Kyle Wang

Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: Pooled analysis of dose-escalation trials delivering 70 to 90 Gy

Purpose The significance of radiotherapy (RT) -associated cardiac injury for stage III non-small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk-adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early‐stage non–small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single‐institution reports. The current multi‐institutional study reported outcomes evaluating the largest such population reported to date.

Caenorhabditis elegans POT-1 and POT-2 repress telomere maintenance pathways.

Telomeres are composed of simple tandem DNA repeats that protect the ends of linear chromosomes from replicative erosion or inappropriate DNA damage response mechanisms. The mammalian Protection Of Telomeres (POT1) protein interacts with single-stranded telomeric DNA and can exert positive and negative effects on telomere length. Of four distinct POT1 homologs in the roundworm Caenorhabditis elegans, deficiency for POT-1 or POT-2 resulted in progressive telomere elongation that occurred because both proteins negatively regulate telomerase. We created a POT-1::mCherry fusion protein that forms discrete foci at C. elegans telomeres, independent of POT-2, allowing for live analysis of telomere dynamics. Transgenic pot-1::mCherry repressed telomerase in pot-1 mutants. Animals deficient for pot-1, but not pot-2, displayed mildly enhanced telomere erosion rates in the absence of the telomerase reverse transcriptase, trt-1. However, trt-1; pot-1 double mutants exhibited delayed senescence in comparison to trt-1 animals, and senescence was further delayed in trt-1; pot-2; pot-1 triple mutants, some of which survived robustly in the absence of telomerase. Our results indicate that POT-1 and POT-2 play independent roles in suppressing a telomerase-independent telomere maintenance pathway but may function together to repress telomerase.

Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers

OBJECTIVES To evaluate the incidence of, and risk factors associated with, mandibular osteoradionecrosis (MORN) following radiation therapy (RT) for oral cavity and oropharyngeal cancers. MATERIALS AND METHODS Patient and treatment records of 252 consecutive patients with oral cavity or oropharynx cancers treated with RT by a single radiation oncologist at a high volume academic institution from August 2009 to December 2015 were retrospectively reviewed. A Cox regression model was used to assess factors associated with the development of MORN. RT dosimetry was compared between patients with MORN and a matched cohort of patients without MORN. RESULTS MORN developed in 14 patients (5.5%), occurring 3-40 (median 8) months post-RT. Factors associated with MORN on univariable analysis included primary diagnosis of oral cavity vs oropharynx cancer (hazard ratio [HR]: 3.0, p=0.04), smoking at the time of RT (HR: 3.1, p=0.04), mandibular invasion of the primary (HR: 3.7, p=0.04), pre-RT tooth extraction (HR: 4.52, p=0.01), and treatment with 3D-conformal RT vs intensity-modulated RT (HR: 5.1, p=0.003). On multivariable analysis, pre-RT tooth extractions and RT technique remained significant. A dosimetric comparison between patients with and without MORN showed no significant differences. CONCLUSIONS AND RELEVANCE The incidence of MORN is low in the modern era at a high volume academic center. Modifiable risk factors including pre-RT tooth extractions, smoking, and RT technique are associated with MORN, and the risk should be minimized with appropriate dental evaluation and treatment, smoking cessation efforts, and the use of intensity-modulated RT.

Evaluation of PET/MRI for Tumor Volume Delineation for Head and Neck Cancer

Introduction Computed tomography (CT), combined positron emitted tomography and CT (PET/CT), and magnetic resonance imaging (MRI) are commonly used in head and neck radiation planning. Hybrid PET/MRI has garnered attention for potential added value in cancer staging and treatment planning. Herein, we compare PET/MRI vs. planning CT for head and neck cancer gross tumor volume (GTV) delineation. Material and methods We prospectively enrolled patients with head and neck cancer treated with definitive chemoradiation to 60–70 Gy using IMRT. We performed pretreatment contrast-enhanced planning CT and gadolinium-enhanced PET/MRI. Primary and nodal volumes were delineated on planning CT (GTV-CT) prospectively before treatment and PET/MRI (GTV-PET/MRI) retrospectively after treatment. GTV-PET/MRI was compared to GTV-CT using separate rigid registrations for each tumor volume. The Dice similarity coefficient (DSC) metric evaluating spatial overlap and modified Hausdorff distance (mHD) evaluating mean orthogonal distance difference were calculated. Minimum dose to 95% of GTVs (D95) was compared. Results Eleven patients were evaluable (10 oropharynx, 1 larynx). Nine patients had evaluable primary tumor GTVs and seven patients had evaluable nodal GTVs. Mean primary GTV-CT and GTV-PET/MRI size were 13.2 and 14.3 cc, with mean intersection 8.7 cc, DSC 0.63, and mHD 1.6 mm. D95 was 65.3 Gy for primary GTV-CT vs. 65.2 Gy for primary GTV-PET/MRI. Mean nodal GTV-CT and GTV-PET/MRI size were 19.0 and 23.0 cc, with mean intersection 14.4 cc, DSC 0.69, and mHD 2.3 mm. D95 was 62.3 Gy for both nodal GTV-CT and GTV-PET/MRI. Conclusion In this series of patients with head and neck (primarily oropharynx) cancer, PET/MRI and CT-GTVs had similar volumes (though there were individual cases with larger differences) with overall small discrepancies in spatial overlap, small mean orthogonal distance differences, and similar radiation doses.

Heart dosimetric analysis of three types of cardiac toxicity in patients treated on dose-escalation trials for Stage III non-small-cell lung cancer

BACKGROUND AND PURPOSE To assess associations between radiation dose/volume parameters for cardiac subvolumes and different types of cardiac events in patients treated on radiation dose-escalation trials. MATERIAL AND METHODS Patients with Stage III non-small-cell lung cancer received dose-escalated radiation (median 74 Gy) using 3D-conformal radiotherapy on six prospective trials from 1996 to 2009. Volumes analyzed included whole heart, left ventricle (LV), right atrium (RA), and left atrium (LA). Cardiac events were divided into three categories: pericardial (symptomatic effusion and pericarditis), ischemia (myocardial infarction and unstable angina), and arrhythmia. Univariable competing risks analysis was used. RESULTS 112 patients were analyzed, with median follow-up 8.8 years for surviving patients. Nine patients had pericardial, seven patients had ischemic, and 12 patients had arrhythmic events. Pericardial events were correlated with whole heart, RA, and LA dose (eg, heart-V30 [p=0.024], RA-V30 [p=0.013], and LA-V30 [p=0.001]), but not LV dose. Ischemic events were correlated with LV and whole heart dose (eg, LV-V30 [p=0.012], heart-V30 [p=0.048]). Arrhythmic events showed borderline significant associations with RA, LA, and whole heart dose (eg, RA-V30 [p=0.082], LA-V30 [p=0.076], heart-V30 [p=0.051]). Cardiac events were associated with decreased survival on univariable analysis (p=0.008, HR 2.09), but only disease progression predicted for decreased survival on multivariable analysis. CONCLUSIONS Cardiac events were heterogeneous and associated with distinct heart subvolume doses. These data support the hypothesis of distinct etiologies for different types of radiation-associated cardiotoxicity.

Impact of post-chemoradiotherapy superselective/selective neck dissection on patient reported quality of life

OBJECTIVES To describe patient-reported quality of life (QoL) for patients with HPV/p16-positive oropharyngeal squamous cell carcinoma undergoing post-chemoradiation (CRT) superselective or selective neck dissection (ND) as part of a prospective de-intensification study. MATERIALS AND METHODS Patients received 60Gy IMRT with concurrent weekly cisplatin (30mg/m(2)), followed by preplanned neck dissection of only originally involved nodal levels. QoL measures were assessed using the EORTC QLQ-C30 (general), EORTC H&N-35 (head and neck specific), EAT-10 (swallowing), and NDII (Neck Dissection Impairment Index) questionnaires. Early and late post-ND time points were compared to baseline and post-CRT/pre-ND time points. RESULTS 37 patients underwent post-CRT superselective or selective ND. Median # of levels and nodes dissected were 2 and 12, respectively. EORTC QLQ-C30, H&N-35, and EAT-10 QoL scores worsened after CRT but continued to improve thereafter despite post-CRT ND. NDII score worsened initially after ND at the early post-ND time point (p=0.023) but had recovered by the late post-ND time point (p=0.672). Initial decrease in NDII was greater with ⩾12 nodes dissected (p=0.007) and was correlated with the total number of nodes dissected (Spearman p=0.027). CONCLUSION Use of post-CRT superselective and selective ND did not prevent recovery of most QoL metrics to near baseline. There was early but not late decrement in neck dissection specific QoL (NDII), more pronounced with more nodes dissected.

Dosimetric Predictors of Symptomatic Cardiac Events After Conventional-Dose Chemoradiation Therapy for Inoperable NSCLC

Introduction: We hypothesized that higher cardiac doses correlates with clinically significant cardiotoxicity after standard‐dose chemoradiation therapy (CRT) (˜60 Gy) for inoperable NSCLC. Methods: We retrospectively reviewed the records of 140 patients with inoperable NSCLC treated with concurrent CRT from 2007 to 2015. Extracted data included baseline cardiac status, dosimetric parameters to the whole heart (WH) and cardiac substructures, and the development of post‐CRT symptomatic cardiac events (acute coronary syndrome [ACS], arrhythmia, pericardial effusion, pericarditis, and congestive heart failure [CHF]). Competing risks analysis was used to estimate time to cardiac events. Results: Median follow‐up was 47.4 months. Median radiation therapy dose was 61.2 Gy (interquartile range, 60 to 66 Gy). Forty patients (28.6%) developed 47 symptomatic cardiac events at a median of 15.3 months to first event. On multivariate analysis, higher WH doses and baseline cardiac status were associated with an increased risk of symptomatic cardiac events. The 4‐year cumulative incidence of symptomatic cardiac events was 48.6% versus 18.5% for mean WH dose ≥ 20 Gy versus < 20 Gy, respectively (p = 0.0002). Doses to the WH, ventricles, and left anterior descending artery were associated with ACS/CHF, whereas doses to the WH and atria were not associated with supraventricular arrhythmias. Symptomatic cardiac events (p = 0.0001) were independently associated with death. Conclusions: Incidental cardiac irradiation was associated with subsequent symptomatic cardiac events, particularly ACS/CHF, and symptomatic cardiac events were associated with inferior survival. These results support the minimization of cardiac doses among patients with inoperable NSCLC receiving standard‐dose CRT.

Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment. Experimental Design: Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to five time points, including before radiotherapy, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of radiotherapy. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR. Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45−/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before radiotherapy to 32 CTCs/mL at completion of radiotherapy (P = 0.001). CTCs declined throughout radiotherapy in patients with complete clinical and/or radiographic response, in contrast with an elevation in CTCs at mid or post-radiotherapy in the two patients with known pathologic residual disease. Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared with multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment. Clin Cancer Res; 24(11); 2539–47. ©2018 AACR.

The Role of Radiation Therapy in the Management of Sinonasal and Ventral Skull Base Malignancies

Sinonasal and ventral skull base malignancies are rare tumors that arise in a complex anatomic location juxtaposed with critically important normal tissues. The standard treatment paradigm for most histologies has been surgery followed by postoperative radiation therapy. Because of their propensity to present at an advanced stage and the presence of nearby critical structures, patients are at risk for severe radiation-induced long-term toxicity. Recent advances in radiotherapy technique have improved the therapeutic ratio between tumor control and normal tissue toxicity. This article reviews issues pertinent to the use of radiotherapy in the management of these tumors.