Survival outcomes in a prospective randomized multicenter Phase III trial comparing patients undergoing anatomical segmentectomy versus standard lobectomy for non-small cell lung cancer up to 2 cm.

OBJECTIVES: The oncological equivalence of anatomical segmentectomy for early stage non-small cell lung cancer (NSCLC) is still controversial. Primary aim of this study was survival outcomes in combination with improved quality of life after segmentectomy compared with lobectomy in patients with pathological stage Ia NSCLC (up to 2 cm, 7th edition) MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial to confirm the non-inferiority of segmentectomy to lobectomy in regard to prognosis (trial No. DRKS00004897). Patients were randomized to undergo either segmentectomy or lobectomy and followed up for 5-years survival and tumor recurrence. The 5-year hazard ratio comparing lobectomy with segmentectomy was required to remain above 0.5. RESULTS: Between October 2013 and June 2016, 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled; 54 were assigned to lobectomy and 54 (1 drop-out) to segmentectomy. In-hospital and 90 days mortality was 0% in both groups. Overall survival at 5 years was 86.52% in the lobectomy compared to 78.21% in the segmentectomy group (HR = 0.61, (95% CI 0.23-1.66), p-value of non-inferiority test, p-ni = 0.687). Disease free survival was 77.29% for the lobectomy and 77.96% for the segmentectomy patients (HR = 1.50, (95% CI 0.60-3.76), p-ni = 0.019). At a median follow-up of 5 years, no differences were noted in either the locoregional or distant recurrent disease in both groups (9.4% vs 7.4%, p-ni = 0.506). CONCLUSION: Overall survival, locoregional and distant recurrences was not significantly difference for patients undergoing either segmentectomy or lobectomy for stage Ia NSCLC. The targeted non-inferiority of segmentectomy to lobectomy could not be proven for primary endpoint overall survival, but was significant for the secondary endpoint of disease free survival.

Bronchoscopic Thermal Vapour Ablation for Localized Cancer Lesions of the Lung: A Clinical Feasibility Treat-and-Resect Study.

BACKGROUND: Bronchoscopic thermal vapour ablation (BTVA) is an established and approved modality for minimally invasive lung volume reduction in severe emphysema. Preclinical data suggest potential for BTVA in minimally invasive ablation of lung cancer lesions. OBJECTIVES: The objective of this study is to establish the safety, feasibility, and ablative efficacy of BTVA for minimally invasive ablation of lung cancers. METHODS: Single arm treat-and-resect clinical feasibility study of patients with biopsy-confirmed lung cancer. A novel BTVA for lung cancer (BTVA-C) system for minimally invasive treatment of peripheral pulmonary tumours was used to deliver 330 Cal thermal vapour energy via bronchoscopy to target lesion. Patients underwent planned lobectomy to complete oncologic care. Pre-surgical CT chest and post-resection histologic analysis were performed to evaluate ablative efficacy. RESULTS: Six patients underwent BTVA-C, and 5 progressed to planned lobectomy. Median procedure duration was 12 min. No major procedure-related complications occurred. All 5 resected lesions were part-solid lung adenocarcinomas with median solid component size 1.32±0.36 cm. Large uniform ablation zones were seen in 4 patients where thermal dose exceeded 3 Cal/mL, with complete/near-complete necrosis of target lesions seen in 2 patients. Tumour positioned within ablation zones demonstrated necrosis in >99% of cross-sectional area examined. CONCLUSION: BTVA of lung tumours is feasible and well tolerated, with preliminary evidence suggesting high potential for effective ablation of tumours. Thermal injury is well demarcated, and uniform tissue necrosis is observed within ablation zones receiving sufficient thermal dose per volume of lung. Treatment of smaller volumes and ensuring adequate thermal dose may be important for ablative efficacy.

Perioperative course and quality of life in a prospective randomized multicenter phase III trial, comparing standard lobectomy versus anatomical segmentectomy in patients with non-small cell lung cancer up to 2 cm, stage IA (7th edition of TNM staging system).

OBJECTIVES: For early stage non-small cell lung cancer (NSCLC) retrospective data of functionally compromised patients undergoing segmentectomy showed equal outcomes for perioperative complications and quality of life (QoL) compared with lobectomy patients. However no prospectively randomized data comparing patients eligible for both procedures are available. MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial and investigated perioperative complications and QoL in patients with NSCLC stage IA (7th edition) undergoing segmentectomy versus lobectomy. The EORTC Questionnaire Core-30 (QLQ C-30) supplemented by thirteen-item lung cancer-specific module (LC13) was assessed before surgery, at discharge, 6 weeks, 3, 6 and 12 months post-surgery. RESULTS: 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled, whereby 54 were assigned to lobectomy and 54 to segmentectomy. Due to nodal disease, tumor size and surgical reasons estimated during the operation, eight patients of the segmentectomy group received a lobectomy. In hospital and 90 days mortality was 0% in both groups. Perioperative complications were observed in 6 (11.3%) patients after segmentectomy and in 8 patients (14.8%) after lobectomy (p = 0.563), while the 90-day morbidity were 17% and 25.9% (9 and 14 patients), respectively (p = 0.452). Twelve months after surgery, there was a significant deterioration to the baselines of physical (p < 0.001) and cognitive functioning (p = 0.025), dyspnea (p < 0.001) and fatigue (p = 0.003) in the lobectomy group. Dyspnea showed a faster recovery in the segmentectomy compared to lobectomy group with statistical significance (p = 0.016 after 12 months). CONCLUSION: In patients with early-stage NSCLC, segmentectomy is associated with a statistically not significant lower perioperative morbidity and appears to provide a superior recovery in QoL compared with lobectomy patients.

Endoscopic one-way valve implantation in patients with prolonged air leak and the use of digital air leak monitoring.

BACKGROUND: Prolonged alveolar-pleural air leaks are associated with increased morbidity and mortality. Endoscopic valve therapy has been recently introduced as a potential less invasive treatment option. We aimed at quantifying the effects of valve therapy on air leak flow and clinical outcomes in patients with prolonged air leaks. METHODS: We report on a series of 16 patients with high comorbidity and evidence of continuous air leak flow in whom chest tubes remained in place for at least 7 days. After identification of the source of the air leak by use of the balloon occlusion technique, endobronchial one-way valves were implanted. Digital chest tube monitoring was used to assess air leak flow before, during, and after valve implantation until chest tube removal. RESULTS: The source of the air leak was endoscopically identified in 13 patients (81%). After valve implantation, air leak flow decreased significantly from 871±551 mL/min to 61±72 mL/min immediately after the intervention (p<0.001). The mean duration of chest tube drainage was 18±8 days before and 9±6 days after the intervention (p<0.01). Ten patients were considered responders, and 3 patients were nonresponders. Responders demonstrated consistent air leak flow levels below 100 mL/min until chest tube removal. Long-term follow-up was available for 9 patients. No adverse events related to the valve implants were reported at follow-up. Seven patients underwent valve removal without any further complications. CONCLUSIONS: Endoscopic implantation of one-way valves leads to a significant reduction in air leakage flow and may thus be a valuable treatment option in patients with prolonged air leakage.

Prospective European multicenter randomized trial of PleuraSeal for control of air leaks after elective pulmonary resection.

OBJECTIVES: We sought to evaluate the efficacy and safety of a synthetic bioresorbable pleural sealant (PleuraSeal; Covidien, Bedford, Mass) to treat air leaks after pulmonary resection. METHODS: Patients with air leaks after lung resection were randomized to treatment with pleural sealant on air leak sites after standard methods of lung closure or standard lung closure only. The primary outcome variable was the percentage of patients remaining air leak free until discharge. The secondary outcome variables were the proportion of patients with successful intraoperative air leak sealing, time to last air leak, and durations of chest tube drainage and hospitalization. RESULTS: The sealant group comprised 62 subjects, and the control group comprised 59 subjects. Most patients (98.3%) underwent open lobectomy for bronchogenic carcinoma. The overall success rates for intraoperative air leak sealing were as follows: sealant group, 71.0%; control group, 23.7% (P < .001). For grade 2 and 3 air leaks (n = 77), the intraoperative sealing rates were as follows: sealant group, 71.7%; control group, 9.1% (P < .001). More patients with grade 2 and 3 air leaks had their leaks remain sealed in the sealant group (43.5% vs 15.2%, P = .013). The median time from skin closure to last observable air leak was 6 hours (sealant group) versus 42 hours (control group, P = .718). No treatment-related complications were reported. No differences in drainage or hospitalization were observed. CONCLUSIONS: In this multicenter study the pleural sealant was safe and effective treatment for intraoperative air leaks after lung resection. Significantly fewer patients with surgically relevant intraoperative air leaks had postoperative air leaks when the pleural sealant was applied.

Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non-small cell lung cancer.

OBJECTIVE: The objective of this study is to establish clinical evidence that the p53 genotype can serve as a predictive marker for response to cisplatin-based induction therapy. METHODS: Patients with advanced non-small cell lung cancer who had received neoadjuvant chemotherapy in the context of a prospective phase II trial were analyzed for the p53 genotype of their tumors. Response to induction therapy was then correlated to the p53 genotype as assessed by complete direct DNA sequencing. Patients had received 3 cycles of cisplatin and etoposide, and 1 cycle of simultaneous radiochemotherapy. All 3 treatment components mediate their cytotoxic effect through induction of apoptosis, which is suggested to require an intact p53 gene. In addition, the results from a previously published hypothesis-finding study are updated to demonstrate the consistency of clinical results and summarize currently available clinical evidence. RESULTS: In the phase II trial, 35 patients underwent resection after induction chemotherapy, allowing a pathohistologic response assessment. The presence of a mutant p53 genotype was highly indicative of resistance to induction chemotherapy (P < .002). The sensitivity of a mutant p53 genotype to identify nonresponders was 94% (71.3-99.9 confidence interval). A normal p53 gene was significantly associated with radical resection (P < .004) and survival advantage (P = .02). CONCLUSION: This is the second clinical evaluation demonstrating a significant relation between p53 genotype and response to induction therapy in non-small cell lung cancer. We conclude that the p53 genotype should be evaluated as a predictive marker for response to induction therapy in prospective randomized protocols.

Pleurovenous shunting in the treatment of nonmalignant pleural effusion.

BACKGROUND: The goals of treatment of chronic nonmalignant pleural effusion are relief of dyspnea and improved quality of life. Treatment options include needle thoracentesis, tube thoracostomy chemical pleurodesis, and pleurectomy. Pleurovenous shunting (PVS) represents an alternative, minimally invasive method. METHODS: Since 1999, 12 patients underwent pleurovenous shunting for right-sided pleural effusion in our center. Indications were hepatic hydrothorax (n = 6, one as bridging to liver transplantation), nephrotic syndrome (n = 4), and chylothorax (n = 2, one as bridging to lung transplantation). All patients received Denver shunt systems from the pleural cavity to either the subclavian or jugular vein. RESULTS: Shunt occlusion was observed in one case (chylothorax) 4 weeks after implantation. There was one early death, which was not related to the procedure (hepatic failure). No air embolism or infection was observed. All systems were patent throughout the observation period of 1 to 40 months (mean = 13.3 months), and none of the patients required further treatment for pleural effusion. CONCLUSION: Pleurovenous shunting offers an efficient, minimally invasive alternative to other surgical methods for treatment of recurrent nonmalignant pleural effusion.

Closed-chest microdialysis to measure antibiotic penetration into human lung tissue.

The majority of bacterial lung infections are localized to the interstitial space fluid, which is therefore an important target site for antimicrobial chemotherapy. Direct measurement of interstitial concentrations of antimicrobial agents in human lung tissue would allow for a more informed approach to appropriate dosing of antimicrobial agents, but until now this was beyond technical reach. In this exploratory pharmacokinetic study, we measured the time versus concentration profile of cefpirome after a single intravenous dose administration of 2 g in the lung interstitial fluid by flexible microdialysis catheters, which were implanted during lung surgery for pulmonary tumors in five patients. Cefpirome concentrations in lung interstitial fluid were 66% of corresponding plasma values within the first 240 min, and exceeded minimal inhibitory concentrations of most relevant bacteria. The experimental procedure was well tolerated by the patients and no adverse events were observed. The present study provides evidence for the first time that closed chest microdialysis of the human lung is a feasible and safe method to measure lung concentrations in patients in vivo. The present data also corroborate the use of cefpirome as a valuable agent in the treatment of lung infections with most extracellular bacteria.