Daniela Brambilla

A 10-Year Single-Center Experience on 708 Lung Metastasectomies: The Evidence of the “International Registry of Lung Metastases”

Introduction: The International Registry of Lung Metastases defined a new staging system based on identified prognostic factors for long-term survival after metastasectomy. The aim of our study was to confirm the validity of the International Registry of Lung Metastases classification system in patients who underwent curative lung metastasectomy in a single center. Methods: We retrospectively reviewed 575 patients who underwent 708 lung metastasectomies from January 1998 to October 2008. Complete curative pulmonary resections were performed in 490 cases (85%). Three hundred seventy-two patients developed lung metastases from epithelial tumors, 80 from sarcomas, 27 from melanomas, and 11 from germ cell tumors. The mean disease-free interval (DFI) was 46.6 months. Open surgical resection was performed in 479 patients. One hundred eighty-five patients had a single-lung metastasis. Lymph node dissection was performed in 353 cases. Results: After a mean follow-up of 34 months, 247 patients (43%) had died. Multivariate analysis disclosed that completeness of resection (p < 0.0001), patients with germ cell tumors (p = 0.04), and DFI ≥36 months (p = 0.01) were also associated with a better prognosis. The actuarial survival after complete metastasectomy was 74% at 2 years and 46% at 5 years. Conclusions: We confirmed completeness of surgery, histology, and DFI ≥36 months as independent prognostic factors. Number of metastases, presence of lymph node metastases, surgical approach, and number of metastasectomies did not statistically influence long-term survival.

Screening-Detected Lung Cancers: Is Systematic Nodal Dissection Always Essential?

Background: To address whether systematic lymph node dissection is always necessary in early lung cancer, we identified factors predicting nodal involvement in a screening series and applied them to nonscreening-detected cancers. Methods: In the 97 patients with clinical T1–2N0M0 lung cancer (<3 cm), enrolled in the Continuous Observation of Smoking Subjects computed tomography (CT) screening study, who underwent curative resection with radical mediastinal lymph node dissection, we examined factors associated with hilar extrapulmonary and mediastinal nodal involvement. Nodule size plus positive/negative positron emission tomography (PET)-CT (usually as maximum standard uptake value [maxSUV]) were subsequently evaluated retrospectively for their ability to predict nodal involvement in 193 consecutive patients with nonscreening-detected clinical stage I lung cancer. Results: Among Continuous Observation of Smoking Subjects patients, 91 (94%) were pN0, and six (6.2%) were pN+. All patients with maxSUV <2.0 (p = 0.08) or pathological nodule ≤10 mm (p = 0.027) were pN0 (62 cases). Nodal metastases occurred in 6 cases among the 29 (17%) patients with lung nodule >10 mm and maxSUV ≥2.0 (p = 0.002 versus the other 62 cases). In the nonscreening series, 42 of 43 cases with negative PET-CT (usually maxSUV <2.0) or nodule ≤10 mm were pN0; 33 of 149 (22%) cases with positive PET-CT (usually maxSUV ≥ 2.0) and nodule >10 mm were pN+ (p = 0.001 versus the 43 cases). Conclusions: This limited experience suggests that in early-stage clinically N0 lung cancers with maxSUV <2.0 or pathological nodule size ≤10 mm, systematic nodal dissection can be avoided as the risk of nodal involvement is very low.

Extrapleural Pneumonectomy for Malignant Mesothelioma: An Italian Multicenter Retrospective Study

BACKGROUND This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. METHODS We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). RESULTS In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). CONCLUSIONS The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.

Lymph node involvement in T1 non-small-cell lung cancer: could glucose uptake and maximal diameter be predictive criteria?

OBJECTIVE The introduction of modern staging systems such as computed tomography (CT) and positron emission tomography/CT (PET/CT) with fluorodeoxyglucose ([(18)F]FDG) has increased the detection of small peripheral lung cancers at an early stage. We analyzed the behavior of pathological T1 non-small-cell lung cancer (NSCLC) to identify criteria predictive of nodal involvement, and the role of cancer size in lymph node metastases. METHODS We retrospectively analyzed 219 patients with pathological T1 NSCLC. All patients were staged by high-resolution CT and PET as stage I, and underwent anatomical resection and radical lymphadenectomy. Our data were collected based on pathological nodule size (0-10 mm; 11-20 mm; and 21-30 mm); morphological features of lung nodule and FDG uptake of the tumor measured by standardized uptake value (SUV). RESULTS A total of 190 patients (87%) were pN0, 14 (6%) pN1, and 15 (7%) pN2. No nodal involvement was observed in any of the 62 patients with nodule size less than 10 mm, in 20 out of 120 patients (17%) with nodule size 11-20 mm, and in nine out of 37 tumors (28%) 21-30 mm in size (p=0.0007). All 55 patients with nodule SUV<2.0 and all 26 non-solid lesions were pN0 (respectively, p=0.0001 and p=0.03). All nodal metastases occurred among the group of 132 patients with size larger than 10 mm and SUV higher than 2.0 with a 22% rate of nodal involvement of (29 patients) (p<0.0001). CONCLUSIONS The low probability of lymph node involvement in NSCLC <1 cm or showing glucose uptake <2 suggests lymphadenectomy could be avoided. A randomized trial should be performed to validate our data.

Impaired quality of life after pneumonectomy: Who is at risk?

OBJECTIVE After pneumonectomy, quality of life may be impaired in a proportion of patients because of the presence of symptoms causing severe limitations in daily activities. This is a prospective study on patients who have undergone pneumonectomy for cancer, assessing quality of life modifications 6 months after surgery. METHODS Beginning in August 2006, candidates for pneumonectomy had their quality of life assessed by the European Organization for Research and Treatment of Cancer questionnaire (QLQ-C30 + LC13) preoperatively and at 1, 3, and 6 months after surgery. Poor quality of life at 6 months was defined as global health values 10% or more below baseline values. The impact of several clinical variables was tested to discover predictors of poor postoperative quality of life. RESULTS Forty-one of the 50 patients enrolled in the study had a complete quality of life follow-up by January 2008, representing the population of the study. Six months after pneumonectomy, global health showed a minimal impairment in the whole population (baseline 60.4 + or - 26.5, at 6 months 56.3 + or - 24.2, P = .15). Ten patients (24.4%) were identified as having poor quality of life at 6 months. Age of 70 years or more was identified as a significant risk factor for poor 6-month quality of life using multivariate analysis (odds ratio, 1.13; 95% confidence interval, 1-1.26). The baseline global health score was the strongest predictor of postoperative global health quality of life (odds ratio, 0.16; 95% confidence interval, 0.02-0.46; P = .0086). CONCLUSION The overall quality of life after pneumonectomy was impaired in 25% of surviving patients at 6 months after surgery; thus, this aspect of recovery should be routinely discussed with patients before pneumonectomy. Patients aged 70 years or more and those with low preoperative quality of life seem to be at risk for unsatisfactory quality of life after surgery.

Bilobectomy for lung cancer: analysis of indications, postoperative results, and long-term outcomes.

BACKGROUND Bilobectomy for lung cancer is considered a high-risk procedure for the increased postoperative complication rate and the negative impact on survival. We analyzed the safety and the oncologic results of this procedure. METHODS We retrospectively reviewed patients who underwent bilobectomy for lung cancer between October 1998 and August 2009. Age, gender, bilobectomy type and indication, complications, pathology, stage, and survival were analyzed. RESULTS Bilobectomy was performed on 146 patients (101 men; mean age, 62 years). There were 77 upper-middle and 69 middle-lower bilobectomies. Indications were tumor extending across the fissure in 27 (18.5%) patients, endobronchial tumor in 39 (26.7%), extrinsic tumor or nodal invasion of bronchus intermedius in 66 (45.2%), and vascular invasion in 14 (9.6%). An extended resection was performed in 24 patients (16.4%). Induction therapy was performed in 43 patients (29.4%). Thirty-day mortality was 1.4% (n=2). Overall morbidity was 47.2%. Mean chest tube persistence was 7 days (range, 6 to 46 days). Overall 5-year survival was 58%. Significance differences in survival were observed among different stages (stage I, 70%; stage II, 55%; stage III, 40%; p=0.0003) and the N status (N0, 69%; N1, 56%; N2, 40%; p=0.0005). Extended procedure (p=0.0003) and superior bilobectomy (p=0.0008) adversely influenced survival. Multivariate analysis demonstrated that an extended resection (p=0.01), an advanced N disease (p=0.02), and an upper-mild lobectomy (p=0.02) adversely affected prognosis. CONCLUSIONS Bilobectomy is associated with a low mortality and an increased morbidity. Survival relates to disease stage and N factor. Optimal prognosis is obtained in patients with lower-middle lobectomy without extension of the resection.

The Role of Extended Pulmonary Metastasectomy

Background: The role of extended pulmonary resection for lung metastases is still unclear, and little information is available in the literature. This study was performed to analyze the outcomes and prognostic factors of patients who underwent extended resections for pulmonary metastases. Methods: From 1998 to 2013, 1027 patients underwent lung metastasectomy procedures. Twenty-nine patients had extended pulmonary resections: three resections of the chest wall, one azygos, one diaphragm, four vascular resections/reconstructions, six sleeve resections, and 14 pneumonectomies. Results: Extended resection was performed for metastatic disease mainly from epithelial (62.1%) and sarcomatous (20.7%) tumors. Complete resection was obtained in all patients. Thirty-day operative morbidity and mortality rates were 38% (11 of 29) and 0%, respectively. Only one patient had a major complication due to a bronchopleural fistula. Mean hospital stay was 6.3 days. After a median follow-up of 27 months, 16 patients (55%) had died. At univariate analysis, survival was determined by primary tumor histology (p = 0.03); the number of metastases, nodal status, disease-free interval or extension of surgery (pneumonectomy vs. lobar resection) were not related to survival probably due to the low number of patients. Overall survival after a complete extended metastasectomy was 66% at 2 years, 42% at 5 years, and 36% at 10 years. Conclusions: Extended resections performed during pulmonary metastasectomies are associated with low mortality and morbidity rates and an acceptable long-term survival when performed in selected patients susceptible to complete resection.

An aggressive subtype of stage I lung adenocarcinoma with molecular and prognostic characteristics typical of advanced lung cancers

Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N = 351) identified as high-risk by the 10-gene signature displayed a 4-fold increased risk of death [HR = 3.98; 95% confidence interval (CI), 1.73–9.14], with a 3-year overall survival of 84.2% (95% CI, 78.7–89.7) compared with 95.6% (92.4–98.8) in low-risk patients. The analysis of TCGA cohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment. Clin Cancer Res; 23(1); 62–72. ©2016 AACR.

Surgical Treatment of Superior Sulcus Tumors: A 15-Year Single-center Experience

This paper reports on the characteristics, treatment modalities, and outcomes of patients with superior sulcus tumors who underwent surgery over a period of 15 years in 1 institution. Clinical records of 94 consecutive patients operated on by the same surgical team for non-small cell lung cancer between July 1998 and December 2013 were retrospectively reviewed. All patients received lung and chest wall en bloc resection. Forty-eight (51%) received induction treatments. Surgery was an anterior approach in 46 patients (48.9%), Paulson incision in 35 (37.2%), and a combined approach in 13 (13.8%). Lung resections were 78 lobectomies (83%), 3 were pneumonectomies (3.2%), 6 were bronchoplastic reconstructions (6.4%), and 7 were wedge resections (7.4%). Nodal dissection was systematic in 96% of patients. The median number of resected ribs was 2 (1-5), chest wall residual defect was reconstructed in 42 patients (44.7%), and 21 patients had an associated vascular resection (22.3%). Resection was radical in 85 patients (90.4%). Overall 90-day mortality was 9.6%. After a median follow-up of 1.9 years, 5-year and 10-year overall survival rates were 35% and 23%, respectively. A lower 5-year survival was observed in patients with nodal disease (48% in N0 vs 18% in N+; P < 0.0001), incomplete resection (21% for incomplete vs 37% for complete resection; P = 0.15), and anteriorly located tumor (anterior vs posterior: 26% vs 50%; P = 0.05). Pancoast tumor is a severe condition, but long-term survival may be achieved in selected cases. Nodal involvement, completeness of resection, and vascular invasion are the most important prognostic factors, and induction treatment may play a role.

Salvage Surgery After Definitive Chemoradiotherapy for Non–small Cell Lung Cancer

Following definitive chemoradiation therapy, 24%-35% of patients with locally advanced non-small cell lung cancer have recurrence. We aimed to evaluate the feasibility of salvage surgery after definitive chemoradiotherapy and perioperative morbidity and mortality rates to determine long-term survival. From June 2003 to June 2013, 35 patients were eligible for lung cancer resection owing to relapse after definitive chemoradiation therapy. All patients received cisplatin-based chemotherapy and definitive radiotherapy (mean Gy: 58) with curative intent and all underwent total body computed tomography scan and 18-fluoro-deoxyglucose positron emission tomography scan after the end of medical treatment and before surgery. Cyto-histologic confirmation was attempted in 20 (57%) patients. Six patients had exploratory thoracotomies. Twenty-nine patients underwent lung cancer resection: 11 lobectomies, 1 bilobectomy, and 17 pneumonectomies (7 right, 10 left). Complete resection was obtained in 27 of 35 (77%) patients. Thirteen (45%) patients underwent extended resection: intrapericardial pneumonectomy in 5 patients, vascular or bronchial sleeve resection in 2, atrial resection in 1, tracheal sleeve in 1, superior vena cava resection and reconstruction in 2 (1 with tracheal-sleeve resection), and chest wall resection in 2. Median time from chemoradiation therapy to resection was 7 months (range: 1-39). Viable tumor was found in 26 of 29 (89.6%) patients. Major complications occurred in 9 patients (25.7%). There were 2 (5.7%) perioperative deaths within 30 days. With a median follow-up of 13 months, postoperative 2- and 3-year survival rates after complete resection were 46% and 37%, respectively. Salvage lung resection after definitive chemoradiation therapy is feasible, with acceptable postoperative survival and complication rates.