Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101).

BACKGROUND: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. PATIENTS AND METHODS: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. RESULTS: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. CONCLUSIONS: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.

Weekly docetaxel and gemcitabine as first-line treatment for metastatic breast cancer: results of a multicenter phase II study.

OBJECTIVES: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. METHODS: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. RESULTS: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53-28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71-16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3-4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. CONCLUSION: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.

Addition of either irinotecan or methotrexate to bolus 5-fluorouracil and high-dose folinic acid every 2 weeks in advanced colorectal carcinoma: a randomised study by the Southern Italy Cooperative Oncology Group.

PURPOSE: The purpose of this study was to compare the activity and toxicity of the combination of irinotecan (IRI) plus folinic acid (FA)-modulated 5-fluorouracil (5-FU) i.v. bolus with a regimen of double modulation of 5-FU with methotrexate (MTX) and FA in patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Two-hundred and thirty-four patients were enrolled: 118 patients received IRI 200 mg/m2 (90-min i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and 5-FU 850 mg/m2 (i.v. bolus) on day 2 (IRIFAFU), and 116 patients received MTX 750 mg/m2 (2-h i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and FU 800 mg/m2 (i.v. bolus) on day 2 (MTXFAFU). Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles. Response rate (RR) was the main end point of the study; responses were assessed every four cycles and confirmed after 2 additional months of treatment. RESULTS: RR was significantly greater with IRIFAFU (36%) than with MTXFAFU (20%) (P <0.001). Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity (P = 0.028). Median progression-free survival was longer with IRIFAFU than with MTXFAFU (7.2 months compared with 4.8 months; P = 0.048). Median survival time (MST) did not differ between the two arms (14.7 months compared with 14.8 months, respectively). Patients not receiving second-line chemotherapy, however, lived longer when treated in the first-line with IRIFAFU (MST 11.9 months compared with 6.4 months; P = 0.038). IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia (40% compared with 9%; P = 0.001) and diarrhoea (13% compared with 4%; P = 0.024), but a significantly lower incidence of stomatitis (3% compared with 12%; P = 0.007), than the comparative regimen. CONCLUSIONS: IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens. IRIFAFU, however, seems easier to administer, because it does not require infusional catheter or pump devices, and it is less expensive. It may represent a new option for treating advanced colorectal carcinoma.

Irinotecan and mitomycin C in 5-fluorouracil-refractory colorectal cancer patients. A phase I/II study of the Southern Italy Cooperative Oncology Group.

PURPOSE: To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma. METHODS: Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle. RESULTS: Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4-27%] and an overall control of tumor growth in 47% (95% CI, 31-64%) of patients. The median time to treatment failure was 6 months (range 1-19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable. CONCLUSIONS: CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.

Behaviour of interleukin-2 serum levels in advanced non-small-cell lung cancer patients: relationship with response to therapy and survival.

Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses. In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer (NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up, using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were shown to have higher IL-2 serum levels than controls (P < 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P < 0.0001), although they were still significantly higher than controls (P < 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P < 0.0001). Moreover, a further significant increase in IL-2 serum levels (P = 0.004) and a significant decrease (P < 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis. In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed.

Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate whether the addition of gemcitabine (G) to vinorelbine (V) improves survival and quality of life (QoL) among elderly patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC aged >/= 70 years with advanced disease were randomly allocated to receive V 30 mg/m(2) on days 1 and 8 every 3 weeks or G 1,200 mg/m(2) + V 30 mg/m(2) on days 1 and 8 every 3 weeks. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned based on the first 60 patients per arm. RESULTS: In May 1999, the survival data were analyzed of 120 eligible patients (V group = 60; G + V group = 60) who had been randomized from June 1997 to February 1999. Forty-nine patients had stage IIIB disease, and 71 had stage IV. At a median potential follow-up of 14 months (range, 3 to 22 months), 93 patients had died (G + V group = 41; V group = 52). In the G + V group, median survival time was 29 weeks and projected 1-year survival was 30%; these values were 18 weeks and 13% in the V group. According to multivariate Cox analysis, the risk of death in the G + V arm compared with the V arm was 0.48 (95% confidence interval, 0. 29 to 0.79; P <.01). Combination therapy was also associated with a clear delay in symptom and QoL deterioration. The overall response rates were 22% and 15% in the G + V and V groups, respectively. CONCLUSION: In elderly patients with NSCLC, G + V treatment is associated with significantly better survival than is V alone.

Amifostine plus cisplatin plus vinorelbine in the treatment of advanced non small cell lung cancer: a multicenter phase II study.

PURPOSE: to evaluate the activity and toxicity of the combination cisplatin plus vinorelbine plus amifostine in advanced non small cell lung cancer (NSCLC). PATIENTS AND METHODS: a two-stage Simon design was applied. To proceed after the first stage, responses from seven of 19 patients were needed. Overall, 17 responses from 40 treated patients were required to comply with the design parameter. Inclusion criteria were cyto-histologically proven stage IIIB-IV NSCLC; age of 70 years or less; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; normal cardiac, hepatic, renal and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination, biochemistry, chest radiograph, brain, thoracic and abdominal computed tomographic (CT) scans, and bone scan. All patients received cisplatin 100 mg/m(2) intravenously (iv) day 1, vinorelbine 25 mg/m(2) iv days 1-8-15-22, amifostine 740 mg/m(2) iv day 1 every 4 weeks up to six cycles. Eleven of 40 enrolled patients were stage IIIB and 29 stage IV, with a median age of 57 years (range, 38-70 years). RESULTS: all patients were evaluable for response and toxicity (intention to treat analysis). We observed 20 (50%) objective responses, with four (10%) complete responses. Median time to progression was 20 weeks, and median survival was 45 weeks. The toxicity was manageable. The reported main toxicities were neutropenia grade 4 in 10% of patients, grade 1 and grade 3 nephrotoxicity both in 5% of patients and grade 1 amifostine-related hypotension in 15% of patients. CONCLUSION: these data show that cisplatin plus vinorelbine plus amifostine is an active and feaseable regimen in stage IIIB-IV NSCLC. A phase III trial comparing cisplatin plus vinorelbine versus cisplatin plus vinorelbine plus amifostine in advanced NSCLC is warranted.

Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group.

PURPOSE: In our previous phase II study, the cisplatin, gemcitabine, and vinorelbine (PGV) regimen produced a median survival time (MST) of approximately 1 year in advanced non-small-cell lung cancer (NSCLC) patients. The present study was aimed at comparing the MST of patients treated with this triplet regimen with the MSTs of patients receiving cisplatin and vinorelbine (PV) or cisplatin and gemcitabine (PG). PATIENTS AND METHODS: From April 1997, patients with locally advanced or metastatic NSCLC, an age of < or = 70 years, and an Eastern Cooperative Oncology Group performance status < or = 1 were randomized to receive one of the following regimens: cisplatin 50 mg/m(2), gemcitabine 1,000 mg/m(2), and vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks (arm A); cisplatin 100 mg/m(2) on day 1 and gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks (arm B); or cisplatin 120 mg/m(2) on days 1 and 29 and vinorelbine 30 mg/m(2)/wk (arm C). According to the two-stage design for phase III trials, an interim analysis was planned when the first 60 patients per arm were assessable for survival. RESULTS: The survival data of 180 NSCLC patients (stage IIIB, 76 patients; stage IV, 104 patients) were analyzed in April 1999. Overall, 128 patients had died (PGV, n = 33; PG, n = 42; and PV, n = 53). The MST of patients in the PGV, PG, and PV arms was 51, 42, and 35 weeks, respectively, and the corresponding 1-year projected survival rates were 45%, 40%, and 34%, respectively. When only patients with stage IV disease were considered, an even stronger difference was seen between PGV (MST = 47 weeks) and both PG (34 weeks) and PV (27 weeks). At multivariate Cox analysis, the estimate hazard of death for patients receiving PGV compared with those receiving PV was 0.35 (95% confidence interval, 0.16 to 0.77; P <.01). The response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm. Both hematologic and nonhematologic toxicities were not substantially worse in patients who received the PGV regimen. CONCLUSION: The PGV regimen is associated with a substantial survival gain (MST > 3 months longer) when compared with the PV combination. Because this difference in survival met one of the early stopping rules, the accrual in the PV arm has been stopped (null hypothesis rejected). Enrollment still continues in the PGV and PG arm to ascertain whether the PGV regimen can also produce a significantly longer survival than that obtained with the PG regimen.

Interim analysis of a phase III trial comparing cisplatin, gemcitabine, and vinorelbine vs. either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non small-cell lung cancer. A Southern Italy Cooperative Oncology Group Study.

In a previous phase II randomized study, a cisplatin/gemcitabine/vinorelbine (PGV) regimen produced a 50-week median survival time (MST) in advanced non small-cell lung cancer (NSCLC) patients. The present trial was planned to randomly compare the outcome of patients treated with this new triplet regimen with those of patients receiving either cisplatin plus vinorelbine (PV) or cisplatin plus gemcitabine (PG) doublet combinations. One hundred eighty patients with stage IIIB (76) or IV (104) disease, aged

Cisplatin, gemcitabine, and paclitaxel in locally advanced or metastatic non-small-cell lung cancer: a phase I-II study. Southern Italy Cooperative Oncology Group.

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 patient's 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.

Cisplatin, gemcitabine, and vinorelbine combination therapy in advanced non-small-cell lung cancer: a phase II randomized study of the Southern Italy Cooperative Oncology Group.

PURPOSE: In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non-small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen. PATIENTS AND METHODS: One hundred eleven chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate. RESULTS: Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION: The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.

Carboplatin-oral etoposide personalized dosing in elderly non-small cell lung cancer patients. Gruppo Oncologico Cooperativo Sud-Italia.

The toxicity and therapeutic activity, including the effect on quality of life, of the carboplatin-oral etoposide combination, given with an intrapatient dose escalation, was tested in 38 non-small cell lung cancer (NSCLC) patients aged over 70 years, and in 8 younger patients with a performance status of 2. In the absence of grade 3-4 toxicity, doses were escalated as follows: first course (carboplatin AUC 4; etoposide 50 mg twice daily orally days 1-14); second course (carboplatin AUC 5; etoposide 50 mg twice daily orally days 1-14); third course (carboplatin AUC 5; etoposide 50 mg twice daily orally days 1-21). A total of 141 chemotherapy cycles were delivered. The treatment was, in general, well tolerated and no toxic deaths occurred. More than 60% of patients received 100% of the planned dose intensity. Transient grade 4 neutropenia or thrombocytopenia occurred in 6 and 2 patients, respectively, but only 2 patients had to be hospitalised because of fever. All patients were evaluated for activity on an 'intention to treat basis'. Ten partial responses and 20 stable disease were recorded, for an overall response rate of 22% (95% confidence interval (CI) = 11-36). 9/38 (24%; 95% CI = 12-41) elderly patients obtained a partial response. The median response duration was 4 months. A quality of life improvement was observed in 19 of the 46 enrolled patients (41%; 95% CI = 27-57), and 15/46 (33%; 95% CI = 19-48) showed a performance status improvement. The quality of life score improved in 17/38 (45%) elderly patients. 8/10 responders and 11/20 patients with stable disease showed a concomitant improvement in quality of life. At a median potential follow-up of 16 months (range 2-21), 31 patients had had progression of disease and 23 had died, for a median time to progression (TTP) and overall survival (OS) of 5 and 10 months, respectively. The median survival time was 11 months in the elderly patients. The median time to subjective impairment (TSI) was 6 months (7 months in the elderly group). One-year estimated TTP, TSI and OS rates were 22, 29 and 41%, respectively. At multivariate Cox analysis, a > 25% improvement in the quality of life score was more predictive of a better survival outcome than the response achievement.

Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Gruppo Oncologico Campano.

A multicentre randomised phase III trial in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) was undertaken to compare the therapeutic activity and toxicity of a cisplatin/carboplatin-etoposide-vinorelbine combination with that of a cisplatin-etoposide regimen. Patients with advanced (stage IIIB-IV) NSCLC were randomised, after stratification for stage (IIIB-IV) and performance status (0-1 and 2), to receive either (A) CDDP 40 mg m-2 + VP16 100 mg m-2 on days 1-3 as standard treatment or (B) CBDCA 250 mg m-2 on day 1 + CDDP 30 mg m-2 on days 2 and 3 + VP16 100 mg m-2 on days 1-3 + NVB 30 mg m-2 on day 1. Therapy was recycled on day 29 in both arms. We hypothesised a 15% minimum increment in the response rate with the experimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early termination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less than 3% at the end of the first stage. A total of 112 patients (arm A = 57, arm B = 55) were enrolled in the study (53 with stage IIIB and 59 with stage IV), of which 105 eligible patients were evaluable for response on an "intention to treat' basis. Seven patients were excluded because they did not fulfil the inclusion criteria. Fifteen responses were observed in arm A (28%, 95% CI = 17-42) and 13 (one complete) in arm B (25%, 95% CI = 13-37). On multivariate logistic analysis, treatment did not affect the response rate, while stage IV and performance status 2 were significantly associated with a lower probability of response. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median survival in patients with poor performance status (21 weeks). On Cox analysis, treatment failed to show a significant impact on survival: stage IV (relative risk = 1.6. CI = 1.0-2.6, P = 0.036) was the only prognostic variable significantly associated with a worse survival outcome and, although poor performance status adversely affected survival, this effect did not reach the level of statistical significance (relative risk = 1.6, CI = 0.98-2.5; P = 0.063). There were no significant differences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment because of the persistence of severe nephrotoxicity (two patients) or neurotoxicity (one patient). In contrast, a significant increase in both neutropenia and thrombocytopenia was observed in the experimental arm. Four treatment-related deaths were registered in arm B (two due to neutropenic sepsis, one to myocardial failure and one to acute renal failure) compared with one toxic death (acute renal failure) in arm A. In view of these results, the trial was stopped and the null hypothesis (< 15% increase in response rate with the experimental regimen) has been accepted. Therefore, our combination does not deserve further evaluation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact on survival of patients with poor performance status, trials to evaluate the activity of new regimens should be conducted separately for each subset of patients with different performance status.

Partial substitution of cisplatin with carboplatin in combination with etoposide in advanced non-small cell lung cancer (NSCLC): a multicentric randomised phase II trial.

Seventy previously untreated patients with advanced NSCLC were randomised, after stratification for stage (IIIB vs. IV) and Performance Status (0-1 vs. 2), to receive either treatment A: CDDP 40 mg/m2 + VP16 100 mg/m2 day 1-3 (37 patients); or treatment B: CBDCA 250 mg/m2 day 1 + CDDP 30 mg/m2 day 2, 3 + VP16 100 mg/m2 day 1-3 (33 patients). Therapy was recycled on day 29 in both arms. The two arms were well balanced for the main pretreatment characteristics. Sixty-six patients (32 with Stage IIIB and 34 with Stage IV disease) were evaluable for toxicity and response (arm A = 34, arm B = 32), while four ineligible patients were excluded from analysis. Acute toxicity was assessed at recycling. Non-hematologic toxicity was higher in arm A. However, the reduction of nephrotoxicity (9% vs. 23%) in arm B was lower than expected. Leukopenia (15 vs. 5 patients) or thrombocytopenia (7 vs. 0 patients) of any grade affected more patients of arm B. Moreover, Grade 3-4 leukopenia (six patients) or thrombocytopenia (four patients) was observed only in arm B. Seventeen patients responded: 11/34 (32%; 95% C.I. = 17-50%) in arm A, and 6/32 (19%; 95% C.I. = 7-36%) in arm B. Median survival times of 40 and 34 weeks, respectively, were reported in arm A and B. Stage IIIB and squamous cell histology were associated with a higher probability of response. In conclusion, the partial replacement of CDDP with CBDCA in combination with VP16 slightly improves the tolerance of the treatment in terms of nephro- and neurotoxicity; however, it induces a significant increase in hematologic toxicity. In view of this unfavourable toxicologic profile and of the discouraging response rate observed, this regimen cannot be recommended as standard treatment in advanced NSCLC.

Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable nonsmall cell lung carcinoma: a multicenter randomized clinical trial.

BACKGROUND: Lonidamine (LND) is an indazol-carboxylic acid derivative that selectively inhibits the energy metabolism of neoplastic cells, and increases the permeability of cell membranes. In vitro studies have demonstrated that LND can potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the acquired multidrug resistance of neoplastic cells. Some clinical trials have suggested a synergism of LND with alkylating agents, cisplatin, and anthracyclines in various solid tumors. METHODS: From June 1990 to June 1993, 158 previously untreated patients with Stage IIIB and IV nonsmall cell lung cancer (NSCLC) were enrolled into a multicentric randomized trial to evaluate the addition of LND to a cisplatin-epirubicin-vindesine regimen. Eighty patients in the control arm (A) received cisplatin, 60 mg/m2 intravenously (i.v.); epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. (PEV), on Day 1 every 4 weeks, whereas 78 patients in the experimental arm (B) received the same regimen with the addition of LND from 75 mg orally three times on Day 1 to 150 mg orally three times on Day 7+ until tumor progression occurred. RESULTS: The experimental treatment achieved a significantly higher proportion of major responses in comparison with the control regimen (43% vs. 24%; P=0.02). The addition of LND apparently potentiated the activity of this cytotoxic treatment, particularly in patients with metastatic disease (overall response rate, 39% vs. 17%). The median time to progression (5 vs. 8 months; P=0.0007) and the median survival time (7.6 vs. 11 months; P=0.0013) were also statistically improved in Arm B. The acute toxicity of the 2 treatments was low: only 6% of patients in Arm A and 4% of patients in Arm B had to withdraw from treatment due to Grade 4 World Health Organization toxicity. The main additional side effects related to the administration of LND were epigastralgia, myalgia, asthenia, and orchialgia. However, these symptoms were mild and controlled by the concomitant administration of low doses of steroids. CONCLUSIONS: The mild acute toxicity of the PEV regimen and the acceptable and nonoverlapping additional side effects of LND render our experimental therapy worthy of consideration for the management of NSCLC patients with poor performance status or low tolerance to more aggressive therapeutic approaches.

Tratamento de longa duraçäo com "Duovent" em pacientes idosas portadores de doença pulmonar obstrutiva crônica / Long term treatment using Duovent in elderly patients with chronic obstructive pulmonary diseases

Doze pacientes, com idade de 60 anos e portadores de doença pulmonar obstrutiva crônica, foram tratados durante 12 semanas com Duovent (fenoterol + brometo de ipratrópio). As avaliaçöes clínicas e índice de obstruçäo brônquica (VEF1, CV, VR, CEVA) foram realizados cada 14 dias. A melhora dos sintomas correspondeu a uma melhora significante dos parâmetros funcionais. Näo se observou efeito cardiovascular negativo, efeitos colaterais significativos ou tolerância após a administraçäo da droga

Duovent compared to carbuterol in the treatment of bronchospasm.

Fourteen patients with chronic obstructive lung disease (COLD) were studied. All were in a relatively stable clinico-functional state, and bronchospasm was reversible with fenoterol. The study was carried out over 3 days. Duovent and Carbuterol were given at random on the 1st or 3rd day to each patient; the placebo was always given on the 2nd day. Each drug was administered with 2 puffs of a metered-dose aerosol, corresponding to 200 micrograms fenoterol + 80 micrograms ipratropium bromide for Duovent and 200 micrograms of active substance for Carbuterol. The patients were studied for 7 h after administration of the 3 preparations. Ventilatory and cardiocirculatory parameters as well as local and systemic tolerance of the drugs were evaluated. The data show that Douvent has a more rapid and powerful bronchodilator action compared to Carbuterol. The action of Duovent is more constant and prolonged compared to the other drug and acts on both proximal and distal airways. Local and systemic tolerance is excellent for both drugs studied. In conclusion, Duovent is a rational and effective combination in the treatment of bronchospasm.

Long-term treatment with 'Duovent' in elderly patients affected by chronic obstructive lung disease.

Twelve patients, aged over 60 years and suffering from chronic obstructive lung disease, were treated for 12 weeks with Duovent (fenoterol + ipratropium bromide). The clinical check-ups and indices of bronchial obstruction (FEV1, VC, RV, sGaw) were performed every 14 days. Improvement in symptoms corresponded to a significant improvement in the functional parameters. No negative cardiovascular effects, significant side-effects, or tolerance were seen after drug administration.

[Survival curves of 169 cases of primary lung cancer]. / Studio delle curve di sopravvivenza in 169 casi di cancro primitivo del polmone.

169 lung cancer patients were studied and their survival curves analysed after classification according to various parameters (clinical stage using the TNM method, histological type, and morphoradiological type). The resulting tragic picture is further confirmation of the primary importance of prompt diagnosis as well as an appropriate prevention strategy.

[Plasma renin activity in hypertensive subjects after posture changes and beta receptor blocking]. / Attività reninica plasmatica in soggetti ipertesi dopo postura e blocco beta recettoriale.

The Authors have esecuted a study about the manners of the PRA in 20 subjects, 10 hypertensive and 10 sound. The dosages have effected with indirect radioimmunology method and the patterns have proportioned in the mg/ml/h. The results obtained indicate that the situation changes, produce, in hypertensive subjects, increment of the PRA without variations of the pressure and that the block of the Beta receivers produces significant changes of the PRA.