Benedict Daly

Segmentectomy Versus Wedge Resection for Non-Small Cell Lung Cancer in High-Risk Operable Patients

BACKGROUND Patients with early-stage lung cancer and limited pulmonary reserve may not be appropriate candidates for lobectomy. In these situations, sublobar resection (wedge or segmentectomy) is generally performed. Many physicians believe that segmentectomy is superior because it allows for an improved parenchymal margin and nodal sampling. METHODS We performed an analysis using operative and pathology reports collected as part of planned data collection for American College of Surgeons Surgical Oncology Group (ACOSG) Z4032. This was a prospective trial in which patients with clinical stage I lung cancer and limited pulmonary function were randomized to sublobar resection with or without brachytherapy. The operative approach (video-assisted thoracic surgery [VATS] vs thoracotomy), extent of resection, and degree of lymph node evaluation were at the discretion of the individual surgeon. The primary aim of this analysis was to compare the parenchymal margin achieved between segmentectomy and wedge resection. Secondary aims included the extent of nodal staging and whether the operative approach (VATS vs open) had an effect on margin status and nodal evaluation. RESULTS Among 210 patients, 135 (64%) underwent a VATS approach and 75 (36%) a thoracotomy. A segmentectomy was performed in 57 patients (27%) and a wedge resection in 153 patients (73%). There were no significant differences in the degree of nodal upstaging, stations sampled, or parenchymal margin obtained between VATS and thoracotomy. However, significant differences were observed between patients who underwent a segmentectomy and those who underwent a wedge resection with regard to parenchymal margin (1.5 cm vs 0.8 cm, p = 0.0001), nodal upstaging (9% vs 1%, p = 0.006), and nodal stations sampled (3 vs 1, p < 0.0001) . Notably, 41% of patients treated by wedge resection had no nodes sampled at the time of operation compared with 2% of those who underwent segmentectomy (p < 0.0001). CONCLUSIONS In ACOSG Z4032, wedge resection, regardless of the approach, was associated with a smaller parenchymal margin and a lower yield of lymph nodes and rate of nodal upstaging when compared with segmentectomy.

Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer.

PURPOSE A major concern with sublobar resection (SR) for non-small-cell lung cancer (NSCLC) is high local recurrence (LR). Adjuvant brachytherapy may reduce LR This multicenter randomized trial compares SR to SR with brachytherapy (SRB). PATIENTS AND METHODS High-risk operable patients with NSCLC ≤ 3 cm were randomly assigned to SR or SRB. The primary end point was time to LR, where LR included recurrence at the staple line (local progression), in the primary tumor lobe away from the staple line, and in ipsilateral hilar nodes. The trial was designed to have a 90% power to detect a hazard ratio (HR) of 0.315 in favor of SRB, using a one-sided type I error rate of 0.05 with a sample size of 100 eligible patients in each arm. RESULTS Two hundred twenty-four patients were randomly assigned; 222 patients were evaluable for intent-to-treat analysis. Median age was 71 years (range, 49 to 87 years). No differences were found in baseline characteristics. Median follow-up time was 4.38 years (range, 0.04 to 5.59 years). There was no difference in time to LR (HR, 1.01; 95% CI, 0.51 to 1.98; log-rank P = .98) or in the types of LR. Local progression occurred in only 17 (7.7%) of 222 patients. In patients with potentially compromised margins (margin < 1 cm, margin-to-tumor ratio < 1, positive staple line cytology, wedge resection, nodule size > 2.0 cm), SRB did not reduce LR, although trends favored the SRB arm. This was most marked in 14 patients with positive staple line cytology (HR, 0.22; P = .24). Three-year overall survival rates were similar for patients in the SR (71%) and SRB (71%) arms (P = .97). CONCLUSION Brachytherapy did not reduce LR after SR. This finding may have been related to closer attention to parenchymal margins by surgeons participating in this study.

FDG PET Metabolic Tumor Volume Segmentation and Pathologic Volume of Primary Human Solid Tumors

OBJECTIVE The purpose of this study was to establish the correlation and reliability among the pathologic tumor volume and gradient and fixed threshold segmentations of (18)F-FDG PET metabolic tumor volume of human solid tumors. MATERIALS AND METHODS There were 52 patients included in the study who had undergone baseline PET/CT with subsequent resection of head and neck, lung, and colorectal tumors. The pathologic volume was calculated from three dimensions of the gross tumor specimen as a reference standard. The primary tumor metabolic tumor volume was segmented using gradient and 30%, 40%, and 50% maximum standardized uptake value (SUVmax) threshold methods. Pearson correlation coefficient, intraclass correlation coefficient, and Bland-Altman analyses were performed to establish the correlation and reliability among the pathologic volume and segmented metabolic tumor volume. RESULTS The mean pathologic volume; gradient-based metabolic tumor volume; and 30%, 40%, and 50% SUVmax threshold metabolic tumor volumes were 13.46, 13.75, 15.47, 10.63, and 7.57 mL, respectively. The intraclass correlation coefficients among the pathologic volume and the gradient-based and 30%, 40%, and 50% SUVmax threshold metabolic tumor volumes were 0.95, 0.85, 0.80, and 0.76, respectively. The Bland-Altman biases were -0.3, -2.0, 2.82, and 5.9 mL, respectively. Of the small tumors (< 10 mL), 23 of the 35 patients had PET segmented volume outside 50% of the pathologic volume, and among the large tumors (≥ 10 mL) three of the 17 patients had PET segmented volumes that were outside 50% of pathologic volume. CONCLUSION FDG PET metabolic tumor volume estimated using gradient segmentation had superior correlation and reliability with the estimated ellipsoid pathologic volume of the tumors compared with threshold method segmentation.

Detection of Impaired Homologous Recombination Repair in NSCLC Cells and Tissues

Introduction: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing the functional HRR status in cells. Here, we monitored the ability of non–small-cell lung cancer (NSCLC) cells to form subnuclear foci of DNA repair proteins as a surrogate of HRR proficiency. Methods: We assessed clonogenic survival of 16 NSCLC cell lines in response to cisplatin, mitomycin C (MMC), and the PARP inhibitor olaparib. Thirteen tumor explants from patients with NSCLC were subjected to cisplatin ex vivo. Cells were assayed for foci of repair-associated proteins such as BRCA1, FANCD2, RAD51, and &ggr;-H2AX. Results: Four cell lines (25%) showed an impaired RAD51 foci-forming ability in response to cisplatin. Impaired foci formation correlated with cellular sensitivity to cisplatin, MMC and olaparib. Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways. Because baseline foci in untreated cells did not predict drug sensitivity, we adapted an ex vivo biomarker assay to monitor damage-induced RAD51 foci in NSCLC explants from patients. Ex vivo cisplatin treatment of explants identified two tumors (15%) exhibiting compromised RAD51 foci induction. Conclusions: A fraction of NSCLC harbors HRR defects that may sensitize the affected tumors to DNA-damaging agents including PARP inhibitors. We propose that foci-based functional biomarker assays represent a powerful tool for prospective determination of treatment sensitivity, but will require ex vivo techniques for induction of DNA damage to unmask the underlying HRR defect.

Electromagnetic Navigation to Aid Radiofrequency Ablation and Biopsy of Lung Tumors

PURPOSE We evaluated an electromagnetic (EM) navigation system (Veran Medical Technologies Inc, St. Louis, MO) to determine its potential to reduce the number of skin punctures and instrument adjustments during computed tomographic-guided percutaneous ablation and biopsy of lung nodules. DESCRIPTION Ten patients undergoing lung percutaneous ablation were prospectively enrolled. The mean age was 70 years. Positioning of the needle device was verified with computed tomographic fluoroscopy prior to the execution of any biopsy or ablation. Each EM navigation-guided procedure was defined as an EM-intervention. EVALUATION Nineteen EM interventions were performed. When an EM-guided biopsy was performed, the intervention was done immediately prior to ablation. For all 19 EM interventions, only one skin-puncture was required. The mean number of instrument adjustments required was 1.2 (range, 0 to 2). The mean time for each EM intervention was 5.2 minutes (range, 1 to 20 minutes). Pneumothorax occurred in 5 patients (50%). Only the number of instrument adjustments was significantly related to the pneumothorax rate (p = 0.005). CONCLUSIONS The EM navigation is feasible and seems to be a useful aid for image-guided procedures. Early experience suggests a low number of skin-puncture and instrument adjustments using the EM navigation system. Instrument adjustments were a key factor in pneumothorax development.

The impact of adjuvant brachytherapy with sublobar resection on pulmonary function and dyspnea in high-risk patients with operable disease: preliminary results from the American College of Surgeons Oncology Group Z4032 trial.

BACKGROUND Z4032 was a randomized study conducted by the American College of Surgeons Oncology Group comparing sublobar resection alone versus sublobar resection with brachytherapy for high-risk operable patients with non-small cell lung cancer (NSCLC). This evaluates early impact of adjuvant brachytherapy on pulmonary function tests, dyspnea, and perioperative (30-day) respiratory complications in this impaired patient population. METHODS Eligible patients with stage I NSCLC tumors 3 cm or smaller were randomly allocated to undergo sublobar resection with (SRB group) or without (SR group) brachytherapy. Outcomes measured included the percentage predicted forced expiratory volume in 1 second (FEV1%), percentage predicted carbon monoxide diffusion capacity (DLCO%), and dyspnea score per the University of California San Diego Shortness of Breath Questionnaire. Pulmonary morbidity was assessed per the Common Terminology Criteria for Adverse Events version 3.0. Outcomes were measured at baseline and 3 months. A 10% change in pulmonary function test or 10-point change in dyspnea score was deemed clinically meaningful. RESULTS Z4032 permanently closed to patient accrual in January 2010 at 224 patients. At 3-month follow-up, pulmonary function data are currently available for 148 (74 SR and 74 SRB) patients described in this report. There were no differences in baseline characteristics between arms. In the SR arm, 9 patients (12%) reported grade 3 respiratory adverse events, compared with 12 (16%) in the SRB arm (P = .49). There was no significant change in percentage change in DLCO% or dyspnea score from baseline to 3 months within either arm. In the case of FEV1%, percentage change from baseline to 3 months was significant within the SR arm (P = .03), with patients reporting improvement in FEV1% at month 3. Multivariable regression analysis (adjusted for baseline values) showed no significant impact of treatment arm, tumor location (upper vs other lobe), or surgical approach (video-assisted thoracoscopic surgery vs thoracotomy) on 3-month FEV1%, DLCO%, and dyspnea score. There was no significant difference in incidence of clinically meaningful (10% pulmonary function or 10-point dyspnea score change) change between arms. Twenty-two percent of patients with lower-lobe tumors and 9% with upper-lobe tumors demonstrated 10% decline in FEV1% (odds ratio, 2.79; 95 confidence interval, 1.07-7.25; P = .04). CONCLUSIONS Adjuvant intraoperative brachytherapy in conjunction with sublobar resection did not significantly worsen pulmonary function or dyspnea at 3 months in a high-risk population with NSCLC, nor was it associated with increased perioperative pulmonary adverse events. Lower-lobe resection was the only factor significantly associated with clinically meaningful decline in FEV1%.

Analysis of longitudinal quality-of-life data in high-risk operable patients with lung cancer: Results from the ACOSOG Z4032 (Alliance) multicenter randomized trial

BACKGROUND Prior studies have suggested that low baseline quality-of-life (QOL) scores predict worse survival in patients undergoing lung cancer surgery. However, these studies involved average-risk patients undergoing lobectomy. We report QOL results from a multicenter trial, American College of Surgeons Oncology Group Z4032, which randomized high-risk operable patients to sublobar resection (SR), or SR with brachytherapy, and included longitudinal QOL assessments. METHODS Global QOL, using the 36-item Short-Form Health Survey (SF36), and the dyspnea score from the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) scale, was measured at baseline, 3, 12, and 24 months. SF36 physical component summary (PCS) and mental component summary (MCS) scores were standardized and adjusted for age and gender normals, with scores <50 indicating below-average health status. SOBQ scores were transformed to a 0-100 (poor-excellent) scale. Aims were to: (1) determine the impact of baseline scores on recurrence-free survival, overall survival, and 30-day adverse events (AEs); and (2) identify subgroups (surgical approach, resection type. tumor location, tumor size, respiratory function) with a ≥ 10-point decline or improvement in QOL after SR. RESULTS Two hundred twelve eligible patients were included. There were no significant differences in baseline QOL scores between arms. Median baseline PCS, MCS, and SOBQ scores were 42.7, 51.1, and 70.8, respectively. There were no differences in grade-3+ AEs, overall survival, or recurrence-free survival in patients with baseline scores ≤ median versus > median values, except for a significantly worse overall survival for patients with baseline SOBQ scores ≤ median value. There were no significant differences between the study arms in percentage change of QOL scores from baseline to 3, 12, or 24 months. Further comparison combining the 2 arms demonstrated a higher percentage of patients with a ≥ 10-point decline in SOBQ scores with segmentectomy compared with wedge resection (40.5% vs 21.9%, P = .03) at 12 months, with thoracotomy versus video-assisted thoracic surgery (VATS) (38.8% vs 20.4%, P = .03) at 12 months, and T1b versus T1a tumors (46.9% vs 23.5%, P = .020) at 24 months. A ≥ 10-point improvement in PCS score was seen at 3 months with VATS versus thoracotomy (16.5% vs 3.6%, P = .02). CONCLUSIONS In high-risk operable patients, poor baseline QOL scores were not predictive for worse overall or recurrence-free survival, or for higher risk for AEs following SR. VATS was associated with improvement in physical function at 3 months, and improved dyspnea scores at 12 months, lending support for the preferential use of VATS when SR is undertaken.

Treatment of chronic pancreatitic pleural effusion by percutaneous catheter drainage of abdominal pseudocyst

A 53-year-old man entered the hospital with a large, right chronic pancreatitic pleural effusion. Computed tomographic examination of the abdomen and chest demonstrated a pancreatic pseudocyst that had extended into the mediastinum. After conventional closed-chest tube thoracotomy drainage failed to empty the pleural space, percutaneous abdominal pseudocyst drainage was instituted using computed tomographic guidance. The pleural effusion cleared promptly, and the pancreatic pseudocyst resolved gradually over seven weeks. Following termination of pseudocyst drainage, the patient has remained well for over two years with no recurrence of pancreatitis, pseudocyst, or pleural effusion. In contrast, three earlier patients with a chronic pancreatitic effusion managed conventionally had a complicated hospital course and required surgical intervention; two had recurrent pancreatitis following hospital discharge. Percutaneous catheter placement was unsuccessful in one of these three and, in retrospect, was infeasible in the other two. It is recommended that thoracoabdominal computed tomography be performed in all patients with a chronic pancreatitic pleural effusion, and that percutaneous abdominal catheter drainage be attempted in all patients with an accessible pancreatic or mediastinal pseudocyst. Such treatment may relieve respiratory insufficiency, minimize the risk of empyema or fibrothorax, and may promote pseudocyst closure without the need for surgery.

Radiofrequency ablation for Barrett's esophagus and low-grade dysplasia in combination with an antireflux procedure: a new paradigm.

OBJECTIVE Radiofrequency ablation for Barretts esophagus in combination with an antireflux procedure has not been widely documented. We report our initial experience with radiofrequency ablation in association with antireflux procedure for Barretts metaplasia and low-grade dysplasia. METHODS A total of 14 patients (10 male and 4 female patients) presented with Barretts metaplasia (n=11) or low-grade dysplasia (n=3). Median age was 60 years (38-80 years). The severity of Barretts esophagus was classified by length (in centimeters), appearance (circumferential/noncircumferential), and histology (1, normal; 2, Barretts metaplasia; and 3, low-grade dysplasia). Radiofrequency ablation was performed with the HALO 360 degrees or 90 degrees systems (BARRX Medical, Sunnyvale, Calif). RESULTS Median follow-up was 17 months. The mean number of ablative procedures undertaken was 2.6 (range, 1-6). There was no mortality, but there were 2 perioperative complications after the antireflux procedure (pneumonia, 1; atrial fibrillation, 1). One patient had mild dysphagia requiring a single dilation 2 months after ablation. The mean length of Barretts esophagus decreased from 6.2 to 1.2 cm after treatment (P=.001). Barretts grade decreased significantly (P=.003). Before therapy, circumferential Barretts esophagus was present in 13 patients. At last endoscopy, only 1 patient had circumferential Barretts esophagus present. The number of radiofrequency ablation treatments was significantly (P < .05) associated with success. All patients receiving 3 or more treatments had complete resolution of Barretts metaplasia. CONCLUSIONS Radiofrequency ablation performed either before or after an antireflux procedure is safe. This approach is effective for reducing or eliminating metaplasia and dysplasia. Long-term studies will be necessary to determine whether this approach can provide durable control of both reflux and Barretts esophagus.

Role of Surgery Following Induction Therapy for Stage III Non–Small Cell Lung Cancer

Over the last 30 years neoadjuvant treatment of stage IIIA non-small cell lung cancer (NSCLC) followed by surgical resection for stage IIIB disease has significantly improved the overall results of treatment for patients with stage III NSCLC as well as for those with locally invasive tumors. Different chemotherapy regimens have been used, although in most studies some combination of drugs that include cisplatin is the standard. Radiation when given as part of the induction protocol appears to offer a higher rate of resection and complete resection, and higher doses of radiation are associated with better nodal downstaging. Resection in patients with persistent N2 disease and pneumonectomy following induction therapy remain controversial. Resection in patients with persistent N2 disease and pneumonectomy following induction therapy remain controversial.