Boris Sepesi

Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients

Purpose: We investigated the correlation between immunohistochemical PD-L1 expression and tumor-associated immune cells (TAICs) density in non–small cell lung carcinoma (NSCLC) and correlated them with clinicopathologic variables. Experimental Design: Tumor tissue specimens from 254 stage I–III NSCLCs [146 adenocarcinomas; 108 squamous cell carcinomas (SCCs)] were examined. PD-L1 expression in malignant cells and macrophages and the density of TAICs expressing CD3, CD4, CD8, CD57, granzyme B, CD45RO, PD-1, FOXP3, and CD68 were evaluated using immunohistochemistry and image analysis. Results: Malignant cells PD-L1 H-score > 5 was detected in 23% of adenocarcinomas and 31% of SCCs, and no significant differences were detected comparing both histologies; the median H-score in macrophages was significantly higher in SCC than in adenocarcinoma (P < 0.001). In adenocarcinoma, high malignant cells PD-L1 expression and high TAIC density correlated with solid histology, smoking history, and airflow limitation. Multivariate analysis demonstrated that high CD57-positive cell density correlated with better recurrence-free survival (RFS; P = 0.0236; HR, 0.457) and overall survival (OS; P = 0.0261; HR, 0.481) rates for SCC. High CD68-positive cell density in intratumoral compartment correlated with better RFS (P = 0.0436; HR, 0.553) for adenocarcinoma. The combination of low CD4/CD8/C68-positive cell density and PD-L1 H-score >5 in malignant cells identified small subset of adenocarcinomas with worse outcomes (RFS: P = 0.036; HR, 4.299; OS: P = 0.00034; HR, 5.632). Conclusions: We detected different PD-L1 expression and TAIC density patterns in NSCLC. Distinct groups of tumor microenvironment correlated with NSCLC clinicopathologic features, including outcome. Clin Cancer Res; 22(24); 6278–89. ©2016 AACR.

Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer

Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

Endoscopic esophageal tumor length: A prognostic factor for patients with esophageal cancer

Pathologic esophageal tumor length (pL) is an independent predictor of long‐term survival. However, whether patients with longer (high‐risk) tumors can be identified by endoscopy before surgery has not been established. The objective of the current study was to determine the value of endoscopically measured tumor length (cL) in predicting overall survival in patients with esophageal adenocarcinoma.

Surgical Resection for Locoregional Esophageal Cancer Is Underutilized in the United States

BACKGROUND Although esophagectomy provides the highest probability of cure in patients with esophageal cancer, many candidates are never referred for surgery. We hypothesized that esophagectomy for esophageal cancer is underused, and we assessed the prevalence of resection in national, state, and local cancer data registries. STUDY DESIGN Clinical stage, surgical and nonsurgical treatments, age, and race of patients with cancer of the esophagus were identified from the Surveillance, Epidemiology and End Results (SEER) registry (1988 to 2004), the Healthcare Association of NY State registry (HANYS 2007), and a single referral center (2000 to 2007). SEER identified a total of 25,306 patients with esophageal cancer (average age 65.0 years, male-to-female ratio 3:1). HANYS identified 1,012 cases of esophageal cancer (average age 67 years, M:F ratio 3:1); stage was not available from NY State registry data. A single referral center identified 385 patients (48 per year; average age 67 years, M:F 3:1). For SEER data, logistic regression was used to examine determinants of esophageal resection; variables tested included age, race, and gender. RESULTS Surgical exploration was performed in 29% of the total and only 44.2% of potentially resectable patients. Esophageal resection was performed in 44% of estimated cancer patients in NY State. By comparison, 64% of patients at a specialized referral center underwent surgical exploration, 96% of whom had resection. SEER resection rates for esophageal cancer did not change between 1988 and 2004. Males were more likely to receive operative treatment. Nonwhites were less likely to undergo surgery than whites (odds ratio 0.45, p < 0.001). CONCLUSIONS Surgical therapy for locoregional esophageal cancer is likely underused. Racial variations in esophagectomy are significant. Referral to specialized centers may result in an increase in patients considered for surgical therapy.

TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088-97. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

The Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non–Small Cell Lung Cancer

Background Population studies suggest that high body mass index (BMI) correlates with a reduced risk for death from lung cancer. The aim of our study was to evaluate definitively the influence of BMI on long‐term overall survival (OS) in surgical patients with NSCLC. Methods The study population consisted of 1935 patients who underwent surgical resection for lung cancer at M. D. Anderson Cancer Center (2000–2014). Study variables included both patient‐ and treatment‐related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with OS. Results On univariate analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I versus stage II, III, or IV), type of surgical procedure (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female sex, and adenocarcinoma histologic subtype (versus squamous) (all p < 0.05). Morbidly obese patients (BMI ≥ 35) demonstrated a trend toward better outcomes than those classified as obese (BMI ≥30 and <35 kg/m2) (p = 0.05), overweight (BMI ≥ 25 and <30 kg/m2) (p = 0.13), or healthy weight (BMI <25 kg/m2) (p = 0.37) (hazard ratio = 0.727, 0.848, 0.926, and 1, respectively). On multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis demonstrated significantly better OS (p = 0.003) in patients with a BMI of 30 kg/m2 or higher as compared with a BMI of 25 kg/m2. Conclusions In this large, retrospective, single‐center series, after control for disease stage and other variables, higher BMI was associated with improved OS after surgical resection of NSCLC. Further studies are necessary to elucidate the precise relationship between BMI and treatment outcomes.

Long-term survival outcomes of cancer-directed surgery for malignant pleural mesothelioma: Propensity score matching analysis

Purpose Small observational studies have shown a survival advantage to undergoing cancer-directed surgery for malignant pleural mesothelioma (MPM); however, it is unclear if these results are generalizable. Our purpose was to evaluate survival after treatment of MPM with cancer-directed surgery and to explore the effect surgery interaction with chemotherapy or radiation therapy on survival by using the National Cancer Database. Patients and Methods Patients with microscopically proven MPM were identified within the National Cancer Database (2004 to 2014). Propensity score matching was performed 1:2 and among this cohort, a Cox proportional hazards regression model was used to identify predictors of survival. Median survival was calculated by using the Kaplan-Meier method. Results Of 20,561 patients with MPM, 6,645 were identified in the matched cohort, among whom 2,166 underwent no therapy, 2,015 underwent chemotherapy alone, 850 underwent cancer-directed surgery alone, 988 underwent surgery with chemotherapy, and 274 underwent trimodality therapy. The remaining 352 patients underwent another combination of surgery, radiation, or chemotherapy. Thirty-day and 90-day mortality rates were 6.3% and 15.5%. Cancer-directed surgery, chemotherapy, and radiation therapy were independently associated with improved survival (hazard ratio, 0.77, 0.74, and 0.88, respectively). Stratified analysis revealed that surgery-based multimodality therapy demonstrated an improved survival compared with surgery alone, with no significant difference between surgery-based multimodality therapies; however, the largest estimated effect was when cancer-directed surgery, chemotherapy, and radiation therapy were combined (hazard ratio, 0.52). For patients with the epithelial subtype who underwent trimodality therapy, median survival was extended from 14.5 months to 23.4 months. Conclusion MPM is an aggressive and rapidly fatal disease. Surgery-based multimodality therapy was associated with improved survival and may offer therapeutic benefit among carefully selected patients.

Salvage pulmonary resection after stereotactic body radiotherapy: A feasible and safe option for local failure in selected patients

Objective For inoperable patients with pulmonary malignancy, stereotactic body radiotherapy is a reasonable therapeutic option. Despite good early tumor control, local failure occurs in up to 10% of patients by 3 years. Because management of local recurrence after stereotactic body radiotherapy is unclear, we evaluated use of surgery as a salvage option. Methods A retrospective review was conducted of consecutive patients from a single institution who underwent salvage resection of primary and metastatic pulmonary malignancies previously treated with stereotactic body radiotherapy. In addition, a literature search was conducted to identify previous reports of pulmonary resection for local stereotactic body radiotherapy failures, to allow cumulative analyses with previously published cases. Results A total of 21 patients met inclusion criteria. The median time between stereotactic body radiotherapy and salvage surgery was 16.2 months (range, 6.4‐71.5). Postoperative complications occurred in 7 patients (18.9%), in whom atrial arrhythmias and prolonged air leaks (>5 days) were most frequent (n = 2 each, 5.4%). There was no local recurrence after salvage surgery. Distant failure occurred in 5 of 21 patients (23.8%) at a median of 36.2 months, and median disease‐free survival was 19.2 months. The 30‐ and 90‐day mortality was 4.8% (1 patient). Cumulative analysis included 37 patients from 4 institutions and comprised 26 (78.8%) primary non–small cell lung cancers and 11 (29.7%) lung metastases. Median overall survival after salvage surgery was 46.9 months, and 3‐year survival was 71.8%. Conclusions After local failure of stereotactic body radiotherapy, salvage resection remains a viable option for operable patients, with acceptable morbidity and survival. As use of stereotactic body radiotherapy continues to expand, further studies to evaluate the optimal management for local failure are needed.

Long-Term Outcomes of Salvage Stereotactic Ablative Radiotherapy for Isolated Lung Recurrence of Non–Small Cell Lung Cancer: A Phase II Clinical Trial

Objectives: Our goal was to evaluate stereotactic ablative radiotherapy (SABR) as a salvage option for isolated recurrence of NSCLC in the lung parenchyma after definitive treatment of stage I to III disease. Methods: Patients who had histologically confirmed, positron emission tomography–staged, isolated NSCLC recurring locally or metastasis in the lung parenchyma (≤3 cm, suitable for SABR) after previous definitive treatment were prospectively enrolled in this trial and treated with volumetric, image‐guided SABR to 50 Gy in four fractions. Patients were then followed with computed tomography or positron emission tomography/computed tomography. Primary end points included the pattern of failure after salvage SABR, overall survival (OS), and progression‐free survival (PFS). Results: Fifty‐nine patients with recurrent disease were treated with salvage SABR. The median age was 70 years (range 45–86 years), and the median follow‐up time after salvage SABR was 58.3 months. Re‐recurrence after salvage SABR developed in 19 patients (32%). Measuring from the date of salvage SABR, the estimated 5‐year rates of local, regional, and distant failure were 5.2%, 10.3%, and 22.4%, respectively; the estimated PFS was 46.2% at 3 years and 41.1% at 5 years; and the OS rates were 63.5% at 3 years and 56.5% at 5 years. A high post‐SABR neutrophil‐to‐lymphocyte ratio was found to predict poor survival. Grade 3 treatment‐related adverse events developed in three patients (5%). No patient had a grade 4 or 5 event. Conclusion: Our study showed that salvage SABR provides excellent 5‐year OS, local control, and PFS rates with minimal toxicity for patients with isolated NSCLC recurrence in the lung parenchyma. These results are striking and comparable to historically reported outcomes of patients with primary early‐stage NSCLC treated with definitive SABR. SABR appears to be a very effective and safe salvage option for patients with isolated lung parenchyma recurrent disease after definitive treatment and should be considered along with surgery as a potential first‐line option for patients with local lung parenchymal recurrent disease.