Francesco Carpagnano

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial

BACKGROUND Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centres policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Phase I/II Study of Gemcitabine Plus Vinorelbine as First-Line Chemotherapy of Non–Small-Cell Lung Cancer

PURPOSE To determine the maximum-tolerated dose of gemcitabine when combined with a fixed dose of vinorelbine in the treatment of non-small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the activity of this combination. PATIENTS AND METHODS Sixty-eight patients with stage IIIB/IV NSCLC were treated with vinorelbine at fixed dose of 30 mg/m(2) intravenously and gemcitabine at increasing dose levels from 800 to 1,500 mg/m(2) intravenously on days 1 and 8 every 3 weeks. RESULTS In phase I, dose-limiting toxicity occurred at the dosage of 1,500 mg/m(2) gemcitabine, with three of five patients developing grade 4 thrombocytopenia. In phase II, with gemcitabine at 1,200 mg/m(2), 19 (36%) of 52 assessable patients responded. Objective response was observed in 11 (39%) of 28 patients with stage IIIB disease and in eight (33%) of 24 patients with stage IV. The median time to progression was 29 weeks (range, 2 to 41 weeks; 35 weeks and 16 weeks for stages IIIB and IV, respectively), and median survival was 54 weeks (range, 2 to 84+ weeks; 63 weeks and 42 weeks for stages IIIB and IV, respectively). One-year survival was 64% for patients with stage IIIB disease and 29% for those with stage IV. Clinical benefit response was observed in 29 (59%) of 49 assessable patients. Grade 4 leukopenia and thrombocytopenia were uncommon (6% and 8% of cases, respectively); however, grade 3/4 leukothrombocytopenia occurred more frequently in patients aged more than 70 years (52% and 24%, respectively). CONCLUSION The combination of vinorelbine and gemcitabine is effective and tolerable in the treatment of NSCLC, thus deserving randomized trials with cisplatin combination regimens.

IL-2, TNF-α, and Leptin: Local Versus Systemic Concentrations in NSCLC Patients

One recent line of cancer research shows increasing interest for biological factor such as IL-2, TNF-α, and leptin, which have been found to participate in the development and progression of non-small cell lung cancer (NSCLC). The aim of this study was to measure IL-2, TNF-α, and leptin concentrations in the airways and in the systemic circle of patients with NSCLC, investigating the role of these factors in the lung tumors. We enrolled 32 patients (17 men, 71 ± 7 years) with a histological diagnosis of NSCLC and 20 healthy ex-smoker controls, negative for computed tomography of the chest (14 men, 69 ± 8 years). IL-2, TNF-α, and leptin levels were measured in the serum, the urine, the bronchoalveolar lavage, the induced sputum, and exhaled breath condensate (EBC) of patients enrolled by means of a specific enzyme immunoassay kit. Higher concentrations of IL-2, TNF-α and leptin were found in NSCLC patients than in controls (p < 0.0001). A statistically significant increase of IL-2, TNF-α, and leptin concentrations was observed in patients from stage I to stage III of NSCLC. These findings suggest that IL-2, TNF-α, and the leptin play an important role in the cancerogenesis of NSCLC. Their measure in the EBC could be proposed as noninvasive markers for an early detection of NSCLC and in the follow-up of this tumor.

Cisplatin, Gemcitabine, and Paclitaxel in Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: A Phase I-II Study

PURPOSE Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non-small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m(2)) and gemcitabine (1,000 mg/m(2)) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m(2) in pretreated patients, whereas it continued to 150 mg/m(2) in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m(2) was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patients disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

Cigarette smoke and increased COX-2 and survivin levels in exhaled breath condensate of lung cancer patients: How hot is the link?

UNLABELLED One of the most current intriguing hypotheses on lung cancerogenesis envisages a role for inflammation as a possible trigger of both epithelial-mesenchymal transition and cancer development. Cigarette smoke has been suggested to be the main factor underlying the inflammation of the airways described in lung cancer patients. Cycloxygenase and survivin, a COX-2 dependent factor of apoptosis resistance, seem to play a key role in this regard. PURPOSE The aim of this study was to study COX-2 and survivin in the airways of lung cancer patients and in those of a group of smokers in a view to increasing our understanding of the link between smoking, airway inflammation and lung cancer. PATIENTS AND METHODS 70 NSCLC patients (28 smokers, 26 ex-smokers and 16 non-smokers) and 30 healthy subjects (20 smokers and 10 non-smokers) were enrolled in the study. Both COX-2 and survivin concentrations were measured in the exhaled breath condensates of all the subjects under study using EIA kits. RESULTS Higher levels of exhaled survivin and COX-2 were found in NSCLC patients compared to healthy smokers and non-smokers. These levels were observed to be significantly elevated in smokers (patients with lung cancer and healthy) and ex-smokers compared to non-smokers and exhibited a positive correlation with the number of cigarettes smoked expressed as pack/year. A correlation was also found between exhaled COX-2 and survivin and the progression of cancer. CONCLUSIONS We support the hypothesis that cigarette smoke be strongly connected to the inflammation of the airways observed in lung cancer patients. On the basis of the results obtained the use of exhaled breath condensate COX-2 and survivin levels could be suggested as two potential markers within an early non-invasive screening of populations of smokers at risk of lung cancer.

Cisplatin-Based Three Drugs Combination (NIP) as Induction and Adjuvant Treatment in Locally Advanced Non-small Cell Lung Cancer: Final Results

Introduction: This phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival. Methods: After three cycles of vinorelbine (N) 25 mg/m2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation. Results: Median tumor diameter was 5.5 cm (1.2–10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35–75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8–65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively. Conclusions: NIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy.

The triplet vinorelbine (NVB), ifosfamide (IFO) and cisplatin (CDDP) (NIP) used as post-operative treatment versus surgery alone in patients having received primary chemotherapy (CT) for locally advanced (LA) non small cell lung cancer (NSCLC)

7172 Background: Neo-adjuvant chemotherapy can allow resection in patients with locally advanced NSCLC. From January 1999 to December 2002, 156 patients have been enrolled in a prospective study aimed to evaluate downstaging after induction CT by NIP. METHODS Patients with IIIA; IIB (only T3N0) and IIIB (only T4N0) were eligible to enter into the study. All patients with clinical N2 had a mediastinoscopy plus biopsy or Fine Needle Aspiration (FNA) to certify the lymph node involvement. After receiving 3 cycles of NIP (NVB 25 mg/m2 d1, 5; IFO 3 g/m2 d1; MESNA 3g/m2 d1 and CDDP 80mg/m2 d1 every 3 weeks) all patients without progression or who were not withdrawn for any reason were eligible for surgery. No RT was allowed in both arms. RESULTS One hundred and seven patients (69%) were operated out of 155 patients treated by neoadjuvant chemotherapy. Lobectomy was possible in 54 patients (50%) and pneumonectomy was performed in 42 patients (39%). Atypical segmentectomy was performed in 1 patient (1%), explorative surgery in 6 patients (6%). Data are missing for 4 patients (4%). Complete resection rate (R0) was of 74% (79/107patients). Post-surgical downstaging was observed in 28% of the N2 patients who were completely resected. The median time to surgery was 32 days (range 21-67 days) from the last NVB administration. Peri-operative toxicity included intestinal obstruction, bronchial infection and empyema (1 patient each) and 3 patients died within 30 days after surgery (2 patients with left pneumonectomy and one with right pneumonectomy). With a median follow-up of 33 months, 16 patients (15%) with local relapse and 4 patients (4%) with supraclavicular lymph node relapse have been reported. CONCLUSION The triplet combination of NIP allowed surgery in LA NSCLC without increasing either morbidity or mortality on this population. Moreover, no delay was reported between end of CT and surgery. [Table: see text].