriate patients who need early brain RT remains undetermined. This is a retrospective study of EGFR-mutant NSCLC patients with newly diagnosed brain metastases (BMs) before EGFR-TKI initiation. Intra-cranial progression free survival (IC-PFS) and overall survival (OS) were measured from the date of EGFR-TKI treatment. A total of 113 patients were eligible, 49 received concurrent early brain RT with EGFR-TKI and 64 were treated with EGFR-TKI alone as initial therapy, including 27 with salvage RT upon BM progression. The patients with early brain RT had superior IC-PFS than those without early brain RT (21.4 vs 15.0 months, P=0.001), which remained significant in multivariate analysis (HR 0.30, P<0.001). The median overall survival (OS) for early RT, EGFR-TKI alone and salvage RT groups was 28.1, 24.5, and 24.6 months, respectively (P=0.604). Similar IC-PFS (23.6 vs 21.4 months, P=0.253) and OS (24.6 vs 28.1 months, P=0.385) were observed between salvage RT and early RT groups. For patients with Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 0 to 2, early brain RT was the independent factor for improved OS (HR 0.33, P=0.025). In conclusion, concurrent early brain RT with EGFR-TKI may improve intracranial disease control in EGFR-mutant NSCLC with BM and have survival benefit in patients with low DS-GPA score. Salvage brain RT upon BM progression may be acceptable in some patients.

Undetected lymph node metastases in presumed early stage NSCLC SABR patients

ABSTRACT Introduction: Stereotactic body radiation therapy (SBRT, also called stereotactic ablative body radiation SABR) is the treatment of choice for many patients with early-stage non-small cell lung cancer (NSCLC), including those who are unfit for surgery or refuse surgery. Areas covered: In an effort to develop optimal staging for the evaluation of SBRT candidates, we review the performance of available lymph node staging methods, as well as risk factors for lymph node involvement. Pubmed was searched to identify relevant literature. Current staging methods for NSCLC, including Positron Emission Tomography/Computed Tomography(PET/CT) and endobronchial ultra sound (EBUS), have limited sensitivities. Expert commentary: There are several factors, including primary tumor location, tumor size, and histology that are possibly associated with the sensitivity of PET/CT to detect mediastinal lymph node metastasis. Small lymph node metastases typically remain undetected by PET/CT. Therefore invasive nodal staging procedures are indicated for most presumed early-stage NSCLC patients, but these also have limited sensitivity. Occult lymph node metastasis is associated with adverse outcome in NSCLC. Moreover, there is overwhelming evidence that certain patients who have lymph node metastases detected at the time of surgery derive an overall survival benefit from adjuvant therapies. It remains to be determined if improved detection of lymph node metastases in SABR candidates can indeed improve prognosis.

Toxicity of Radiosurgery for Brainstem Metastases

BACKGROUND Although stereotactic radiosurgery (SRS) is an effective modality in the treatment of brainstem metastases (BSM), radiation-induced toxicity remains a critical concern. To better understand how severe or life-threatening toxicity is affected by the location of lesions treated in the brainstem, a review of all available studies reporting SRS treatment for BSM was performed. METHODS Twenty-nine retrospective studies investigating SRS for BSM were reviewed. RESULTS The rates of grade 3 or greater toxicity, based on the Common Terminology Criteria for Adverse Events, varied from 0 to 9.5% (mean 3.4 ± 2.9%). Overall, the median time to toxicity after SRS was 3 months, with 90% of toxicities occurring before 9 months. A total of 1243 cases had toxicity and location data available. Toxicity rates for lesions located in the medulla were 0.8% (1/131), compared with midbrain and pons, respectively, 2.8% (8/288) and 3.0% (24/811). CONCLUSIONS Current data suggest that brainstem substructure location does not predict for toxicity and lesion volume within this cohort with median tumor volumes 0.04-2.8 cc does not predict for toxicity.

In Vitro Cell-free DNA Quantification: A Novel Method to Accurately Quantify Cell Survival after Irradiation

Circulating tumor DNA (ctDNA) analysis has been shown to aid in both the detection of cancer and evaluation of somatic mutations in tumors. CtDNA concentration in plasma increases in proportion to tumor volume and/or metabolic activity and growth; however, this principle has yet to be applied to cell culture. We hypothesized that cell line-specific cell-free DNA (cfDNA) can be used to measure cell viability and cell survival in cell culture. Clonogenic assays on non-small cell lung cancer (NSCLC) cell lines H322, A549 and H322 were exposed to radiation doses of 0, 4 and 8 Gy. Prior to colony fixation and counting, cfDNA was extracted and quantified from cell culture media. The correlation between cell line-specific cfDNA and number of colonies grown on culture plates was examined. An H1299:A549 coculture model was used to evaluate the differential release of cell line-specific cfDNA. The results of this work indicate a strong correlation between CfDNA quantification from cell culture media and clonogenic survival at all radiation doses and in all cell lines tested (R2 range = 0.77–0.99). Cell survival curves derived from cfDNA were virtually indistinguishable from matched traditional clonogenic survival data (P > 0.05; no significant difference exists between clonogenic curves). CfDNA quantification also accurately estimates colony count in a two-cell-line coculture model. In conclusion, cell-free DNA quantification from cell culture media can be used to measure cell survival, and appears suitable for development in a high-throughput clonogenic assay and radiosensitizer screening platform.

Chemoradiotherapy versus chemotherapy alone for unresected intrahepatic cholangiocarcinoma: practice patterns and outcomes from the national cancer data base

Background Current guidelines recommend chemotherapy (CT) with or without radiotherapy (RT) for unresected intrahepatic cholangiocarcinoma (IC). Although there is currently lack of consensus, previous smaller studies have illustrated the efficacy of local therapy for this population. This investigation evaluated outcomes of chemoradiotherapy (CRT) versus CT alone in unresected IC using a large, contemporary national database. Methods The National Cancer Data Base (NCDB) was queried for primary IC cases (2004-2013) receiving CT alone or CRT. Patients undergoing resection or not receiving CT were excluded, as were those with M1 disease or unknown M classification. Logistic regression analysis ascertained factors associated with CRT administration. Kaplan-Meier analysis evaluated overall survival (OS) between both groups. Cox proportional hazards modeling assessed variables associated with OS. Results In total, 2,842 patients were analyzed [n=666 (23%) CRT, n=2,176 (77%) CT]. CRT was less likely delivered at community centers, in more recent time periods (2009-2013), to older patients, and in certain geographic locations. Median OS in the CRT and CT groups were 13.6 vs. 10.5 months, respectively (P<0.001). On multivariate analysis, poorer OS was associated with age, male gender, increased comorbidities, treatment at a community center, and treatment at earlier time periods (2004-2008) (P<0.05 for all). Notably, receipt of CRT independently predicted for improved OS (P<0.001). Conclusions As compared to CT alone, CRT was independently associated with improved survival in unresected IC. These findings support a randomized trial evaluating this question that is currently accruing.

Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy

Introduction: It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods: The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early‐stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in‐field tumor control censored by either death or progression. Involved lobe control was also assessed. Results: At 6.7 years median follow‐up, 3‐year in‐field control, involved lobe control, overall survival, and progression‐free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with &agr;/&bgr; = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in‐field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in‐field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in‐field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions: In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.

Brainstem metastases treated with Gamma Knife stereotactic radiosurgery: the Indiana University Health experience

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01–2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14–22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8–45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14–22 Gy) to brainstem metastases.

Blood-Based Nucleic Acid Biomarkers as a Potential Tool to Determine Radiation Therapy Response in Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide, with smoking as the main risk factor. The use of low-dose computed tomography (LDCT) as a screening method has shown a 20% lung cancer specific mortality benefit; however, widespread implementation is estimated to add