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.

Prognostic markers in resected large cell neuroendocrine carcinoma: a multicentre retrospective analysis.

BACKGROUND: Large cell neuroendocrine carcinomas (LCNEC) are rare pulmonary malignancies. Reported survival rates are heterogeneous and the optimal therapeutic strategy is still debated. The prognosis of LCNEC is generally inferior compared to other non-small lung cancers. In early stages, surgery is recommended but might not be sufficient alone. METHODS: We retrospectively analyzed all consecutive LCNEC patients operated at three institutions with curative intent between May 2005 and January 2017. Data retrieved from individual clinical databases were analyzed with the aim to identify prognostic parameters. RESULTS: A total of 251 patients with LCNEC underwent curative intent surgery during the observation period. The median age was 64 years, 156 patients (62.2%) were male and 88.4% were smokers. The pathologic AJCC stage was I in 136 patients, II in 77, III in 33, and IV in 5 patients. Median follow-up was 26 months. Lymphatic vessel invasion (P=0.031) was identified as significant prognostic factor by multivariable analysis. There was a trend towards decreased survival in patients with blood vessel invasion (P=0.067). Even in earlier tumor stages, adjuvant chemotherapy had a positive effect on survival. The overall 1-, 3- and 5-year survival rates were 79.2%, 48.6% and 38.8% respectively. CONCLUSIONS: Lymphatic invasion (L1) is an independent prognostic factor. Surgery in LCNEC is beneficial in early tumor stages and platinum-based adjuvant chemotherapy may help in achieving better long-term outcomes resulting in most obvious survival differences in stage Ib.

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.

10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)-a multicenter phase-II trial (CISTAXOL).

BACKGROUND: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. PATIENTS AND METHODS: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50 mg/m(2) day 1+8) and paclitaxel (175 mg/m(2)d1) qd 22. Concurrent CTx/RTx followed: 45 Gy (1.5 Gy bid) with cisplatin 50 mg/m(2) day 2+9 and etoposide 100 mg/m(2) d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20 Gy; 2 Gy qd) followed. Here we report 10-year-LTS for this cohort. RESULTS: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. CONCLUSIONS: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).

A new technique for complete intraluminal repair of iatrogenic posterior tracheal lacerations.

Tracheal laceration is a rare complication of endotracheal intubation. Early surgical treatment is mandatory in cases of pneumomediastinum with difficulty in ventilation to prevent mediastinitis and stricture. Surgical access to the posterior tracheal wall is via a right posterolateral thoracotomy, transcervical tracheotomy or tracheostomy, each of which is associated with specific morbidities. We developed a new optical needle holder consisting of a 12° HOPKINS telescope in a fixed attachment with an endoscopic needle holder to allow for complete intraluminal repair of posterior tracheal wall lacerations. Four patients were admitted with an iatrogenic tracheal laceration due to emergency intubation. In all cases, the repair of the tracheal laceration started with the introduction of a 14-mm rigid tracheoscope and subsequent jet-ventilation. Three of the tears were successfully repaired endotracheally with a running suture. In one case, the repair had to be converted to an open closure via posterolateral thoracotomy. Two patients were discharged extubated for further treatment of their underlying diseases. One patient died from a third cardiac infarction two days after the tracheal repair. We think that an exclusively endoluminal repair of longitudinal tracheal lacerations is feasible. This repair has convincing advantages including little surgical trauma, lack of scars and diminished postoperative pain.

A new endoscopic technique for intraluminal repair of posterior tracheal laceration.

This report describes an endoscopic repair of a tracheal tear with a newly developed optical needle holder. No surgical access was necessary. A 71-year-old woman with a 5-cm gaping iatrogenic tracheal laceration and a distinctive mediastinal and subcutaneous emphysema was successfully repaired with an endotracheal running suture through a 14-mm rigid tracheoscope. Operation time was 105 minutes, and borderline jet ventilation was used to maintain oxygen saturation. A bronchoscopy 9 days later revealed the tracheal tear had completely closed and the running suture was in place. No postoperative complications were noted.

Intensified high-dose chemoradiotherapy with induction chemotherapy in patients with locally advanced non-small-cell lung cancer-safety and toxicity results within a prospective trial.

PURPOSE: To analyze the toxicity profile of an intensified definitive chemoradiotherapy (CRT) schedule in patients with locally advanced non-small-cell lung cancer (Stage IIIA N2/selected IIIB) treated within a prospective multicenter trial. PATIENTS AND METHODS: After mediastinoscopy and routine staging procedures, three cycles of induction chemotherapy (cisplatin 50 mg/m(2), Days 1 and 8; paclitaxel 175 mg/m(2) Day 1, every 21 days) were planned, followed by concurrent CRT (accelerated-hyperfractionated regimen, 45 Gy, 2 x 1.5 Gy/d, cisplatin 50 mg/m(2), Days 64 and 71, vinorelbine 20 mg/m(2), Days 64 and 71). At 45 Gy, a multidisciplinary panel decision was made regarding operability. Inoperable patients received definitive radiotherapy (total dose 65 or 71 Gy, depending on the mean lung dose) with additional concurrent chemotherapy (cisplatin 40 mg/m(2), Day 85; vinorelbine 15 mg/m(2), Days 85 and 92). RESULTS: A total of 28 patients (23 men and 5 women; median age, 58 years; range 41-73; Stage IIIA in 3 and Stage IIIB in 25) were judged ineligible for surgery by the multidisciplinary panel and underwent definitive CRT (75% of the patients received 71 Gy). The maximum toxicity (Grade 3 or greater) during induction chemotherapy included leukopenia (11%) and anemia (4%). During concurrent CRT, leukopenia (Grade 3 or greater) was observed in 39% of the patients. The maximal nonhematologic toxicity during concurrent CRT included esophagitis (Grade 3 or greater) in 18% and pneumonitis (Grade 3 or greater) in 4% of the patients. At 3 years, the locoregional control rate was 52% (95% confidence interval, 29-75%) and the overall survival rate was 31% (95% confidence interval, 12-50%). CONCLUSION: This intensified treatment protocol with induction chemotherapy and concurrent CRT, including hyperfractionated-accelerated RT, showed only moderate toxicity and proved feasible. This treatment represents the definitive CRT arm of our ongoing multicenter randomized trial comparing definitive CRT and trimodality treatment.

Pulmonary metastases of breast cancer. When is resection indicated?

OBJECTIVE: While resection of pulmonary metastases is a common treatment in other primaries, the role of breast cancer metastasectomy is still unclear. The objective of the present study was to investigate the clinical outcome of our operated patients with pulmonary breast cancer metastases and discuss the different indications for metastasectomy. METHODS: From January 1998 to December 2007 we retrospectively analysed 47 patients with histologically proven pulmonary metastases from breast cancer. The mean age of the 47 female patients was 56.2 years, the median disease-free interval (DFI) was 3.66 (0-25.8) years and the median follow-up was 20.6 months (3.2-110). RESULTS: The grading of the metastases was higher than the primary tumour in 12 of 45 (26.7%) and lower in 6 of 45 (13.3%) patients. R0, R1 and R2 resections were achieved in 27, 6 and 14 cases. The oestrogen receptor status of the metastases differed from the primary tumour in 11 out of 39 (28.2%) tested cases. Her2-neu receptor status differed in 4 out of 16 tested patients. The histological reports described a tumour spread around the metastasis in lymph or blood vessels in at least one resection specimen in 25 out of 47 (53.2%) patients. The rate of major complications was 5.8%. The overall survival from the first pulmonary metastasectomy was 32 months with a 5-year survival of 36%. The main prognostic factor was the oestrogen receptor status with a 5-year survival for receptor positive patients of 76% and 12.1% for receptor negative ones (p=0.002). A similar survival difference was found for the status of Her2-neu receptor (p=0.037). No prognostic influence could be demonstrated for age, number of metastases, initial tumour stage, complete versus incomplete resection, lymphatic spread, lymph node or parietal pleural involvement. CONCLUSION: The gain in life expectancy in breast cancer patients with pulmonary metastases is based on chemotherapy and antihormone treatment. Tissue of the lung metastasis is needed to adjust medical therapy to oestrogen and Her2-neu expression and to reliably rule out primary lung cancer. In case of proved pulmonary metastases, the level of evidence for a curative approach is low but some patients might benefit.

Long-term survival after repeated resection of pulmonary metastases from colorectal cancer.

BACKGROUND: The purpose of this study was to evaluate the outcome of patients undergoing repeated resection of pulmonary metastases from colorectal cancer and specify factors promising long-term survival. METHODS: From January 1993 to December 2003, 175 patients were diagnosed and resected for pulmonary metastases of colorectal cancer. Follow-up information was collected for 169 patients, and 33 (19.5%) had had recurrent metastasectomies up to three times. Their follow-up information was updated in August 2006. The first repeated resection was performed for up to six bilateral metastases, the second and third metastasectomies were each unilateral and for a single metastasis only. Lymph node involvement was present in 5 patients who underwent repeat resections. RESULTS: The overall (n = 169) median survival was 47.2 months after the first metastasectomy. The 33 patients with repeated resections had a median survival of 72.6 months, with survival of 53.8% at 5 years and 20.6% at 10 years. After reoperation, age, sex, primary tumor stage, preoperative carcinoembryonic antigen, disease-free interval, prior resection of liver metastases, and lymph node involvement were not found to be of prognostic importance. The only factor that significantly influenced survival was the number of metastases (hazard risk, 1.299). Perioperative mortality even for repeated resections was 0%. CONCLUSIONS: Repeated resection of pulmonary metastases secondary to colorectal cancer is safe and can provide long-term survival for highly selected patients.

Correlation of PET/CT findings and histopathology after neoadjuvant therapy in non-small cell lung cancer.

OBJECTIVES: Prediction of histopathological response with PET/CT scans after neoadjuvant chemoradiotherapy is limited by confounding factors which have been evaluated in this analysis. METHODS: (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT findings [standard uptake value (SUV), residual tumor volume] were correlated with histopathological parameters of the resection specimens (tumor cell density, necrosis, scar, macrophage infiltration) in patients with locally advanced non-small cell lung cancer (stage IIIA/IIIB) after neoadjuvant induction chemotherapy (platinum-based doublet) and concurrent chemoradiotherapy (cisplatin/vinorelbine/45 Gy). RESULTS: Sixty patients [40 male/20 female, median age 56 years (34-78)] completed induction therapy, 46 patients (stage IIIA/IIIB: 16/30; squamous cell carcinoma 41%, adenocarcinoma 48%, large cell carcinoma 11%) were resected. Pathologic complete response of the primary tumor was observed in 19 patients (41%) with a broad range of SUV(mean) (0.4-9.8, mean 3.0) after neoadjuvant therapy. A high rate of histopathological complete remissions (44%) was observed in tumors with a postinduction SUV >2.5 and volumes larger than the median (7.9 cm(3)) before resection. SUV(mean) was positively correlated with the macrophage score (r = 0.39, p = 0.007) and tumor cell density (r = 0.32, p = 0.03). CONCLUSIONS: These observations suggest that postinduction FDG uptake should be interpreted with caution in larger residual tumor volumes, since high SUV levels may be due to macrophage infiltration and not viable tumor tissue.

Prognostic impact of lymph node involvement in pulmonary metastases from colorectal cancer.

OBJECTIVE: The purpose of this study was to identify the prognostic impact of unexpected lymph node metastases in patients undergoing resection of pulmonary metastases from colorectal cancer and specify the influence of pulmonary and mediastinal nodal involvement according to the modified Narukes lymph node mapping [Mountain CF, Dresler CM. Regional lymph node classification for lung cancer. Chest 1997;111(6):1718-23.]. METHODS: From January 1993 to December 2003, 175 patients were diagnosed and resected for pulmonary metastases of colorectal cancer. Follow up informations were collected for 169 patients and an analysis of prognostic factors was performed. Ninety-six men (56.8%) and 73 women (43.2%) with a median age of 62 (range 34-81) were identified, 28 (16.7%) patients were found to have lymph node metastases, five of them were identified during a recurrent procedure. Probability of survival was calculated according to the method of Kaplan-Meier. The prognostic influence of lymph node metastases on survival was analyzed with the log-rank test. RESULTS: Median survival was 47.2 months after first metastasectomy. Ten patients with intrapulmonary nodal involvement had a median survival of 86 months whereas 12 patients with hilar and six patients with mediastinal lymph node metastases had a median survival of 24.5 and 34.7 months. The survival difference between pulmonary and hilar/mediastinal metastases was statistically significant (p=0.008/p=0.07). Five year survival with pulmonary, hilar, and mediastinal metastases was 78.5, 0, and 0%, respectively. Perioperative mortality was 0%. CONCLUSIONS: Resection of pulmonary metastases secondary to colorectal cancer is safe and indicated in highly selected patients. Because tumor involvement of lymph nodes has a strong impact on survival; depending on their location, at least a lymph node sampling should always be performed. Adjuvant chemotherapy in case of proven lymph node metastases might be a good option to improve prognosis.