Randomized phase III PITCAP trial and meta-analysis of induction chemotherapy followed by thoracic irradiation with or without concurrent taxane-based chemotherapy in locally advanced NSCLC.

BACKGROUND: Chemo-radiotherapy is standard of care in the treatment of unresectable stage III NSCLC. We aimed at assessing whether the addition of concurrent taxane-chemotherapy to thoracic irradiation following chemotherapy was able to improve treatment outcome. MATERIAL AND METHODS: In PITCAP trial, patients with unresectable stage III NSCLC were randomized to receive 2 cycles of platinum-paclitaxel followed by 60-61.2Gy thoracic irradiation (control arm) or by same radiotherapy with concomitant weekly paclitaxel (experimental arm). A literature-based meta-analysis including all studies with same design was also performed. RESULTS: At the time of the second interim analysis, when 151 patients were randomized, accrual was terminated. With a median follow-up of 6.1 years, median survival was 13.2 vs 15.1 months, with a 3-year survival rate of 19.5 vs 21.2% in the control and experimental arm, respectively (HR: 0.97; 95% CI 0.69-1.36; p=0.845). Treatment toxicity was manageable in both arms. The meta-analysis of 5 trials (n=866) confirmed the lack of a meaningful effect on 1-year overall survival of a taxane added concurrently to radiotherapy. CONCLUSIONS: These results do not support a meaningful survival benefit with the addition of single agent taxane given concurrently to radiotherapy after platinum-based induction in locally advanced NSCLC.

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study.

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC.

Prognostic impact of education level of patients with advanced non-small cell lung cancer enrolled in clinical trials.

BACKGROUND: Socioeconomic status can potentially affect prognosis of cancer patients. Our aim was to describe potential differences in demographic and clinical characteristics, treatment, and survival by education level in patients with advanced non-small cell lung cancer (NSCLC) enrolled in clinical trials of first-line treatment. METHODS: Individual data of Italian patients with advanced NSCLC (stage IV, or IIIB with supraclavicular nodes or malignant pleural effusion), ECOG performance status (PS) 0-2, enrolled in four phase III randomized trials conducted between 1996 and 2005 were pooled. Information about education was available for 1680 of 1709 patients (98.3%). Patients were divided in two groups according to education level: high (patients with at least high school diploma) or low (those with less than high school diploma). Survival analyses were stratified by treatment arm within trial. RESULTS: There were 312 (19%) and 1368 (81%) patients with high and low education, respectively. Education level was significantly different among birth cohorts, with a time-trend toward higher education level. Patients with high education were significantly younger (median age 65 vs. 70), were less frequently unfit at diagnosis (ECOG PS2 5% vs. 16%), and their tumor type was more frequently adenocarcinoma (47% vs. 37%). Number of treatment cycles received was not significantly different between education groups. Median survival was 9.4 and 7.6 months in high and low education, respectively (p=0.012). At multivariable analysis, female sex, better PS and high education level (Hazard Ratio 0.85, 95%CI 0.73-0.99, p=0.03) were independently associated with longer survival. CONCLUSIONS: In Italian patients enrolled in four randomized trials of first-line chemotherapy for advanced NSCLC, high education was significantly more frequent among younger patients, and was associated with lower proportion of PS2 patients. Education level did not significantly affect number of chemotherapy cycles received. Overall survival was longer in patients with high education, after adjustment for PS and other prognostic factors. The exact underlying mechanisms of the independent prognostic role of education level are substantially unknown, but lead-time bias (anticipation in diagnosis and time to inclusion in the trial), differences in adherence to care outside the trial procedures, differences in comorbidities and life-style factors may all contribute.

Phase I-II trial of gemcitabine-based first-line chemotherapies for small cell lung cancer in elderly patients with performance status 0-2: the G-STEP trial.

INTRODUCTION: Treatment of elderly patients with small cell lung cancer (SCLC) is based on scanty evidence. METHODS: Patients with extensive SCLC, age >70 years, and performance status 0-2 were eligible for a study looking for optimal two-drug combination of gemcitabine (Gem) with vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Gemcitabine dose was the same (1000 mg/m2, days 1-8) in all combinations. A two-stage minimax flexible design for response was applied to GemVin combination (Vin 25 mg/m2, days 1-8). For GemCar, GemCis, GemEto, a phase I-II Bayesian design was applied, looking for the optimal dose of the partner drugs. Objective response rate ≥ 60% and unacceptable toxicity ≤ 25% were required to define a combination worthy of further studies. RESULTS: Median age of 78 eligible patients was 74 years. GemVin produced a 36.7% objective response rate. GemEto and GemCis arms were found not sufficiently active. GemCar produced 16 responses (14 with area under the curve [AUC] 3.5 and 2 with AUC 4.0) in 26 patients (61.5%) and 6 cases of unacceptable toxicity (3 at each Car dose). CONCLUSIONS: In elderly patients with extensive SCLC, GemVin, GemEto, and GemCis are not enough active and do not merit further studies. Gem plus Car might deserve further attention.

Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational "SUN" (Survey on the lUng cancer maNagement) study.

Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists.

The MILES-2G phase 2 study of single-agent gemcitabine with prolonged constant infusion in advanced non-small cell lung cancer elderly patients.

BACKGROUND: Gemcitabine has been widely studied in elderly patients affected by advanced non-small cell lung cancer (NSCLC). A prolonged constant infusion (10 mg/m2/min) has been proposed as a way to improve its efficacy. Aim of this study is to describe activity and toxicity of single-agent gemcitabine given as prolonged infusion in the treatment of elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients aged 70 years or older, with stage IV or IIIB (effusion/supraclavicular nodes) NSCLC, good performance status (0 or 1 according to ECOG classification) who had never received chemotherapy were eligible. Gemcitabine was administered at the dose of 1200 mg/m2 by prolonged infusion (10 mg/m2/min) on days 1 and 8 of each cycle. Courses were repeated every 21 days, for a maximum of 6 cycles, unless disease progression or severe toxicity. A single stage phase 2 design was applied, with 51 patients required to estimate a 25% +/- 10% response rate. Ten responses were required to define the treatment as active. RESULTS: Fifty-one patients were enrolled, with a median age of 76 years (range 70-83). Two complete responses and seven partial responses were observed, for an overall response rate of 17.6% (95% exact C.I.: 8.4-30.9%). The median time to disease progression was 16.1 weeks (95% C.I.: 11.1-20.6) and the median overall survival was 41.3 weeks (95% C.I.: 27.6-50.6). There were 2 toxic deaths, due to bleeding and liver toxicity, and one patient had an ischemic stroke. Other non-haematological toxicities were: fatigue (44% of patients), grade 2-3 pulmonary toxicity (8%), grade 2-3 hepatic toxicity (16%). Nausea and stomatitis were mild and no cases of cardiac toxicity were observed. Haematological toxicity was mild, with no case of febrile neutropenia. CONCLUSION: Gemcitabine at prolonged constant infusion produced a response rate lower than that required by study design and should no longer be of interest for the treatment of elderly patients with advanced NSCLC.

Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study.

BACKGROUND: The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. METHODS: Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2 x 2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m(2) in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m(2) in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. FINDINGS: Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29-71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40-55] vs 44 [36-52], with standard gemcitabine infusion, hazard ratio (HR) of death 0.93 [0.74-1.17], p=0.41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36-55] vs 44 [40-54] without rofecoxib, and HR of death 1.00 [0.75-1.34], p=0.85), or progression-free survival, but did improve response rate (41%vs 26%, p=0.02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0.06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0.03). INTERPRETATION: Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.

Pretreatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study.

PURPOSE: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy. PATIENTS AND METHODS: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. RESULTS: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. CONCLUSIONS: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials.

BACKGROUND: Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy. METHODS: We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1-2), or severe (grade 3-4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival. FINDINGS: In the landmark group, hazard ratios of death were 0.65 (0.46-0.93) for patients with severe neutropenia and 0.74 (0.56-0.98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31.4 weeks (95% CI 25.7-39.6) for patients without neutropenia compared with 42.0 weeks (32.7-59.7) for patients with severe neutropenia, and with 43.7 weeks (36.6-66.0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0.0118). Findings were much the same for the out-of-landmark group. INTERPRETATION: Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.

A multicenter, randomized, Phase II study of cisplatin, etoposide, and gemcitabine or cisplatin plus gemcitabine as first-line treatment in patients with poor-prognosis small cell lung carcinoma.

BACKGROUND: The objective of this study was to evaluate the activity and toxicity of combined cisplatin, etoposide, and gemcitabine (PEG) and combined cisplatin plus gemcitabine (PG) in previously untreated patients with extensive-stage and poor-prognosis limited-stage small-cell lung carcinoma. METHODS: One hundred forty patients (70 patients in two arms) were randomized to receive either cisplatin 70 mg/m2 on Day 1, etoposide 50 mg/m2 on Days 1-3, and gemcitabine 1000 mg/m2 on Days 1 and 8 or cisplatin 70 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8. Both regimens were recycled every 21 days. RESULTS: In total, 626 cycles were delivered (303 cycles of PEG and 323 cycles of PG), with a median of 4 cycles per patient in both arms. The objective response rate was 63% (95% confidence interval [95%CI], 49-71%) for PEG and 57% (95%CI, 43-67%) for PG, with the suggestion of a higher complete response rate in the PEG arm (18.6% and 4.3%, respectively). A similar time to disease progression (6 months in the PEG arm and 7 months in the PG arm) and a similar median survival (9.5 months in the PEG arm and 10 months in the PG arm) were observed in both arms. The PEG regimen was associated with more severe hematologic toxicity in terms of neutropenia, febrile neutropenia, and a higher rate of treatment delays and dose reductions, whereas nonhematologic toxicities did not differ between the two arms. CONCLUSIONS: According to the results of this Phase II randomized trial, the PEG regimen produced a higher complete response rate but more toxicity compared with the PG regimen in patients with extensive-stage or poor-prognosis, limited-stage small cell lung carcinoma.

Supportive care in patients with advanced non-small-cell lung cancer.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient's quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. PATIENTS AND METHODS: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. RESULTS: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. CONCLUSION: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.

Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.

BACKGROUND: Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer (NSCLC). Some studies have also suggested that gemcitabine is well tolerated and effective in such patients. We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial in elderly patients with advanced NSCLC. METHODS: Patients aged 70 years and older, enrolled between December 1997 and November 2000, were randomly assigned to receive intravenous vinorelbine (30 mg/m(2) of body surface area), gemcitabine (1200 mg/m(2)), or vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)). All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles. The primary endpoint was survival. Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test. Secondary endpoints were quality of life and toxicity. RESULTS: Of 698 patients available for intention-to-treat analysis, 233 were assigned to receive vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine. Compared with each single drug, the combination treatment did not improve survival. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving gemcitabine. Although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly. CONCLUSION: The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC.