Reza J. Mehran

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

BACKGROUND The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Stereotactic Body Radiation Therapy in Centrally and Superiorly Located Stage I or Isolated Recurrent Non–Small-Cell Lung Cancer

PURPOSE To evaluate the efficacy and adverse effects of image-guided stereotactic body radiation therapy (SBRT) in centrally/superiorly located non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS We delivered SBRT to 27 patients, 13 with Stage I and 14 with isolated recurrent NSCLC. A central/superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body, but 1 cm away from the spinal canal. All patients underwent four-dimensional computed tomography-based planning, and daily computed tomography-on-rail guided SBRT. The prescribed dose of 40 Gy (n = 7) to the planning target volume was escalated to 50 Gy (n = 20) in 4 consecutive days. RESULTS With a median follow-up of 17 months (range, 6-40 months), the crude local control at the treated site was 100% using 50 Gy. However, 3 of 7 patients had local recurrences when treated using 40 Gy. Of the patients with Stage I disease, 1 (7.7%) and 2 (15.4%) developed mediastinal lymph node metastasis and distant metastases, respectively. Of the patients with recurrent disease, 3 (21.4%) and 5 (35.7%) developed mediastinal lymph node metastasis and distant metastasis, respectively. Four patients (28.6%) with recurrent disease but none with Stage I disease developed Grade 2 pneumonitis. Three patients (11.1%) developed Grade 2-3 dermatitis and chest wall pain. One patient developed brachial plexus neuropathy. No esophagitis was noted in any patient. CONCLUSIONS Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.

Management of Primary Pulmonary Artery Sarcomas

The objective of this review is to determine the outcome of patients with sarcomas involving the main pulmonary artery, pulmonic valve, or right ventricular outflow tract. Survival data were analyzed using an aggregate series derived from the published literature in conjunction with a current series. Median survival was 36.5 +/- 20.2 months for patients undergoing an attempt at curative resection compared with 11 +/- 3 months for those undergoing incomplete resection. Median survival was 24.7 +/- 8.5 months for patients undergoing multimodality treatment compared with 8.0 +/- 1.7 months for patients having single-modality therapy. A complete review of diagnosis, evaluation, treatment, and surveillance of primary pulmonary artery sarcomas follows.

Intrathoracic Leaks Following Esophagectomy Are No Longer Associated With Increased Mortality

Objectives:Assess outcomes following intrathoracic leaks after esophagectomy from 1970 to 2004 to evaluate the impact of evolving surgical and perioperative techniques on leak-associated mortality (LAM). Summary Background Data:An intrathoracic leak following esophagectomy has historically been considered a catastrophic event, with mortality as high as 71%. Concerns about this complication often affect choice of surgical approach for esophagectomy. Methods:A retrospective review of all esophagectomies for cancer from 1970 to 2004 (n = 1223) was performed. Outcomes following intrathoracic anastomoses (n = 621) were analyzed by era: historical 1970–1986 (n = 145) and modern 1987–2004 (n = 476). Results:There was no difference in the frequency of leak between the time intervals (4.8% versus 6.3%, P = 0.5). Despite a significant increase in the use of preoperative chemoradiation (1% versus 42%, P < 0.001) in the historical versus modern era, the overall mortality decreased from 11% to 2.5% (P < 0.001). The LAM was markedly reduced from 43% to 3.3% (P = 0.016). Factors associated with LAM included failure to use enteral nutrition (HR 13.22, CI 1.8–96.8) and era in which the surgery was performed (HR 18.3, 1.9–180). Other differences included an increased proportion of successful reoperations for leak control (11/30 versus 0/7, P = 0.08) and use of reinforcing muscle flaps (7/11). In the modern era, perioperative mortality is not significantly different for patients with or without intrathoracic leaks (3.3% versus 2.5%, P = 0.55), nor is long-term survival (P = 0.16). Conclusions:Modern surgical management of intrathoracic leaks results in no increased mortality and has no impact on long-term survival. Clinical decisions regarding the use of intrathoracic anastomoses should not be affected by concerns of increased mortality from leak.

Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a "no fly zone".

PURPOSE We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. METHODS AND MATERIALS Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. RESULTS At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial Dmax <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. CONCLUSIONS SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.

Clinical outcome and predictors of survival and pneumonitis after stereotactic ablative radiotherapy for stage I non-small cell lung cancer

BackgroundStereotactic ablative radiotherapy (SABR) can achieve excellent local control rates in early-stage non-small cell lung cancer (NSCLC) and has emerged as a standard treatment option for patients who cannot undergo surgery or those with isolated recurrences. However, factors that may predict toxicity or survival are largely unknown. We sought here to identify predictors of survival and pneumonitis after SABR for NSCLC in a relatively large single-institution series.MethodsSubjects were 130 patients with stage I NSCLC treated with four-dimensional computed tomography (4D CT) –planned, on-board volumetric image–guided SABR to 50 Gy in 4 fractions. Disease was staged by positron emission tomography/computed tomography (PET/CT) and scans were obtained again at the second follow-up after SABR.ResultsAt a median follow-up time of 26 months, the 2-year local control rate was 98.5%. The median overall survival (OS) time was 60 months, and OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% at 3 years. No patient experienced grade 4–5 toxicity; 15 had radiation pneumonitis (12 [9.3%] grade 2 and 3 [2.3%] grade 3). Performance status, standardized uptake value (SUV)max on staging PET/CT, tumor histology, and disease operability were associated with OS on univariate analysis, but only staging SUVmax was independently predictive on multivariate analysis (P = 0.034). Dosimetric factors were associated with radiation pneumonitis on univariate analysis, but only mean ipsilateral lung dose ≥9.14 Gy was significant on multivariate analysis (P = 0.005).ConclusionsOS and radiation pneumonitis after SABR for stage I NSCLC can be predicted by staging PET SUVmax and ipsilateral mean lung dose, respectively.

Resection of Pulmonary and Extrapulmonary Sarcomatous Metastases Is Associated With Long-Term Survival

BACKGROUND The presence of extrapulmonary sarcomatous metastases has traditionally been a contraindication for the resection of pulmonary metastases. We, therefore, reviewed our experience with resection of pulmonary metastases in patients who had documented extrapulmonary metastases to determine long-term outcome. METHODS From 1998 to 2006, 234 patients underwent pulmonary metastasectomy. They were grouped as follows: group A (lung metastasectomy only); group B1 (with either synchronous or prior extrapulmonary metastasectomy); group B2 (with nonsurgical treatment of synchronous or prior extrapulmonary metastases); group C1 (with later extrapulmonary metastasectomy); group C2 (with later extrapulmonary metastasis which was not resected). RESULTS Groups A, B1, and B2 consisted of 147 (62.8%), 26 (11.1%), and 13 (5.6%) patients, respectively. The median survival from lung metastasectomy date was 35.5, 37.8, and 13.5 months in groups A, B1, and B2, respectively. Comparison among the three groups showed no significant survival difference in groups A versus B1 (p = 0.96), but a survival difference was found comparing groups A versus B2 (p < 0.001) and B1 versus B2 (p < 0.001). Prognostic factors for increased survival included 3 or greater redo pulmonary operations, greater than 12 month mean time between pulmonary recurrences, greater than 24 month mean time between extrathoracic recurrences, and a prolonged disease-free interval. Prognostic factors for decreased survival included 3 or greater pulmonary metastases and group B2 patients. CONCLUSIONS These results suggest extrapulmonary metastases should no longer be viewed as a contraindication to resection of sarcomatous pulmonary metastases. Long-term survival can be achieved when a complete resection is possible for both the pulmonary and extrapulmonary metastases.

Patterns of Failure, Toxicity, and Survival after Extrapleural Pneumonectomy and Hemithoracic Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma

Introduction: We investigated safety, efficacy, and recurrence after postoperative hemithoracic intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma treated with extrapleural pneumonectomy (EPP), during the past decade at a single institution. Methods: In 2001–2011, 136 consecutive patients with malignant pleural mesothelioma underwent EPP with planned adjuvant IMRT. Eighty-six patients (64%) underwent hemithoracic IMRT; the rest were not eligible because of postoperative complications, disease progression, or poor performance status. We assessed toxicity, survival, and patterns of failure in these 86 patients. Toxicity was scored with the Common Terminology Criteria for Adverse Events version 4.0; survival outcomes were estimated with the Kaplan–Meier method; and locoregional patterns of failure were classified as in-field, marginal, or out-of-field. Risk factors related to survival were identified by univariate and multivariate Cox regression analysis. Results: Median overall survival time for all 86 patients receiving IMRT was 14.7 months. Toxicity rates of grade of 3 or more were: skin 17%, lung 12%, heart 2.3%, and gastrointestinal toxicity 16%. Five patients experienced grade 5 pulmonary toxicity. Rates of locoregional recurrence-free survival, distant metastasis-free survival, and overall survival (OS) were 88%, 55%, and 55% at 1 year and 71%, 40%, and 32% at 2 years. On multivariate analysis, pretreatment forced expiratory volume in 1 second, nonepithelioid histology, and nodal status were associated with distant metastasis-free survival and OS. Conclusion: IMRT after EPP is associated with low rates of locoregional recurrence, though some patients experience life-threatening lung toxicity. Tumor histology and nodal status can be helpful in identifying patients for this aggressive treatment.

Salvage esophagectomy after failed definitive chemoradiation for esophageal adenocarcinoma

BACKGROUND Outcomes of salvage esophagectomy after definitive chemoradiation (CRT) for squamous cell carcinoma are well defined. Previous reports of salvage esophagectomy in patients with recurrent adenocarcinoma after definitive CRT are limited by small numbers and high morbidity and mortality rates. METHODS We reviewed our experience of 65 patients with esophageal adenocarcinoma treated from 1997 to 2010 who underwent salvage esophagectomy after failed definitive CRT. We then compared this group to 65 matched patients of 521 total patients with esophageal adenocarcinoma who received preoperative CRT followed by planned esophagectomy. Propensity matching and multivariable analysis were performed. RESULTS Median time to surgery from completion of therapy for the salvage group was 216 days. Major postoperative events (major pulmonary event, conduit loss, leak, readmission to intensive care unit) occurred in 35% (23 of 65) of salvage patients and 31% (20 of 65) of the planned resection matched group. Anastomotic leak occurred in 18.5% (12 of 65) and 11.3 (59 of 521) of salvage and planned groups, respectively. Thirty-day mortality was 3.1% (2 of 65) after salvage resection and 4.6% (3 of 65) after planned resection. There was no difference in 3-year overall or median survival between the two groups of patients (32 months, 48% salvage, versus 40 months, 57% planned resection). Multivariable analysis did not identify salvage strategy or time from completion of therapy to resection as a predictor of major event or death. CONCLUSIONS Postoperative morbidity, mortality, and overall survival of patients after salvage esophagectomy are comparable to matched patients after planned resection. These results suggest that patients with esophageal adenocarcinoma who fail definitive CRT and recur locoregionally should be considered for salvage esophagectomy at experienced esophageal centers.

Impact of tumor length on long-term survival of pT1 esophageal adenocarcinoma

INTRODUCTION The impact of esophageal tumor length on pT1 esophageal adenocarcinoma has not been well evaluated. METHODS Case histories of all patients (n = 133) undergoing esophageal resection from 1979 to 2007 with pT1 adenocarcinoma of the esophagus were reviewed. Univariate and multivariate analyses of esophageal tumor length and other standard prognostic factors were performed. RESULTS Patients with early-stage pT1 esophageal adenocarcinoma with tumors less than 3 cm demonstrate decreased long-term survival (3 years: >3 cm = 46% vs 93%; P < .001) and higher risk of lymph node involvement (lymph node positive: >3 cm = 47% vs 10%; P < .001). Multivariable analysis shows that esophageal tumor length (>3 cm) is an independent risk factor for survival in patients with pT1 early-stage esophageal cancer (hazard ratio: 4.8, 95% confidence intervals: 1.4-16.5; P < .001) even when controlled for submucosal involvement, lymph node involvement, and lymphatic/vascular invasion status. In combination with submucosal involvement, esophageal tumor length (>3 cm) identifies a high-risk population of pT1 esophageal adenocarcinoma (3 years: group 1 [0 risk factors] = 100%, group 2 [1 risk factor] = 87%, and group 3 [2 risk factors] = 33%; P < .001). CONCLUSIONS This study demonstrates that esophageal tumor length (>3 cm) is a risk factor for long-term survival and lymph node involvement in early-stage pT1 esophageal adenocarcinoma. Esophageal tumor length (>3 cm) in combination with submucosal involvement may help to identify a high-risk group of patients with pT1 esophageal adenocarcinoma.