Gemcitabine and vinorelbine followed by weekly docetaxel in patients with advanced non-small-cell lung cancer: a phase II trial of sequential chemotherapy

Objective We conducted this phase II trial to evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by weekly docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Eligibility criteria: stage IV NSCLC, Performance status ≤2, adequate renal, hepatic and bone marrow function. Treatment consisted on: VNR 25 mg/m² plus gemcitabine 1000 mg/m², on days 1 and 8 of each 21-day cycle, followed by docetaxel 36 mg/m² weekly until progression or unacceptable toxicity. Results 21 stage IV patients were enrolled. All patients are evaluable for treatment response and toxicity profile. The mean age of the patients was 63 years (range: 51 to 72) with 18 (86%) males and 3 (14%) females. Histology types were: adenocarcinoma in 8 patients (38%), large cell carcinoma in 1 patients (5%) and squamous cell carcinoma in 12 patients (57%). The majority of the patients had and ECOG PS of 1. Eight patients (38%) did not complete six cycles of gemcitabine-navelbine. The median number of cycles of gemcitabine-navelbine was 4 (range 2–6). Of the 13 patients (61%) who completed six cycles of gemcitabine-navelbine, all of them went on to receive weekly docetaxel and received at least 3 cycles, with a median number of 8 cycles (range 3–16). The overall response rate was 33%. Respect survival, the minimum follow-up was 6 months (range, 6–25 months). The median survival time (MST) was 7.9 months, and the 1-year survival was 30%, and the median progression-free survival was 4.7 months. Toxicity was mild, well tolerated and mostly hematologic. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 14%, two patients with febrile neutropenia. Grade 3 anaemia in 1 patients (5%) and grade 3 thrombocytopenia in 1 patient (5%). Nonhematologic toxicity was also mild: 1 patient with Grade 3 skin toxicity with docetaxel, 1 patient with grade 3 infection, 2 patients with grade 3 astenia and 1 patient with a mild allergic reaction postchemotherapy treatment with docetaxel. Conclusion The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by weekly DOC is active and can be administered safely in advanced NSCLC. Our results are similar with other sequential regimens and did not represent a significant improvement in the treatment of this disease.     

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

Purpose: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival.Patients and methods: Patients with cytologically- or histologically-proven stage IIIB–IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m² on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m² on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m² and GEM 1200 mg/m² on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse.Results: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m² and GEM 1200 mg/m² on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1–16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3–4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3–4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia.Conclusions: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.     

Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non-small-cell lung cancer: A phase I study

Purpose: The objective of this study was to determine the maximally tolerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a fixed dose of cisplatin (CDDP).Patients and methods: Chemotherapy-naïve patients with stage IIIB–IV non-small-cell lung cancer (NSCLC) received a fixed dose of CDDP (50 mg/m²) and escalating doses of VNR (starting from 20 mg/m²) and GEM (starting from 800 mg/m²) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m² at each step, was initially planned up to a dose of 1,200 mg/m², to be followed by increments of the VNR dose of 5 mg/m² at each step.Results: Thirty-one patients were enrolled at five different dose levels. The escalation was stopped at level 4 (GEM 1,200 mg/m² and VNR 25 mg/m²) since two of six patients of this cohort showed dose-limiting neutropenia at treatment cycle 1. Two different dose levels, GEM 1,200 mg/m² + VNR 20 mg/m², and GEM 1,000 mg/m² + VNR 25 mg/m², were fairly well tolerated. No treatment-related deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total of eight patients (26%) experienced grade 4 neutropenia lasting more than seven days; in five of them it occurred in the first course. Neutropenic fever was observed in four cases. Grade 4 thrombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No complete responses were obtained, but sixteen out of 31 (52%) patients achieved partial responses. The median duration of response was 20 (range 6–56+) weeks, while at a nine-month median follow-up, the median survival time has not yet been reached. To date, 18 patients are still alive. The one-year projected survival for all patients was 51%.Conclusions: Our results show that CDDP, VNR and GEM can be safely given together without substantial reductions in their individual dose intensities. In our opinion, the dose level of GEM 1,000 mg/m² + VNR 25 mg/m² given in combination with CDDP 50 mg/m² on days 1 and 8 of a three-week cycle can be recommended for phase II trials, since it provides a better balance in dose intensity of GEM and VNR. A phase II randomised study is underway to establish the activity of this new regimen (at the above-cited dose level) in chemo-naïve NSCLC patients.     

Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.

PURPOSE: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI). RESULTS: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001). CONCLUSION: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m(2) on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m(2) on day 1 (regimen A) or GEM 1200 mg/m(2) on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m(2) on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32-77) years; median Karnofsky Performance Status (PS) 80 (range 70-100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology - epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR+PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III-IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1-2 peripheral neurotoxicity and grade 1-2 local toxicity with regimen A and grade 1-2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet.     

Phase II trial of gemcitabine and docetaxel in patients with completely resected stage IIA–IIIA non-small-cell lung cancer

Background Few clinical phase II studies using non-platinum doublet as adjuvant chemotherapy following complete resection of non-small-cell lung cancer (NSCLC) have been published, so this clinical study was designed to evaluate the toxicity profile and efficacy of the non-platinum doublet of docetaxel (DOC) + gemcitabine (GEM). Methods Eligibility criteria included completely resected NSCLC, pathological stage II or IIIA, younger than 76 years old, and performance status 0–1. Treatment consisted of DOC 60 mg/m² on day 8, and GEM 1,000 mg/m² on days 1, 8, and 15 every 4 weeks (4 cycles). The GEM dosage was decreased to 800 mg/m² after the initial 21 patients because 3 patients developed interstitial lung disease (ILD). Results Thirty-five patients (male/female 21/14) were enrolled. The median age was 62 years (range 47–74), with five (14.3%) over the age of 70. Performance status was 0 in 34 patients. The diagnosis was ad in 28 patients, sq in 6, and adsq in 1. The pathological stage was IIA in 5 patients, IIB in 1 and stage IIIA in 29 (82.9%). All patients underwent at least one cycle of chemotherapy, with 29 patients completing three cycles of chemotherapy and 23 (66%) had four cycles. The main grade 3/4 toxicities comprised neutropenia (n = 21, 60%), thrombocytopenia (n = 3, 8.6%), anorexia (n = 4, 11.4%), and ILD (n = 3, 8.6%), which responded well to corticosteroids. There were no treatment-related deaths. The 4-year recurrence-free survival rate was 42.9%, and the 4-year survival rate was 65.8%. Conclusions The non-platinum doublet regimen of DOC + GEM as adjuvant chemotherapy following complete resection of NSCLC is feasible, with good compliance, the only problem being ILD.     

Vinorelbine and docetaxel as first-line chemotherapy in metastatic breast cancer

PURPOSE: To evaluate the efficacy and tolerability of a combination of vinorelbine (VNR) and docetaxel (DOC) as first-line chemotherapy in patients with metastatic breast cancer. PATIENTS AND METHODS: The study group comprised 40 women with untreated metastatic breast cancer with visceral (85%) and bone (70%) metastases. Of the 40 patients, 24 (60%) had previously received adjuvant chemotherapy, which had included anthracyclines in 12 patients (30%). Treatment consisted of VNR 25 mg/m(2) on days 1 and 5, and DOC 75 mg/m(2) on day 1 every 3 weeks. Depending on the neutrophil nadir (grade 3 or 4 neutropenia by WHO criteria) recombinant human granulocyte colony-stimulating factor (G-CSF) 5 micro g/kg on days 2-4 and 6-13 was given for all subsequent treatment cycles. RESULTS: The overall response rate (ORR) was 40% (95% confidence interval, CI 15-65). Six patients (15%) achieved a complete response (CR) and ten patients (25%) achieved a partial response (PR). Stable disease (SD) was observed in six patients (15%), and 18 patients (45%) had progressive disease (PD). The median duration of response was 8 months and the median predictive time to progression (TTP) was 6 months. The main toxicity was neutropenia grade 3 and 4 in 28 patients (70%). Febrile neutropenia requiring hospitalization occurred in 12 patients (30%). Grade 3 or 4 anemia was seen in two patients (5%) and grade 3 or 4 thrombocytopenia was seen in one patient (2.5%). Severe nonhematologic toxicity, except alopecia, was uncommon and included stomatitis in two patients (5%), vomiting in two (5%) and diarrhea in one (2.5%). There were no treatment-related deaths. CONCLUSIONS: The combination of VNR and DOC at the doses used in this study showed moderate activity as first-line chemotherapy in metastatic breast cancer. Neutropenia was considerable despite G-CSF administration.     

Randomized phase II three-arm trial with three platinum-based doublets in metastatic non-small-cell lung cancer. An Italian Trials in Medical Oncology study.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) do not tolerate cisplatin-based regimens because of its nonhemathological toxicity. PATIENTS AND METHODS: We evaluated the response rate safety of new platinum analogue regimens, randomizing 147 patients with nonoperable IIIB/IV NSCLC to (i) carboplatin (area under the curve = 5 mg min/ml) on day 1 plus gemcitabine (GEM) (1000 mg/m(2)) on days 1 and 8 for six cycles; (ii) same regimen for three cycles followed by docetaxel (Taxotere) (40 mg/m(2)) on days 1 and 8 plus GEM (1250 mg/m(2)) on days 1 and 8 for three cycles; (iii) oxaliplatin (130 mg/m(2)) on day 1 plus GEM (1250 mg/m(2)) on days 1 and 8 for six cycles. RESULTS: Intention-to-treat objective response rates were 25%, 25% and 30.6% in arms A, B and C, respectively. Median survival was 11.9, 9.2 and 11.3 months in arms A, B and C, respectively. Grade 3/4 neutropenia/anemia occurred in 29%/12.5%, 10%/16.5% and 8%/6% of arms A, B and C, respectively; grade 3/4 thrombocytopenia in 20.5%, 16.5% and 6%; grade 1/2 neurological toxicity in 43% of arm C. CONCLUSIONS: Oxaliplatin/GEM (arm C) had similar activity to carboplatin/GEM (arm A), but milder hematological toxicity and may be worth testing in a phase III study against carboplatin/GEM in patients not suitable for cisplatin. The sequential regimen gave no additional benefit.     

Bi-weekly administration of gemcitabine plus vinorelbine in elderly patients with advanced non-small-cell lung cancer: multicenter phase II trial

PURPOSE: Gemcitabine (GEM) and vinorelbine (VNR) have demonstrated activity as a first-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). We conducted a multicenter phase II trial to evaluate the efficacy and toxicity of bi-weekly administration of GEM plus VNR in elderly patients with advanced NSCLC. PATIENTS AND METHODS: Forty-six chemotherapy-naive elderly (age: >or=70 years) NSCLC patients were enrolled. Patients were eligible if they had histologically or cytologically confirmed unresectable NSCLC with measurable and/or assessable disease. Patients received GEM (1000 mg/m2) and VNR (25 mg/m2) every 2 weeks. RESULTS: The objective response rate of this treatment was 22.7% (95% confidence interval (CI), 10.3-35.1%), median survival time was 310 days, and median time to progression was 133 days. The one-year survival rate was 40.9% (95% CI, 26.3-55.4%), and most adverse events were mild. Only three (6.8%) patients needed to omit GEM because of grade 4 neutropenia or due to physician judgment. No patients suffered treatment-related death. CONCLUSIONS: Bi-weekly administration of GEM plus VNR in elderly patients was an effective, feasible and well-tolerated treatment schedule.     

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.     

A phase I trial of gemcitabine, docetaxel and carboplatin administered every 2 weeks as first line treatment in patients with advanced breast cancer

Objective  To determine the maximum tolerated doses (MTDs) and dose limiting toxicities (DLTs) of gemcitabine (GEM), docetaxel (DOC) and carboplatin (CARBO) combination. Patients and methods  A total of 33 previously untreated HER-2 negative patients with stage IIIB-IV breast cancer received escalated doses of GEM, DOC and CARBO all given sequentially on day 1 every 2 weeks. Twenty-three patients (70%) had previously received adjuvant or neoadjuvant chemotherapy. Results  The recommended MTDs are GEM 1,500 mg/m², DOC 50 mg/m² and CARBO 3AUC. Seven dose levels were evaluated and neutropenia was the primary dose-limiting event. Of 319 chemotherapy cycles delivered, grade 3–4 neutropenia occurred in 13.5% of them with two cases of febrile neutropenia. Diarrhea and asthenia were the most common non-hematological toxicities. Three (16%) complete and 6 (32%) partial responses were observed among 19 patients with measurable disease. Conclusion  The biweekly administration of GEM, DOC and CARBO is a well-tolerated regimen which merits further evaluation.     

A dose escalation study of docetaxel plus capecitabine in combination with gemcitabine in patients with advanced solid tumors

Capecitabine (CAP), gemcitabine (GEM), and docetaxel (DOC) have shown interesting activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of their combination in patients with refractory solid tumors. Eighteen patients were enrolled. The patients' median age was 60 years, 15 were male, and 11 were chemo-naive. DOC was administered on day 1 as an 1-h (IV) infusion at escalating doses ranging from 40 to 50 mg/m2. GEM was administered on day 1 as a 30-min (IV) infusion at a standard dose of 1500 mg/m2. CAP was administered orally on days 1 to 7 at escalating doses ranging from 1750 to 2500 mg/m2 given as two daily divided doses. Treatment was repeated every 2 weeks. Five different dose levels were examined. At dose level V two out of three enrolled patients presented DLTs (one patient grade 4 neutropenia and grade 3 stomatitis and another grade 3 diarrhea), and thus the recommended MTD for future phase II studies are CAP 2250 mg/m2, DOC 50 mg/m2, and GEM 1500 mg/m2. A total of 124 treatment cycles were administered. Toxicity was generally mild. Grade 3/4 neutropenia was observed in eight (7%) treatment cycles and grade 3 thrombocytopenia in one (1%). There was no febrile episode. Grade 2/3 asthenia was observed in six (33%) patients, grade 2/3 diarrhea in four (22%), and grade 2/3 hand-foot syndrome in three (17%). Other toxicities were uncommon. There was no treatment-related death. One (6%) CR, four (25%) PRs, and six (38%) SD were observed among 16 evaluable patients. Responses were seen in patients with breast (one CR), gastric (three PRs), and pancreatic (one PR) cancer. These results demonstrate that CAP, DOC, and GEM can be safely combined at clinically relevant doses and this regimen merits further evaluation.     

Combination therapy with vinorelbine and gemcitabine in unresectable non-small cell lung cancer

Vinorelbine (VNR) and gemcitabine (GEM) were used in combination to treat 10 patients with unresectable non-small cell lung cancer to study the efficacy, safety, possibility of out-patient administration, and improvement of subjective symptoms. One course of treatment consisted of i.v. drip infusion of VNR at 25 mg/m2 followed by i.v. drip infusion of GEM at 1,000 mg/m2 on day 1 and day 8. This course was repeated more than twice, as a rule, at 3-week intervals. In 10 patients registered from November 1999 to March 2000, we observed PR in 5, SD in 4 and PD in 1. The response rate was 50%. PS was improved in 5 out of 6 patients with PS 1 or worse. All 4 patients with subjective symptoms reported improvement. Adverse effects of leukopenia of grade 3 or more occurred in 50% of patients and neutropenia in 80%. By dose reduction, we could administer 7.1 courses to each patient on average. Non-hematological toxicities, excluding eruption of grade 3 which occurred in the first course and made it impossible to continue the treatment, were phlebitis in 40% of patients, anorexia in 30% (only grades 1 and 2) and transient drug fever (only grade 1) in 50%. All were tractable, and no lung toxicity occurred. Antibiotic chemotherapy could be performed in 7 patients on an outpatient basis. Combination therapy with VNR and GEM also seemed to be a safe and useful treatment on an outpatient basis.     

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-na?ve patients with advanced non-small-cell lung cancer

Background:Gemcitabine (GEM) and paclitaxel (TAX) are active,non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performeda phase I study to determine the maximum-tolerated dose (MTD), antitumoractivity and pharmacokinetics of GEM and TAX given weekly in chemo-naïvepatients with advanced NSCLC. Patients and methods:Escalating doses of GEM (800–2000mg/m²) and TAX (60–100 mg/m²) were administeredon days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasmapharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results:Dose-escalation was discontinued in absence of MTDbecause of increased cumulative toxicity leading to dose modification ortreatment delay at levels 6 and 7 (TAX 100 mg/m² plus GEM 1750 and,respectively, 2000 mg/m²). Hematological toxicity included grade4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycleand febrile neutropenia in three cycles. Maximal non-hemathological toxicitywas grade 3 elevation in serum transaminases and grade 2 neuro-sensorytoxicity in 8% and 5% of cycles, respectively. At the two higherdose-levels a non-linear pharmacokinetics of GEM was observed with aremarkable variability of C_max and AUC. No pharmacokineticinteractions were reported. Objectives responses were seen at all dose levels,with an overall response rate of 43% (95% confidence interval(95% CI): 25.5%–62.6%) in 30 evaluable patients. Conclusions:The weekly administration of GEM and TAX is very welltolerated, and has shown promising antitumor activity in NSCLC. In view of thecumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500mg/m² of GEM and 100 mg/m² of TAX are recommended forphase II studies.     

A dose escalation study of leucovorin (LV) and 48-hour continuous infusion of 5-fluorouracil in combination with cyclophosphamide and vinorelbine in pretreated patients with metastatic breast cancer

PURPOSE: To determine the maximum tolerated doses (MTD) and dose-limiting toxicities (DLTs) of vinorelbine (VNR) with fixed doses of cyclophosphamide (CPM) and 5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: Eighteen patients with MBC pretreated with anthracyclines and taxanes were enrolled. VNR was administered as a 10-min intravenous infusion (i.v.) on day 1 at escalated doses with CPM 300 mg/m2 i.v. bolus and LV 500 mg/m2 as a 2-hour i.v. infusion, followed by 5-FU 1500 mg/m2 as a 22-hour continuous infusion (c.i.) for two consecutive days. Treatment was repeated every two weeks. RESULTS: At the dose of VNR 22.5 mg/m2 without rhG-CSF and 25 mg/m2 with rhG-CSF support, the DLT had been reached. Grade 3 or 4 neutropenia occurred in six (33%) patients and in fourteen (27%) cycles with no episode of febrile neutropenia. One (5.5%) patient developed grade 4 thrombocytopenia. Grade 3 neurotoxicity occurred in two patients and grade 2 and 3 asthenia in five (28%). CONCLUSION: The recommended doses for phase II studies are 20 mg/m2 for VNR (22.5 mg/m2 with rhG-CSF support) and 300 mg/m2 for CPM on day 1, with 500 mg/m2 for LV and 1500 mg/m2 for 5-FU on days 1 and 2.     

A novel triplet regimen with paclitaxel, carboplatin and gemcitabine (PACCAGE) as induction chemotherapy for locally advanced unresectable non small cell lung cancer (NSCLC)

Phase II study of 3 cycles of triplet induction chemotherapy (response, toxicity) followed by radiotherapy in locally advanced non small cell lung cancer (NSCLC). BACKGROUND: Patients with locally advanced inoperable non-small cell lung cancer are currently treated with concomitant or sequential chemotherapy and radiotherapy. However, the outcome of existing treatment modalities is unsatisfactory. Development of new strategies including more efficient systemic chemotherapy is warranted. OBJECTIVE: To study the antitumour activity and toxicity of a triplet combination of paclitaxel, carboplatin and gemcitabine as induction chemotherapy before radiotherapy, in locally advanced NSCLC and to evaluate time to progression and survival. METHODS: Three cycles of paclitaxel (175 mg/m(2) by 3h infusion on day 1), carboplatin (AUC 5mg/(mlmin) by IV bolus on day 1) and gemcitabine (1000 mg/m(2) by IV bolus on day 1 and 8) were administered every 3 weeks in reasonably fit patients. Fractionated radiotherapy with curative intent was initiated 4 weeks after the last chemotherapy administration. Toxicity was assessed weekly during cycle 1 and on day 1 and 8 in cycles 2 and 3. Response evaluation was performed at the end of cycle 3. RESULTS: Forty-eight patients (20 stage IIIA and 28 stage IIIB) received a total of 134 cycles of chemotherapy. Forty-two patients received the intended 3 cycles. Thirty patients obtained an objective response (1 complete and 29 partial response) or 62.5% on the intent to treat analysis (95% confidence interval: 49-76%). None of the responders became eligible for surgery. The median time to progression and survival for all patients was 10.1 and 15.7 month, respectively. A significant difference was observed in survival parameters between stage IIIA and stage IIIB patients. Haematological toxicity grade 3/4, mainly neutropenia and thrombocytopenia, was most prominent on day 15 of the treatment cycles. Haematological support by means of recombinant erythropoietin, red blood cell or platelet transfusion, filgrastim administration or a combination was needed in 21 patients. None of the patients discontinued chemotherapy because of haematotoxicity. Grade 3/4 non-haematological toxicity leading to chemotherapy withdrawal occurred early during induction (2 and 1 in cycles 1 and 2, respectively). CONCLUSION: Three cycles of the novel triplet combination of paclitaxel, carboplatin and gemcitabine (PACCAGE) is an active and feasible induction regimen for patients with locally advanced inoperable NSCLC. Neutropenia and to a lesser extent thrombocytopenia represent the main haematological toxicity. Whether this triplet regimen can improve outcome when compared to specific cisplatin doublet regimens should be evaluated in a phase III study.     

Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma

BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is expected to increase due to delayed control of occupational exposure to asbestos in Japan. We investigated the use of triplet combination chemotherapy with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR) for the treatment of Japanese patients with MPM. METHODS: From December 2000 to August 2003, 12 patients received the following regimen: CDDP 40 mg/m(2), GEM 800 mg/m(2) and VNR 20 mg/m(2) on days 1 and 8 every 4 weeks. Among the 12 patients, six selected patients underwent an extrapleural pneumonectomy (EP) after a median of three cycles of triplet chemotherapy. RESULTS: The overall response rate for all patients and the response rate for chemotherapy-naive cases were 58 and 67%, respectively. The median survival time and survival rate at 2 years for all patients were 11 months and 50%, respectively. The 2-year survival rates for the patients with and without EP were 83.3 and 16.7%, respectively. CONCLUSIONS: Triplet chemotherapy with CDDP, GEM and VNR was thus found to be highly effective for patients with MPM and its toxicity was manageable. A multi-institutional phase II trial is now being planned to establish the effectiveness of this new regimen in chemotherapy-naive patients with MPM.     

GP方案治疗晚期非小细胞肺癌疗效观察

目的观察GP方案治疗晚期非小细胞肺癌的疗效与毒性反应。方法60例符合条件的患者接受下述联合方案化疗2周期,吉西他滨1250mg/m2iv d1、8,顺铂25 mg/m2iv d1~3,至少2周期进行评价。结果本组患者总有效率为46.67%;III期及IV期与复发转移者比较疗效均无显著性差别;鳞癌与腺癌比较疗效无显著性差异。毒性反应以骨髓抑制为主,III~IV度白细胞减少发生率61.82%,其中粒细胞减少性发热30.91%。其它不良反应耐受性良好。结论GP方案是治疗晚期非小细胞肺癌有效、耐受性良好的方案。     

Gemcitabine, Ifosfamide and Navelbine (GIN): activity and safety of a non-platinum-based triplet in advanced non-small-cell lung cancer (NSCLC).

To evaluate activity and toxicity of a non platinum-based triplet including Gemcitabine, Ifosfamide and Navelbine (GIN) in advanced NSCLC. Stage IIIB/IV NSCLC patients with WHO PS < 2 and bidimensionally measurable disease entered the study. Gemcitabine 1000 mg/sqm day 1 and 1000-800 mg/sqm day 4, Ifosfamide 3 g/sqm day 1 (with Mesna), Navelbine 25 mg/sqm day 1 and 25-20 mg/sqm day 4 were administered intravenously every 3 weeks. Objective responses (ORs) were evaluated every 2 courses: a maximum of 6 courses were administered in responding patients. According to Simon's optimal two-stage design more than 18 ORs out of 54 patients were required to establish the activity of this regimen. Fifty patients entered the study. Main characteristics of the 48 evaluated patients were: median age 63 years, ECOG performance status 0 = 65%, stage IV disease 79% and non-squamous histology 71%. The total number of courses administered was 200, median per patient 4 (range 1-6). Toxicities were evaluated according to WHO criteria: neutropenia grade 3-4 occurred in 47% of the courses; thrombocytopenia grade 3-4 in 6.6%; anaemia grade 3 in 3.5%. Twelve episodes of febrile neutropenia were reported and three patients required hospital admission. No toxic death was reported. Non-haematological toxicity, including skin rash, alopecia and fatigue, were generally. Twenty-five ORs (1 complete response and 24 partial responses) were obtained for a response rate of 52% (95% CI: 37.4-66.5%). One-year survival was 46.5%. This non-platinum-based outpatient triplet showed promising activity against NSCLC with myelosuppression, in particular neutropenia, being dose-limiting. The GIN regimen may represent a valuable alternative to standard platinum-based doublets and triplets in the treatment of advanced NSCLC and further studies with this platinum-free combination are warranted.