Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and results.

BACKGROUND: Trimodality therapy seems to be the best treatment for malignant pleural mesothelioma (MPM). A large experience served to evaluate the efficacy of surgery followed by adjuvant chemo-radiotherapy. Trimodality therapy results have led us to test induction chemotherapy followed by EPP and adjuvant radiotherapy in stages I-III of MPM. The aim of our study was to evaluate the feasibility of this protocol and to estimate survival. METHODS: From 2000 to 2003, 21 patients with MPM (14 males and 7 females, median age 59 years) were enrolled in the prospective study. Induction chemotherapy consisted of Carboplatin (AUC 5mg/mL/min on Day 1) and Gemcitabine (1000mg/m(2) on Days 1, 8, 15) for three to four cycles. EPP was performed 3-5 weeks after induction therapy, while post-operative RT was given 4-6 weeks after operation. RESULTS: Ten patients received three cycles of chemotherapy, 10 patients received four cycles and 1 patient had two cycles. Grades 3-4 haematological toxicity occurred in eight (38.1%) patients. Chemotherapy response rate was: complete 0%, partial 33.3% and stable disease 66.7%. Seventeen (80.9%) out of 21 patients underwent EPP with no intra or post-operative mortality with an overall major and minor morbidity rate at 52.4%. Median survival was 25.5 months, with an overall 1, 3 and 5-year survival rate of 71, 33 and 19%, respectively. CONCLUSIONS: In MPM, the combined modality approach using the Carboplatin/Gemcitabine combination as induction chemotherapy is feasible, with good results in terms of survival and morbidity. Our results are similar to those of other studies using a heavier modality treatment.

A multicenter, randomized, phase 3 trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in extensive small-cell lung cancer (SCLC) patients: The Small-cell-lung cancer Toxicity Adjusted Dosing (STAD-1) trial.

OBJECTIVES: Data supporting the prognostic role of chemotherapy induced haematological toxicity suggest that toxicity-adjusted-dosing (TAD) of chemotherapy might improve treatment efficacy. We tested whether TAD of the cisplatin-etoposide combination might improve the response rate, in previously untreated extensive stage disease (ED)-SCLC patients, as compared with standard fixed-dosing (FD). METHODS: Patients with ED-SCLC were randomized to receive either TAD or FD of cisplatin-etoposide as first-line treatment. Primary endpoint was the objective response rate (ORR) according to the RECIST 1.0 criteria, secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: Hundred-fifty-eight patients were randomized. Most patients were male, with ECOG-PS 1, without brain metastases and had not received radiotherapy before study entry. Response rate was 54.4 (95%CI: 43.5-64.9%) and 58.2 (95%CI: 47.2-68.5%) in the control and experimental arms, respectively (P=0.75). No significant differences were found in terms of PFS (HR 1.04; 95%CI: 0.74-1.44, P=0.84) and OS (HR1.01; 95%CI 0.71-1.42, p=0.97). Seven patients died on treatment, one in the standard arm and 6 in the experimental arm. The most frequent cause of death was neutropenia with infection and, apart in one, death was not related to dose modification. Severe toxicity was more frequent in the experimental arm (91% vs 60%). CONCLUSIONS: In our population of chemonaïve ED SCLC patients, TAD failed to improve the ORR, PFS and OS over the FD of cisplatin-etoposide as first line chemotherapy and was associated with increased toxicity.

Treatment of Unfit Patients With Advanced Non-Small-Cell Lung Cancer: Definition Criteria According an Expert Panel.

The assessment of special categories of non-small-cell lung cancer (NSCLC) patients requires a comprehensive analysis of all factors potentially influencing the daily quality of life and the relative contribution of tumor-related symptoms on the overall patient health status. While for elderly patients prospective evidence and recommendations allow clinicians to better address their patients to a shared treatment, a paucity of reliable data refers to treatment opportunities for these patients, termed frail or unfit, who are not considered eligible for chemotherapy usually administered to adult patients. This consensus was inspired by the absence of clear criteria to define the category of unfit patients in the context of advanced NSCLC in order to share all the available tools for their classification and evaluation and to support decisions for clinical practice on a daily basis. After review of the literature and panelist consensus, a series of items was identified as relevant: age, performance status, renal function, heart failure, previous cerebrovascular events, uncontrolled hypertension, neuropathy, hearing loss, symptomatic brain metastases, severe psychiatric disorders, and absence of caregiver support. On the basis of these factors, a treatment algorithm for clinical practice to categorize unfit NSCLC patient into 3 major clinical scenarios was defined: (1) unfit for cisplatin-based chemotherapy, (2) unfit for carboplatin-based chemotherapy, and (3) unfit for single-agent chemotherapy.

Results of surgical resection after induction chemoradiation for Pancoast tumours †.

OBJECTIVES: Pancoast tumour is a rare neoplasia in which the optimal therapeutic management is still controversial. The traditional treatment of Pancoast tumour (surgery, radiotherapy or a combination of both) have led to an unsatisfactory outcome due to the high rate of incomplete resection and the lack of local and systemic control. The aim of the study was to determine the efficacy of the trimodality approach. METHODS: Fifty-six patients (male/female ratio: 47/9, median age: 64 years) in stage IIB to IIIB were treated during a period between 1994 and 2013. Induction therapy consisted of 2-3 cycles of a platinum-based chemotherapy associated with radiotherapy (30-44 Gy). After restaging, eligible patients underwent surgery 2 to 4-week post-radiation. RESULTS: Thirty-two (57.1%) patients were cT3 and 24 (42.9%) cT4, 47 (83.9%) were N0 and 9 (16.1%) N+. Forty-eight (85.7%) patients underwent R0 resection and 10 (17.9%) had a complete pathological response (CPR). Thirty-day mortality rate was 5.4%, major surgical complications occurred in 6 (10.7%) patients. At the end of the follow-up, 17 (30.4%) patients were alive and 39 (69.6%) died (29 for cancer-related causes), with an overall 5-year survival of 38%. At statistical analysis, stage IIB (P = 0.003), R0 resection (P = 0.03), T3 tumour (P = 0.002) and CPR (P = 0.01) were significant independent predictors of better prognosis. CONCLUSIONS: This combined approach is feasible, and allows for a good rate of complete resection. Long-term survival rates are acceptable, especially for early stage tumours radically resected. Systemic control of disease still remains poor, with distant recurrence being the most common cause of death.

Outcomes and prognostic factors of non-small-cell lung cancer with lymph node involvement treated with induction treatment and surgical resection.

OBJECTIVES: Induction therapy (IT) has gained popularity in recent years, becoming a standard of treatment in resectable lymph node-positive NSCLC. IT aims to downstage the disease (shrinkage of tumour and clearance of lymph node-metastases), clear distant micrometastases and prolong survival. Potential disadvantages are increased morbidity and/or mortality after surgery and risk of progression of disease that could have been initially resected. The purpose of this study was to evaluate the outcomes and prognostic factors in a series of patients with lymph node-positive NSCLC receiving IT followed by surgery. METHODS: A total of 86 patients (75.6% males, median age 63 years) affected by NSCLC in clinical stage IIIA (n = 80) or IIIB (n = 6), with pathologically proven lymph node involvement, underwent platinum-based IT followed by surgery between 2000 and 2009. RESULTS: Eighty (93%) patients received a median of 3 cycles of chemotherapy, and 6 (7%) underwent induction chemoradiotherapy. Response to IT was complete in 3.5%, partial in 59.3% and stable disease in 37.2% of patients. Postoperative morbidity and mortality were 25.6 and 2.3%, respectively. At pathological evaluation, 38.4% of patients had a downstaging of disease with a complete lymph node clearance in 31.4%. Median overall survival was 23 months (5-year survival 33%). Univariate analysis found clinical stage (P = 0.02), histology (P = 0.01), response to IT (P = 0.02) and type of intervention (P = 0.047) to have predictive roles in survival. A better but not significant survival was also found for pN0 vs pN+ (P = 0.22), downstaged tumours (P = 0.08) and left side (P = 0.06). On multivariate analysis, clinical response to neoadjuvant therapy (P = 0.01) and age (P = 0.03) were the only independent predictors of survival. CONCLUSIONS: The use of IT for lymph node-positive NSCLC seems justified by low morbidity and/or mortality and good survival rates. Patients with response to IT showed greater benefit in the long term.

Phase II randomized study of vandetanib plus gemcitabine or gemcitabine plus placebo as first-line treatment of advanced non-small-cell lung cancer in elderly patients.

INTRODUCTION: The aim of the present study was to evaluate the efficacy and tolerability of vandetanib plus gemcitabine (V/G) compared with gemcitabine alone in elderly patients with untreated advanced non-small-cell lung cancer. METHODS: This was a phase II, randomized, double-blind study. A total of 124 elderly patients (mean age, 75 yr; age range, 70-84 yr; 73% men) received V/G (n = 61) or placebo plus gemcitabine (n = 63). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival, objective response rate, duration of response, disease control rate, time to deterioration of performance status, and safety outcomes. RESULTS: PFS was significantly prolonged with V/G (median, 183 days; 95% confidence interval, 116-214) compared with placebo plus gemcitabine (median, 169 days; 95% confidence interval, 95-194; p = 0.047). No statistically significant differences between arms were observed in all secondary endpoints, including overall survival. The addition of vandetanib to gemcitabine was well tolerated. The rate of patients with ≥1 treatment-related adverse event was comparable in the two arms, pyrexia, dyspnea, and neutropenia being the most common adverse events. CONCLUSIONS: V/G combination was associated with a statistically significant prolongation of PFS compared with gemcitabine alone in untreated elderly patients with advanced non-small-cell lung cancer, with an acceptable safety profile.

Multidisciplinary approach for advanced stage thymic tumors: long-term outcome.

BACKGROUND: In advanced stage thymic tumors complete surgical resection is not always achievable. Although surgery remains the cornerstone of therapy, there is growing evidence that multimodality treatment increases resectability and reduces the incidence of local and systemic relapses. METHODS: Between 1980 and 2008, 75 patients with stages III (n = 51), IVA (n = 18) and IVB (n = 6) thymic tumors were treated. Twenty-six patients had A-AB-B1 and 49 B2-B3-C histotype. Thirty-eight (50.6%) patients considered not radically resectable at preoperative workup, received induction chemotherapy; postoperatively 37 (49.3%) had radiotherapy, 25 (33.3%) chemoradiotherapy and 4 (5.3%) chemotherapy. RESULTS: No perioperative mortality was recorded. Sixty-one (81.3%) had complete resection (CR) and 14 (18.7%) incomplete resection (IR). CR was lower in patients who received induction chemotherapy (73.7% vs 89.2%, p = 0.02). In 11 (14.7%) cases a vascular procedure was carried out. Overall 5- and 10-year survivals were 70% and 57%, respectively. Five and 10-year tumor-related survival was 78% and 70%. Ten-year survival was better for CR vs IR resection (62% vs 28%; p = 0.003) and for type A-AB-B1 vs B2-B3-C (60% vs 53%; p = 0.03). No statistical difference was found between stage III and IV (10-year survival: 63% and 43%; p = 0.42) and induction vs no induction chemotherapy (10-year survival: 52% vs 56%; p = 0.54). At multivariate analysis CR (p = 0.001) and type A-AB-B1 (p = 0.04) were independent predictors of better survival. During follow-up, 34.4% of CR developed tumor recurrence. CONCLUSIONS: Multimodality treatment of stages III and IV thymic tumors guarantees good disease control and provides high survival and acceptable recurrence rates.

A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report.

Malignant pleural mesothelioma is an aggressive tumour with poor prognosis and short duration of response probably due to the high chemo-refractoriness. Multimodality treatment based on preoperative chemotherapy, surgery and adjuvant radiotherapy seems to be a feasible and effective therapeutic option in selected patients.We report on a case of pathological complete response in a patient affected by malignant pleural mesothelioma who was treated with four cycles of preoperative chemotherapy based on carboplatin plus pemetrexed followed by parietal pleurectomy and lung decortication. Carboplatin plus pemetrexed was a well tolerated regimen without grade 3-4 haematological toxicity, and this confirm the feasibility of such a treatment as an alternative to the current golden standard based on cisplatin plus pemetrexed.Complete resection allows the pathologist to better describe biological markers of mesothelioma cells, in order to select patients with different treatment outcome and prognosis.

Effect of induction chemotherapy on lung function and exercise capacity in patients affected by malignant pleural mesothelioma.

OBJECTIVES: The effect of induction chemotherapy (IC) on lung function and exercise capacity in patients with malignant pleural mesothelioma (MPM) has not been largely examined. The aim of this study was to evaluate the changes in pulmonary function and oxygen consumption following IC in patients with MPM. METHODS: Between 2004 and 2009, 36 consecutive patients (mean age 62.1 + or - 1.5 years, M/F = 25/11) were prospectively investigated. Data concerning medical history, histology, staging and response to chemotherapy were collected. All patients underwent pulmonary function test before (in the absence of pleural effusion) and after chemotherapy (platinum-based agent plus pemetrexed); 23 out of 36 patients also performed a cardiopulmonary incremental exercise test. RESULTS: An epithelioid histotype was documented in 88.8% of patients. A partial response to chemotherapy was observed in 44.5% of cases and 36.1% of patients experienced grade 2-3 toxicity. A significant improvement in forced expiratory volume in 1s (FEV(1)) (0.13 + or - 0.30 l; P = 0.01), in VO(2) peak (1.76 + or - 2.91 ml kg(-1) min(-1); P = 0.005), in PaO(2) at rest (4.76 + or - 9.84 mmHg; P = 0.03) and in PaO(2) at peak exercise (6.26 + or - 12.72 mmHg; P = 0.04) was detected. The diffusion capacity of the lung for carbon monoxide (DLCO) also increased (1.25 + or - 4.68 ml min(-1) mmHg(-1)), although not significantly (P = 0.20). The stratified analysis based on the response to IC showed a significant improvement in FEV(1), forced vital capacity (FVC) and vital capacity (VC) (both absolute and percentage of predicted values) only in patients with a partial response. CONCLUSIONS: An improvement in lung function and exercise capacity was seen after IC in patients with MPM. These data suggest that IC does not compromise cardiopulmonary performance in this subset of patients.