Luca Luzzi

Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy

OBJECTIVE Chemotherapy of stage IIIA non-small cell lung cancer (NSCLC) using second generation, cisplatin-based combinations has shown to improve the results; however, the distant relapses remain the major problem. Encouraging results in the treatment of stage IV NSCLC with newer agents (gemcitabine, placlitaxel) has encouraged us to use them in stage III. The aim of this study was to assess feasibility and efficacy of induction chemotherapy with cisplatin and gemcitabine followed by surgery for patients with stage IIIA (N2) NSCLC. METHODS From February 1996 to December 1999, 36 consecutive patients with mediastinoscopically staged N2 NSCLC received three cycles of cisplatin (80 mg/m(2), day 2) and gemcitabine (1200 mg/m(2), day 1+8) followed by surgery in responding patients. Patients with stable disease or even local progression received radiotherapy. All patients had clinical N2 disease (mediastinal lymph nodes metastasis) observed on CT scan. RESULTS No major complications of the chemotherapy occurred. Twenty-five patients (70%) had a clinical partial response and were surgically explored, with 18 complete resections (70%). There were no in-hospital deaths, although four (16%) major complications: bronchopleural fistula (two), respiratory insufficiency (one), oesophagospleural fistula (one). In the total group of 36 patients, 3-year survival was 20%. So far, no patient without surgery has survived longer then 27 months; median survival was 8 months. In the group of the 25 patients who underwent surgery 3-year survival was 30%, with a median survival of 21 months. The difference is significant (P=0.0027). In the surgical group, the survival of patients with down staged disease (56%) was greater than that of patients with persistent N2 disease (44%) after chemotherapy (3-year survival of 59 and 0%, respectively; P=0.0013). CONCLUSION induction chemotherapy with cisplatin and gemcitabine resulted in major tumour regression in a large percentage of patients with clinical N2 disease. In responding patients both the complete respectability rate and survival were higher when compared to historical controls. Survival was significantly better in patients down-staged to a mediastinal negative disease.

Surgical treatment of synchronous multiple lung cancer located in a different lobe or lung: high survival in node-negative subgroup

BACKGROUND The International Association for Study of Lung Cancer Staging Committee proposes for the next revision of TNM (tumour, nodes, metastases) classification that additional nodules in a different lobe of the ipsilateral lung moves from an M1 designation to T4, while additional nodule(s) in the contralateral lung should be classified as M1a, because of poorer survival. We analysed the survival after surgery of patients presenting with synchronous lung cancers located in a different lobe or lung. METHODS A database of 1551 patients operated on for non-small-cell lung cancer (NSCLC) between 1990 and 2007 was evaluated for unilateral (other lobe) (n=15) and bilateral (n=28) synchronous multiple lung cancers. The relationships among the location of tumours, histology, date of surgery (before and after 2000), lymph node metastasis, type of surgery, adjuvant therapy and survival were analysed. RESULTS The 5-year survival for all synchronous multiple lung cancers (n=43) was 34%, with a median survival of 32 months. Postoperative mortality was 7%. On univariate analysis, only lymph node metastasis and surgery before the year 2000 affected the overall survival adversely, and both prognostic factors maintained a statistical significance on multivariate analysis. The 5-year survivals were 57% and 0% for patients without (n=25) and with (n=18) lymph node metastasis, respectively (p=0.004), and were 43% and 18% for patients operated upon after (n=27) and before (n=16) the year 2000, respectively (p=0.01), perhaps reflecting a better selection process related to the extensive use of positron emission tomography (PET) scanning. The 5-year survival was not different between bilateral (43%) and unilateral (27%) synchronous lung cancers (p=n.s.). CONCLUSIONS Our data support complete surgical resection of synchronous multiple lung cancers in patients with node-negative NSCLC. Even patients with bilateral lung cancer should not be treated as metastatic disease. Provided there is no evidence of node and distant metastasis, after an extensive preoperative work-up, including PET scanning and mediastinoscopy, bilateral surgical resection should be performed in fit patients.

Iterative surgical resections for local recurrent and second primary bronchogenic carcinoma

OBJECTIVE To report our experience with repeated pulmonary resection in patients with local recurrent and second primary bronchogenic carcinoma, to assess operative mortality and late outcome. METHODS The medical records of all patients who underwent a second lung resection for local recurrent and second primary bronchogenic carcinoma from 1978 through 1998 were reviewed. RESULTS There were 27 patients. They constituted 2.5% of 1059 patients who had undergone lung resection for bronchogenic carcinoma in the same period. Twelve patients (1.1%) (group 1) had a local recurrence that developed at a median interval of 24 months (range 4-83). The first pulmonary resection was lobectomy in ten patients and segmentectomy in two. The second operation consisted of completion pneumonectomy in ten cases, completion lobectomy in one and wedge resection of the right lower lobe after a right upper lobectomy in one. The other 15 patients (1.4%) (group 2) had a new primary lung cancer that developed at a median interval of 45 months (range 21-188). The first pulmonary resection was lobectomy in 12 patients, bilobectomy in one and pneumonectomy in two. The second pulmonary resection was controlateral lobectomy in seven patients, controlateral sleeve lobectomy in two, controlateral pneumonectomy in 1, controlateral wedge resection in four and completion pneumonectomy in one. Overall hospital mortality was 7.4%, including one intraoperative and one postoperative death in group 1 and 2, respectively. Five-year survival after the second operation was 15.5 and 43% with a median survival of 26 and 49 months in groups 1 and 2, respectively (P=ns). CONCLUSIONS Long-term results justify complete work-up of patients with local recurrent and second primary bronchogenic carcinoma. Treatment should be surgical, if there is no evidence of distant metastasis and the patients are in good health. Early detection of second lesions is possible with an aggressive follow-up conducted maximally at 4 months intervals for the first 2 years and 6 months intervals thereafter throughout life.

Impact of interstitial lung disease on short-term and long-term survival of patients undergoing surgery for non-small-cell lung cancer: analysis of risk factors

OBJECTIVES The study aimed to determine the impact of interstitial lung disease (ILD) on postoperative morbidity, mortality and long-term survival of patients with non-small-cell lung cancer (NSCLC) undergoing pulmonary resection. METHODS We performed a retrospective chart review of 775 consecutive patients who had undergone lung resection for NSCLC between 2000 and 2009. ILD, defined by medical history, physical examination and abnormalities compatible with bilateral lung fibrosis on high-resolution computed tomography, was diagnosed in 37 (4.8%) patients (ILD group). The remaining 738 patients were classified as non-ILD (control group). We also attempted to identify the predictive factors for early and late survival in patients with ILD following pulmonary resection. RESULTS There was no significant difference between the two groups in terms of age (69 vs 66 years), sex (79 vs 72% male), smoking history (93 vs 90% smokers), forced expiratory volume in 1 s % of predicted (89 vs 84%), predicted values of forced vital capacity (FVC)% (92 vs 94%), types of surgical resection and histology. Patients with ILD had a higher incidence of postoperative acute respiratory distress syndrome (ARDS; 13 vs 1.8%, P < 0.01) and higher postoperative mortality (8 vs 1.4%, P < 0.01). The overall 5-year survival rate was 52% in the ILD and 65% in the non-ILD patients, respectively (P = 0.019). In the ILD group, at the median follow-up of 26 months (range 4-119), 19 (51%) patients were still alive and 18 (49%) had died in the ILD group. The major cause of late death was respiratory failure due to the progression of fibrosis (n = 7, 39%). In the ILD group, lower preoperative FVC% (mean 77 vs 93%, P < 0.01) and lower diffusing capacity of the lung for carbon monoxide (DLCO%; 47 vs 62%; P < 0.01) were significantly associated with postoperative ARDS. CONCLUSIONS In conclusion, major lung resection in patients with NSCLC and ILD is associated with an increased postoperative morbidity and mortality. Patients with a low preoperative FVC% should be carefully assessed prior to undergoing surgery, particularly in the presence of a lower DLCO%. Long-term survival is significantly lower when compared with patients without ILD, but still achievable in a substantial subgroup. Thus, surgery can be offered to properly selected patients with lung cancer and ILD, keeping in mind the risk of respiratory failure during the evaluation of such patients.

Role of fluorine-flurodeoxyglucose positron emission tomography/computed tomography in preoperative assessment of anterior mediastinal masses

OBJECTIVE The purpose of the study was to explore the usefulness of fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET-CT) in the preoperative assessment of isolated anterior mediastinal lesions, especially in the planning of operative strategy (biopsy or upfront resection). METHODS During the last 36 months, 19 consecutive patients (10 males, mean age 54+/-16 years) underwent PET-CT in the preoperative work-up of isolated anterior mediastinal diseases. Maximal transverse diameter at CT and the postoperative histology and Masaoka staging for thymomas were collected and related to the maximum standardised uptake values (SUVs). Thymomas were divided into low-risk thymoma (LRT=A, AB and B1) and high-risk thymoma (HRT=B2, B3 and C). RESULTS There were 13 thymomas (six LRT and seven HRT), three lymphomas and three other primitive thymic tumours (one paraganglioma, two non-seminomatous germ cell tumours). In LRT, the mean SUV was 3.3+/-0.5 resulting significantly lower than HRT, 13.5+/-7 (p=0.009). The SUV in LRT was also significantly lower with respect to lymphoma, 12.4+/-4 (p=0.001), and the other primitive anterior mediastinal tumours, 8+/-0.8 (p=0.001). Between thymomas we found a significant correlation between Masaoka stage and SUV, r=0.718, p=0.006. No correlation was found between transverse diameters and SUV, r=0.141, p=0.6. CONCLUSIONS In our experience, low SUV (<5) is associated with LRT and minimal invasive thymoma (Masaoka stages I-II) and, therefore, susceptible to upfront surgery. For lesions with an infiltrative aspect on CT scan associated with a higher SUV (>5), an open biopsy is mandatory to exclude mediastinal lymphomas or, in case of HRT, to address a neoadjuvant treatment.

Phase II trial of bevacizumab and dose/dense chemotherapy with cisplatin and metronomic daily oral etoposide in advanced non-small-cell-lung cancer patients

Bevacizumab, is a humanized monoclonal antibody to vasculo-endothelial-growth-factor, with anticancer activity in non-small-cell-lung cancer (NSCLC) patients. Our previous results from a dose/finding phase I trial in NSCLC patients, demonstrated the anti-angiogenic effects and toxicity of a newest bevacizumab-based combination with fractioned cisplatin and daily oral etoposide. We designed a phase II trial to evaluate in advanced NSCLC patients the antitumor activity and the safety of this novel regimen. In particular, 45 patients (36 males and 9 females), with a mean age of 54 years, an ECOG ≤ 2, stage IIIB/IV and NSCLC (28 adenocarcinomas, 11 squamous-cell carcinomas, 2 large-cell carcinomas, 4 undifferentiated carcinomas), were enrolled. They received cisplatin (30 mg/sqm, days 1-3), oral etoposide (50 mg, days 1-15) and bevacizumab (5 mg/kg, day 3) every three weeks (mPEBev regimen). Patients who achieved an objective response or stable disease received maintenance treatment with bevacizumab in combination with erlotinib until progression. Grade I-II hematological, mucosal toxicity and alopecia were the most common adverse events. The occurrence of infections (17%), thromboembolic events (4.4%) and severe mood depression (6.7%) was also recorded. A partial response was achieved in 31 (68.8%) patients, disease remained stable in 8 (17.8%), and disease progressed in 6 (13.3%) with a progression-free-survival of 9.53 months (95%CI, 7.7-11.46). Our bio-chemotherapy regimen resulted very active in advanced NSCLC, however, the toxicity associated with the treatment requires strict selection of the patients to enroll in future studies.

Surgery for bronchogenic cysts: Always easy?

A few cases of major complications after surgery for bronchogenic cyst have been reported. The purpose of this study was to analyze the complicated and unusual cases among 30 consecutive patients with bronchogenic cysts treated surgically at our institution between 1975 and 2007. There were 3 cases of mediastinal bronchogenic cyst characterized by significant surgical complications or very unusual pathological findings. The operations were performed through a thoracotomy in 25 patients, and by video-assisted thoracoscopic surgery in 5. Two patients suffered iatrogenic injury of the contralateral main bronchus during excision of a mediastinal cyst; in one of them, late development of foreign body granuloma was related to migration towards the bronchial wall of cyanoacrylate used to reinforce suturing of the bronchial tear. Histological examination of one resected specimen showed a large-cell anaplastic carcinoma arising from the wall of a mediastinal bronchogenic cyst. Bronchogenic cysts should be excised before they become symptomatic or infected, which leads to more difficult surgery and complications. The small risk of developing malignancy within a bronchogenic cyst also justifies early intervention.

Long-term respiratory functional results after pneumonectomy.

INTRODUCTION The aim of this study is to evaluate the long-term respiratory outcome of patients who underwent pneumonectomy for non-small cell lung cancer (NSCLC), analysing functional tests. MATERIALS AND METHODS Twenty-seven consecutive patients who were candidates for pneumonectomy performed spirometry before and at least 24 months after surgery in the same laboratory. Diffusion of carbon monoxide and the most common dynamic and static lung volumes were evaluated in percentage of predicted and compared. RESULTS A significant inverse correlation was observed between the preoperative FEV1 (%) and FVC (%) and their postoperative loss, respectively r=-641 (p<0.0001) and r=-789 (p<0.0001). Also the correlation between the RV/TLC ratio and the FEV1 loss confirmed a better postoperative outcome in patients with major airway obstruction (p=0.02). To investigate these data, the series were divided into two groups: group A included BPCO patients with a FEV1 lower than 80%, the others were considered group B. Group B showed a significant major postoperative FEV1 (%) and FVC (%) impairment, 31% versus 12%, p=0.005, and FVC (%) loss, 37% versus 16% (p=0.02), meanwhile group A showed a significant major postoperative RV (%) reduction, 43% versus 17%, p=0.03. Despite being significantly higher preoperatively in BPCO patients, the RV% becomes similar between the two groups in the postoperative. CONCLUSIONS In our experience patients with major preoperative airway obstruction who underwent pneumonectomy had lower impairment in FEV1% at almost one year after surgery than those with normal respiratory function. The resection of a certain amount of non-functional parenchyma associated with the mediastinal shift, with an improvement of the chest cavity for the remaining lung, could give a reduction volume effect in BPCO/emphysematous patients.

Short- and long-term results of lung resection for cancer in octogenarians

To analyze short- and long-term results of surgery in octogenarians, we reviewed data of 96 consecutive patients aged 80 years or more who were operated on for non-small-cell lung carcinoma from 1990 to 2005. Risk factors for complications, perioperative mortality, and long-term survival were assessed by univariate and multivariate analysis. Major complications developed in 17 (17.7%) patients, leading to death in 9 (9.4%) of them. Resection of more than 1 lobe, cardiorespiratory comorbidity, PaO2 < 75 mm Hg, and CO diffusion capacity <60% were predictive of major complications; extended resection was also predictive of 30-day mortality. The overall 5-year survival rate was 38%, with a significant difference between stage I/II and stage III. In multivariate analysis only pathological stage was related to long-term survival. Surgery is feasible for octogenarians, and even patients in stage II can achieve remarkable survival.

Impact of lobectomy for non-small-cell lung cancer on respiratory function in octogenarian patients with mild to moderate chronic obstructive pulmonary disease

OBJECTIVE To assess the long-term impact of standard lobectomy on respiratory function in octogenarian patients with mild/moderate chronic obstructive pulmonary disease (COPD). METHODS We reviewed all octogenarians (n=38), who underwent lobectomy for stage I-II non-small-cell lung cancer (NSCLC) from 2000 to 2006. Inclusion criteria were: Tiffenau index<0.7, no adjuvant therapies, smoking cessation after surgery, spirometric data available after 12±3 months from surgery in the absence of relapsing disease. RESULTS After excluding 14 patients (three died perioperatively), 24 fulfilled the inclusion criteria. The median preoperative forced expiratory volume in 1s (FEV1) was 80% (range 56.7-100%). The mean change in FEV1 after lobectomy resulted in a loss of 11% (range -32% to +7%, p=0.004). Considering two groups on the basis of median FEV1 (group 1: FEV1≤80%, group 2: FEV1>80%), mean FEV1 loss after surgery was 7.9% in group 1 and 14.9% in group 2, respectively (p=0.17). No statistical differences were found between the two groups in changes after surgery of forced vital capacity (FVC), arterial oxygen and carbon-dioxide tension. Diffusion capacity of the lung for carbon monoxide (DLCO)% loss was significantly higher in group 2 compared with group 1 (-22.5% vs +1.5%, p=0.001). Six patients showed an improvement of postoperative FEV1: all had a preoperative FEV1 less than 60%, an upper or homogeneous pattern of emphysema, and received an upper lobectomy. In group 2, the FEV1 loss was not affected by the type of lobectomy whereas in group 1, the resection of lower lobe was associated to a major FEV1 loss (-14.5% vs +5.3%, p=0.05). CONCLUSIONS Octogenarians with lower preoperative FEV1% have a better late preservation of pulmonary function after lobectomy. Upper lobectomy seems to produce a lung-volume reduction effect, leading to an improvement in the expiratory volume in patients with higher airflow obstruction.