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Purpose: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy., Methods and Materials: We performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression., Results: Statin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively., Conclusions: Among patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Mean heart dose (MHD) over 10 Gy and left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) greater than 10% can significantly increase the risk of major adverse cardiac events (MACE) in patients with non-small cell lung cancer (NSCLC). We sought to characterize the discordance between MHD and LAD dose and the association of this classification on the risk of MACE after radiation therapy., Methods and Materials: The coefficient of determination for MHD and LAD V15Gy was calculated in this retrospective analysis of 701 patients with locally advanced NSCLC treated with radiation therapy. Four groups were defined on the basis of high or low MHD (≥10 Gy vs <10 Gy) and LAD V15Gy (≥10% vs <10%). MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated, and Fine and Gray regressions were performed., Results: The proportion of variance in LAD V15Gy predictable from MHD was only 54.5% (R 2  = 0.545). There was discordance (where MHD was high [≥10 Gy] and LAD low [V15Gy < 10%], or vice versa) in 23.1% of patients (n = 162). Two-year MACE estimates were 4.2% (MHD high /LAD low ), 7.6% (MHD high /LAD high ), 1.8% (MHD low /LAD low ), and 13.0% (MHD low /LAD high ). Adjusting for pre-existing coronary heart disease and other prognostic factors, MHD high /LAD low (subdistribution hazard ratio [SHR], 0.34; 95% CI, 0.13-0.93; P = .036) and MHD low /LAD low (SHR, 0.24; 95% CI, 0.10-0.53; P < .001) were associated with a significantly reduced risk of MACE., Conclusions: MHD is insufficient to predict LAD V15Gy with confidence. When MHD and LAD V15Gy dose exposure is discordant, isolated low LAD V15Gy significantly reduces the risk of MACE in patients with locally advanced NSCLC after radiation therapy, suggesting that the validity of whole heart metrics for optimally predicting cardiac events should be reassessed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer., Objective: To examine independent cardiac substructure radiotherapy factors for major adverse cardiac events (MACE) and all-cause mortality in patients with locally advanced non-small cell lung cancer (NSCLC)., Design, Setting, and Participants: A retrospective cohort analysis of 701 patients with locally advanced NSCLC treated with thoracic radiotherapy at Harvard University-affiliated hospitals between December 1, 2003, and January 27, 2014, was performed. Data analysis was conducted between January 12, 2019, and July 22, 2020. Cardiac substructures were manually delineated. Radiotherapy dose parameters (mean, maximum, and the volume [V, percentage] receiving a specific Gray [Gy] dose in 5-Gy increments) were calculated. Receiver operating curve and cut-point analyses estimating MACE (unstable angina, heart failure hospitalization or urgent visit, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were adjusted for preexisting CHD and other prognostic factors., Main Outcomes and Measures: MACE and all-cause mortality., Results: Of the 701 patients included in the analysis, 356 were men (50.8%). The median age was 65 years (interquartile range, 57-73 years). The optimal cut points for substructure and radiotherapy doses (highest C-index value) were left anterior descending (LAD) coronary artery V15 Gy greater than or equal to 10% (0.64), left circumflex coronary artery V15 Gy greater than or equal to 14% (0.64), left ventricle V15 Gy greater than or equal to 1% (0.64), and mean total coronary artery dose greater than or equal to 7 Gy (0.62). Adjusting for baseline CHD status and other prognostic factors, an LAD coronary artery V15 Gy greater than or equal to 10% was associated with increased risk of MACE (adjusted hazard ratio, 13.90; 95% CI, 1.23-157.21; P = .03) and all-cause mortality (adjusted hazard ratio, 1.58; 95% CI, 1.09-2.29; P = .02). Among patients without CHD, associations with increased 1-year MACE were noted for LAD coronary artery V15 Gy greater than or equal to 10% (4.9% vs 0%), left circumflex coronary artery V15 Gy greater than or equal to 14% (5.2% vs 0.7%), left ventricle V15 Gy greater than or equal to 1% (5.0% vs 0.4%), and mean total coronary artery dose greater than or equal to 7 Gy (4.8% vs 0%) (all P ≤ .001), but only a left ventricle V15 Gy greater than or equal to 1% increased the risk among patients with CHD (8.4% vs 4.1%; P = .046). Among patients without CHD, 2-year all-cause mortality was increased with an LAD coronary artery V15 Gy greater than or equal to 10% (51.2% vs 42.2%; P = .009) and mean total coronary artery dose greater than or equal to 7 Gy (53.2% vs 40.0%; P = .01)., Conclusions and Relevance: The findings of this cohort study suggest that optimal cardiac dose constraints may differ based on preexisting CHD. Although the LAD coronary artery V15 Gy greater than or equal to 10% appeared to be an independent estimator of the probability of MACE and all-cause mortality, particularly in patients without CHD, left ventricle V15 Gy greater than or equal to 1% appeared to confer an increased risk of MACE among patients with CHD. These constraints are worthy of further study because there is a need for improved cardiac risk stratification and aggressive risk mitigation strategies.

Background: Radiotherapy-associated cardiac toxicity studies in patients with locally advanced non-small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints., Objectives: The purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM)., Methods: This retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD)., Results: After a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028)., Conclusions: Despite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: There is concern that patients with collagen vascular disease (CVD) are at higher risk of developing radiation toxicity. We analyzed radiation toxicities in patients with intrathoracic malignancy and CVD treated using modern radiotherapy., Materials and Methods: This single-institution retrospective study included 31 patients with CVD and 825 patients without CVD treated from 1998 to 2014. Radiation esophagitis (RE) and radiation pneumonitis (RP) were scored by RTOG scales. RE was analyzed with logistic regression and RP with Cox regression., Results: CVD patients experienced similar grade ≥3 RE compared to control patients (23% vs. 19%, p = 0.64) but more grade ≥3 RP (26% vs. 10%, p = 0.01). There was no significant association between CVD subtype and toxicities. In multivariate analysis, CVD and lung V20 >30% were associated with grade ≥3 RP. We identified V20 ≤30%, V5 ≤50%, and MLD ≤18 Gy as dose thresholds in patients with CVD. CVD patients with mild severity disease and only 1 organ system involved were at low risk for RP., Conclusions: Patients with CVD may be at higher risk of RP. However, CVD patients may be offered curative thoracic RT with particular attention to risk-reduction strategies and maintaining recommended dose constraints as described in this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Locally advanced non-small cell lung cancer (LA-NSCLC) patients have poorer survival and local control with mediastinal node (N2) tumor involvement at resection. Earlier assessment of nodal burden could inform clinical decision-making prior to surgery. This study evaluated the association between clinical outcomes and lymph node volume before and after neoadjuvant therapy., Materials and Methods: CT imaging of patients with operable LA-NSCLC treated with chemoradiation and surgical resection was assessed. Clinically involved lymph node stations were identified by FDG-PET or mediastinoscopy. Locoregional recurrence (LRR), distant metastasis (DM), progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method, concordance index and Cox regression., Results: 73 patients with Stage IIIA-IIIB NSCLC treated with neoadjuvant chemoradiation and surgical resection were identified. The median RT dose was 54 Gy and all patients received concurrent chemotherapy. Involved lymph node volume was significantly associated with LRR and OS but not DM on univariate analysis. Additionally, lymph node volume greater than 10.6 cm3 after the completion of preoperative chemoradiation was associated with increased LRR (p<0.001) and decreased OS (p = 0.04). There was no association between nodal volumes and nodal clearance., Conclusion: For patients with LA-NSCLC, large volume nodal disease post-chemoradiation is associated with increased risk of locoregional recurrence and decreased survival. Nodal volume can thus be used to further stratify patients within the heterogeneous Stage IIIA-IIIB population and potentially guide clinical decision-making.

Introduction: Quantification of volume changes on cone beam computed tomography (CBCT) during lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) may provide a useful radiological marker for radiation response and for adaptive treatment planning. This study quantifies inter-scan and inter-observer variability in tumour volume delineation on CBCT., Methods: Three clinicians independently contoured the primary gross tumour volume (GTV) manually on CBCTs taken immediately before SBRT treatment (pre) and after the same SBRT treatment (post) for 19 NSCLC patients. Relative volume differences (RVD) were calculated between the pre- and post-CBCTs for a given treatment and between any two of three observers for a given CBCT. Coefficient of variation (CV) was used to quantitatively measure and compare the extent of variability., Results: Inter-observer variability had a significantly higher CV of 0.15 ± 0.13 compared to inter-scan CV of 0.03 ± 0.04 with P < 0.0001. The greatest variability was observed with tumours (<2 cm in diameter) versus larger tumours with 95% limit of agreement (LOA) (Mean ± Standard Deviation) of 1.90% ± 19.55% vs. -0.97% ± 12.26% for inter-scan RVD and 29.99% ± 73.84% vs. 9.37% ± 29.95% for inter-observer RVD respectively., Conclusions: Inter-observer variability was greater than inter-scan variability for tumour volume delineation on CBCT with greatest variability for small tumours (<2 cm in diameter). LOA for inter-scan variability (~12%) helps defines a threshold for clinically meaningful tumour volume change during SBRT treatment for tumours with diameter greater than 2 cm, with larger thresholds needed for smaller tumours., (© 2016 The Royal Australian and New Zealand College of Radiologists.)

Objectives: Accurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response., Materials and Methods: Patients with operable LA-NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints., Results: 101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54Gy (range, 46-70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p=0.002) and LRR (HR 1.01 [1.00-1.02], p=0.048). Conventional response assessment determined by RECIST (p=0.213) was not associated with pCR or any secondary endpoints., Conclusion: CT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: We analyzed outcomes after lung stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung-carcinoma (NSCLC) by histology and KRAS genotype., Patients and Methods: We included 75 patients with 79 peripheral tumors treated with SBRT (18 Gy × 3 or 10 to 12 Gy × 5) at our institution from 2009 to 2012. Genotyping for KRAS mutations was performed in 10 patients. Outcomes were analyzed by the Kaplan-Meier method/Cox regression, or cumulative incidence method/Fine-Gray analysis., Results: The median patient age was 74 (range, 46 to 93) years, and Eastern Cooperative Oncology Group performance status was 0 to 1 in 63%. Tumor histology included adenocarcinoma (44%), squamous cell carcinoma (25%), and NSCLC (18%). Most tumors were T1a (54%). Seven patients had KRAS-mutant tumors (9%). With a median follow-up of 18.8 months among survivors, the 1-year estimate of overall survival was 88%, cancer-specific survival (CSS) 92%, primary tumor control 94%, and freedom from recurrence (FFR) 67%. In patients with KRAS-mutant tumors, there was a significantly lower tumor control (67% vs. 96%; P = .04), FFR (48% vs. 69%; P = .03), and CSS (75% vs. 93%; P = .05). On multivariable analysis, histology was not associated with outcomes, but KRAS mutation (hazard ratio, 10.3; 95% confidence interval, 2.3-45.6; P = .0022) was associated with decreased CSS after adjusting for age., Conclusion: In this SBRT series, histology was not associated with outcomes, but KRAS mutation was associated with lower FFR on univariable analysis and decreased CSS on multivariable analysis. Because of the small sample size, these hypothesis-generating results need to be studied in larger data sets., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation., Materials and Methods: We retrospectively analyzed NSCLC patients with 1-4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain., Results: Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p=0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p<0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p=0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p=0.032) and initial combined modality brain therapy (HR 0.34, p=0.046)., Conclusion: Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, "oligometastatic" disease, may benefit from more aggressive local therapy., Methods and Materials: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival., Results: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status ≥ 2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P<.01). The number of metastatic lesions and radiologic size of the primary tumor were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR, 0.65, P=.043)., Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict for improved survival in these patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) mutations identify a unique biological subtype of non-small cell lung cancer (NSCLC). Treatment outcomes for EGFR-mutant locally advanced NSCLC patients have not been well described., Methods: We retrospectively examined outcomes after combined modality therapy including thoracic radiation therapy (RT) in 123 patients with locally advanced NSCLC and known EGFR mutation status. Outcomes were compared using Kaplan-Meier analysis, the log-rank test, and multivariate Cox regression models., Results: All 123 patients underwent thoracic RT; 25% had tumors with EGFR mutations and 94% had stage III disease. Overall, 81% received chemotherapy concurrent with RT and 55% underwent surgical resection. With a median follow-up of 27.5 months, the overall survival (OS) rate was significantly higher in patients with EGFR-mutant tumors than in those with wild-type EGFR tumors (2-year estimate: 92.6% versus 69.0%; p = .04). The 2-year relapse-free survival and distant recurrence rates did not differ significantly by genotype. The 2-year locoregional recurrence rate (LRR) was significantly lower in EGFR-mutant than in wild-type EGFR patients (17.8% versus 41.7%; p = .005). EGFR-mutant genotype was associated with a lower risk for LRR on multivariate analysis, but not OS, after adjusting for surgery and other potential confounders., Conclusion: We observed that EGFR-mutant patients with locally advanced NSCLC treated with RT had lower rates of LRR than wild-type EGFR patients, raising the hypothesis that EGFR mutations may confer sensitivity to RT and/or chemotherapy. The association between mutation status and OS after combined modality therapy was less robust. Our data may serve as a useful baseline estimate of outcomes by EGFR genotype for future prospective studies.

Background: The objective of this study was to identify the factors associated with improved outcome after treatment for stage III nonsmall cell lung cancer (NSCLC)., Methods: A retrospective review of stage III NSCLC patients treated at who were treated at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center was done with institutional review board approval. Patients were followed for toxicity, local and distant failure, and overall survival. Multivariate Cox logistic regression analysis was used to determine the factors associated with treatment outcome., Results: Between August 2000 and November 2006, 144 patients received concurrent chemoradiation (CRT) for stage III NSCLC. Eighty of 144 patients were men (56%), and the median age was 61 years (range, 33-81 years). Sixty-two patients (43%) had stage IIIA NSCLC, and 82 patients (57%) had stage IIIB NSCLC. Radiotherapy (RT) was given concurrently with chemotherapy to all patients; 100 patients (69%) received CRT without surgery, and 44 patients (31%) received with neoadjuvant CRT followed by surgical resection. The median RT dose was 60 grays (Gy) (range, 46-70 Gy). The median follow-up was 15 months (range, 3-64 months), the median potential follow-up was 37 months (range, 12-84 months), and the median overall survival was 22 months (95% confidence interval, 15-28 months). The 1-year and 2-year survival rates were 68% and 47%, respectively. Among the 44 patients who underwent resection, the median survival was 61 months, and the 2-year survival rate was 73%. On multivariate analysis, stage at the time of treatment (stage IIIA vs stage IIIB) and use of surgery were the only factors associated with improved outcome (P=.01 and P=.001, respectively)., Conclusions: In this retrospective series, those patients who were able to undergo resection appeared to have improved outcome after induction CRT., (Copyright (c) 2009 American Cancer Society.)

Background: The current study was conducted to examine the outcomes of pneumonectomy after induction chemoradiotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC)., Methods: All patients undergoing pneumonectomy after induction therapy at the Brigham and Women's Hospital were retrospectively evaluated for 30-day and 100-day mortality and treatment-related complications with Institutional Review Board approval. Multivariate and univariate analyses for clinical factors correlating with toxicity and/or survival were calculated., Results: Between 1995 and 2005, 73 patients underwent pneumonectomy for NSCLC after induction therapy. All patients received radiation (median dose of 54 gray [Gy]) and 69 patients (95%) received concurrent chemotherapy. The median age was 62 years and 43 patients (59%) were male; Thirty-seven patients (51%) had American Joint Committee on Cancer stage IIIA NSCLC, 27 (37%) had stage IIIB, 6 had stage IIB, and 4 had stage IV NSCLC because of a resected solitary brain metastasis. A majority (44; 60%) of patients received the combination of carboplatin and paclitaxel, whereas 15 (21%) received the combination of cisplatin and etoposide. Forty-five patients (62%) underwent left pneumonectomy. With a median follow-up of 28 months, the 1-year and 2-year overall survival rates were 70% and 49%, respectively. The 30-day and 100-day mortality rates were 6% and 10%, respectively. Only 4 of 73 patients (6%) died of acute respiratory distress syndrome. The rate of nonfatal treatment-related morbidity was 11%. On univariate analysis, right-sided pneumonectomy was associated with a higher risk of treatment-related mortality (P = .099)., Conclusions: With an acceptable mortality rate, a single-institutional series demonstrated that trimodality therapy including pneumonectomy can be safely accomplished in patients with advanced NSCLC.

Purpose: Lung cancer is the leading cause of cancer mortality in the United States. We sought to review our experience with surgically staged IIIA (N2) non-small-cell lung cancer (NSCLC), focusing on the patterns of failure in consecutively treated patients from 1988 to 2000., Patients and Methods: The records of 177 patients were reviewed. Collected data included stage, histology, use of chemotherapy and radiation, initial and subsequent sites of failure, and survival. One hundred twenty-four patients have died; follow-up time is 35 months among the remaining patients., Results: The median survival from the time of surgery was 21.0 months, with a 3-year overall survival (OS) of 34%. Nodal downstaging to N0 disease correlated with OS and progression-free survival (PFS; P < .001). The most common site of recurrence was the brain. Thirty-four percent of patients recurred in the brain as their first site of failure, and 40% of patients developed brain metastases at some point in their course. In patients with nonsquamous histology and residual nodal involvement after neoadjuvant therapy, the risk of brain metastases was 53% at 3 years., Conclusion: Patients treated with neoadjuvant therapy for N2-positive stage IIIA NSCLC enjoy an advantage in both OS and PFS if their lymph node status is downstaged to N(0). Because brain metastases constitute the most common site of failure in these patients, future studies focusing on prophylaxis of brain metastases may improve the outcome in patients with stage IIIA NSCLC.

Purpose: Hypofractionated chest radiotherapy regimens have provided excellent palliation of pulmonary symptoms in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status in studies from Asia and Europe. We conducted a prospective study of this approach in patients from the United States., Methods and Materials: Twenty-three patients with symptomatic NSCLC and an Eastern Cooperative Oncology Group performance status of > or =2 were enrolled between December 1994 and October 2001. Two "involved-field" fractions of 8.5 Gy were delivered 1 week apart. Patients were assessed for efficacy, toxicity, and tumor response at baseline, treatment completion, and 1 week, 1 month, and 4 months after completing radiotherapy., Results: The median follow-up after treatment began was 4.3 months (range, 0.3-38). The median forced expiratory volume in 1 s and Eastern Cooperative Oncology Group performance status as measured at baseline was 1.05 L and 3, respectively. The most common presenting pulmonary symptoms were dyspnea (100%), cough (96%), anorexia/nausea (65%), and chest pain (52%). Between treatment completion and up to 4 months after treatment, dyspnea, cough, anorexia/nausea, chest pain, hoarseness, hemoptysis, and dysphagia had improved in 30%, 60%, 67%, 75%, 25%, 100%, and 100% of patients, respectively. No cases of treatment-related esophagitis, pneumonitis, or radiation myelopathy occurred. Progressive local disease was seen in only 1 (6%) of 18 assessable patients 4 months after treatment., Conclusion: For patients with poor performance status and inoperable NSCLC causing pulmonary symptoms, hypofractionated, involved-field radiotherapy, 8.5 Gy in two fractions, offers acceptable palliation with minimal toxicity. A clear advantage of the very short hypofractionated regimen is that it enables patients with a short expected survival time to spend more of their remaining time away from the hospital.

Forty-six patients with pathologic clinical stage II non-small-cell lung carcinoma underwent resection with or without adjuvant radiotherapy from 1989 through 1994. These patients were analyzed to determine patterns of recurrence and survival. Surgery consisted of pneumonectomy for 11 patients, bilobectomy for two patients, lobectomy for 29 patients, and wedge or segmental resection for four patients. Adjuvant radiotherapy was delivered to 29 patients, and the median total dose was 54 Gy (range, 44-60 Gy). Median follow-up time was 23 months for all patients and 25 months for surviving patients. Twenty-six of 46 patients have had recurrence. The site of first recurrence was locoregional for 9 of 46 patients (20%) and distant for 17 of 46 patients (37%). The median time to locoregional recurrence was 18 months for patients treated with radiotherapy and 13 months for patients treated without radiotherapy. An isolated locoregional recurrence (with no simultaneous distant recurrence) was seen in 2 of 28 evaluable patients (7%) treated with radiotherapy compared with 3 of 17 patients (18%) not treated with radiotherapy. For all patients, the 3-year disease-free survival rate was 52%, and the overall survival rate was 52%. Among patients treated with radiotherapy, the 3-year disease-free survival and overall survival rates were 56% and 56%, respectively, compared with 46% and 43%, respectively, for patients who did not receive radiotherapy (p values were not significant). The locoregional recurrence rate was 33% for patients with adenocarcinoma and 15% for those with squamous cell carcinoma. The distant recurrence rates by histologic characteristic were 56% and 20%, respectively. For patients with clinical stage II non-small-cell lung cancer, postoperative radiotherapy appears to improve locoregional control. However, the preponderance of recurrences remains distant. Further study is warranted with special emphasis on control of systemic disease.

Introduction: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92., Methods: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy., Results: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery., Conclusions: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

The palliative treatment of patients with NSCLC should be individualized. Treatment decisions should be directed by the goal of maximizing the patient's quality of life, and the patient's wishes should always be ascertained. The approaches to palliative radiation treatment of the chest, bones, and brain are quite similar. Treatment of the chest and bones is usually reserved until symptoms are significant. Brain metastases are generally treated soon after diagnosis. With respect to dose-fractionation schedules, the data are not conclusive. In theory, more protracted schedules of 40 to 50 Gy in 4 to 5 weeks are associated with more durable responses and less long-term morbidity than are shorter and lower-dose schedules. These regimens are therefore worth considering for the most favorable subset of palliative patients (i.e., those with good performance status and low burden of disease). At the other end of the spectrum, very ill patients with poor performance status may be best served by short hypofractionated schedules such as 20 Gy in five fractions, 17 Gy in two fractions, or possibly 8 to 10 Gy in one fraction. Response rates with these regimens are good, trips to the treatment facility are minimized, and these ill patients will probably not live long enough to experience the higher long-term toxicity rates associated with larger treatment fractions. The majority of patients, however, fall between these two extremes and are well served by schedules such as 30 Gy in 10 fractions. Radiation treatment fields should not be excessive but cover gross disease with a limited margin. (In the setting of brain metastases, treatment of the whole brain is recommended.) Further study of palliative treatment approaches should focus not only on assessments of response and toxicity but also on the impact of different treatments on overall quality of life.