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 MethodsFrom 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. ResultsIn 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. ConclusionCardiac 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.

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 1996–2009. 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.

RTOG 0617, a randomized phase III cooperative group trial using 2 x 2 factorial design, with radiation dose as one factor and cetuximab as the other factor. Materials/Methods: Patients enrolled in RTOG 0617 with retrievable RT dosimetry were eligible for this study. Circulating immune cells, including rapidly circulating ones in the heart, lung and blood vessels, and slowly circulating ones in the lymphatic system and blood reservoirs (a portion of veins/capillaries), were considered as a surrogate for OARIS. The effective dose to the immune cells (EDIC) was modeled with assumptions that in each fraction, radiation dose was uniformly delivered to all cells for rapidly circulating ones, and only to those in the irradiated volume for slowly circulating ones. EDIC was thus calculated as a function of the number of RT fractions and doses to the lung, heart, and the whole body (integral dose). Associations between EDIC and local tumor control, denoted as local progression-free survival (LPFS), and OS were assessed using Cox regression model. Results: The analysis included 464 patients (261 from 60-Gy arm and 203 patients from 74-Gy arm). EDIC was significantly higher in the 74-Gy group (6.9 AE 2.1 Gy) than in the 60-Gy group (5.7 AE 1.7 Gy) (P < 0.0001). EDIC was associated with LPFS (P < 0.0001) and OS (P < 0.0001) in the whole group of all 464 patients, and within the 60-Gy (P Z 0.007 for LPFS and P < 0.0001 for OS) and 74-Gy groups (P Z 0.04 for LPSF and P Z 0.003 for OS). The 2-year OS rates were 72, 52, 49, and 15% for EDIC in the range of <4.0, 4.0-6.5, 6.5-9.5, and >9.5 Gy, respectively (P < 0.0001). Conclusion: Radiation dose to OARIS was significantly associated with local tumor control and overall survival for patients with stage-III NSCLC, suggesting that radiation-induced immune toxicity could be an important contributing factor to tumor progression and death. In-depth study of OARIS is warranted and will be reported at the meeting.Purpose/Objective(s): Recent data demonstrate an association between radiation (RT) dose to the heart and Grade 3+ cardiac events (CEs) in patients with locally advanced non-small cell lung cancer. Those with baseline coronary artery disease (CAD) were at particularly increased risk. A majority of patients, however, do not have overt pretreatment CAD and we sought to determine which combinations of pretreatment cardiac risk and RT dose are associated with an elevated CE rate.

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There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.