A phase I-II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients.

Thirty patients with chemotherapy-naïve advanced non-small-cell lungcancer (NSCLC) were given escalating doses of paclitaxel (150, 175, 200mg/m²) on day 1 in three consecutive cycles, together with a fixeddose of gemcitabine 1000 mg/m² on days 1 and 8; cycles wererepeated every three weeks. The dose escalation of paclitaxel was feasible inthe majority of patients. Subsequently, 30 other NSCLC patients received adose of 200 mg/m² paclitaxel with gemcitabine 1000 mg/m²in a phase II study. The major side effect was mild myelosuppression. Aresponse rate of 24% was achieved in 49 fully evaluable patients. Thisregimen proved to be safe and easy to administer on an out-patient setting,and constitutes now one of the arms of the current EORTC randomized study foradvanced NSCLC.     

A randomised phase II study of weekly paclitaxel or vinorelbine in combination with cisplatin against inoperable non-small-cell lung cancer previously untreated

Cyclooxygenase-2 (COX-2) expression is increased in breast cancer and surgery has been shown to increase the growth of metastatic tumours. We investigated the effect of selective COX-2 inhibition on the growth of metastases in either an experimental metastasis model or following excision of a murine primary breast tumour. 50,000 4T1 mammary carcinoma cells were injected into the mammary fat pad of female BALB/c mice. When the mean TD reached 8+/-0.4 mm, tumours were excised and the mice were randomised into two groups (n=12 per group) to receive daily intraperitoneal injections of the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days. Alternatively, experimental metastases were established by tail-vein injection of 50,000 4T1 cells. Mice received either the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days (n=12 per group). SC-236 treatment significantly reduced tumour burden, the number and size of spontaneous metastases following primary tumour excision. SC-236 treatment also reduced tumour burden, the number and size of experimental metastases. Immunohistochemical staining demonstrated that COX-2 inhibition reduced microvessel density and increased apoptosis within both spontaneous and experimental metastases. These data clearly demonstrate that the selective COX-2 inhibitor, SC-236, has potent antimetastatic activity against both spontaneous metastases arising following primary tumour excision and experimental metastases.     

Phase I/II study of paclitaxel, gemcitabine and vinorelbine as first-line chemotherapy of non-small-cell lung cancer.

BACKGROUND: The aim of our study was to determine the maximum tolerated dose of paclitaxel combined with a fixed dose of gemcitabine and vinorelbine in the treatment of non-small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the efficacy of this combination. PATIENTS AND METHODS: Sixty-two patients with stage IIIB/IV NSCLC were treated with paclitaxel in escalating doses from 40-80 mg/m(2) combined with gemcitabine and vinorelbine at fixed doses of 1000 mg/m(2) and 25 mg/m(2), respectively. All drugs were given intravenously on day 1 and 8 every 3 weeks. RESULTS: In a phase I trial, carried out on 21 patients, grade 4 neutropenia, as dose-limiting toxicity, occurred at the dosage level of paclitaxel 80 mg/m(2). In a phase II trial, with paclitaxel administered at 70 mg/m(2), 27 out of 41 (66%) assessable patients responded (10% complete responses and 56% partial responses). Objective response was observed in 13 of 16 patients (81%) with stage IIIB disease and in 14 of 25 (56%) with stage IV disease. The median time to treatment failure was 26 weeks (range 3-72 weeks; 32 weeks and 20 weeks for stages IIIB and IV, respectively) and median survival 62 weeks (range 4-176 weeks; 72 weeks and 56 weeks for stages IIIB and IV, respectively). One-year survival was 64% for all patients (72% for patients with stage IIIB and 52% for those with stage IV). Grade 3 and 4 neutropenia were observed in 11 (27%) and seven (17%) cases, respectively; grade 3 thrombocytopenia was observed in three patients (7%) and grade 3 anemia in four patients (10%). The most relevant non-hematological toxicity was grade 2/3 asthenia, which was observed in 12 patients (29%). Alopecia was almost universal, whereas nausea and vomiting were absent. CONCLUSIONS: The combination of paclitaxel, gemcitabine and vinorelbine is effective and tolerable in the treatment of NSCLC. The high activity and low toxicity of this regimen warrant randomized studies with platinum-containing combinations.     

Front-line paclitaxel and irinotecan combination chemotherapy in advanced non-small-cell lung cancer: a phase I-II trial

Our purpose was to determine the efficacy of irinotecan plus paclitaxel administered on day 1, repeated every 2 weeks, in untreated patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In total, 56 patients with inoperable or metastatic stage III and IV NSCLC with a histologically or cytologically confirmed diagnosis were enrolled. None of the patients had undergone prior chemotherapy or radiation therapy. Treatment involved irinotecan 125 mg m(-2) and paclitaxel 135 mg m(-2) administered on day 1 and repeated every 2 weeks for a planned number of nine cycles. With a standard dose of paclitaxel at 135 mg m(-2), the dosage of irinotecan was escalated at four levels: 75, 100, 125 and 150 mg m(-2); 125 mg m(-2) was established as the maximum tolerated dose; this dosage was administered to 46 patients. A total of 52 patients (median age 65 years, range 38-77 years) were assessable for toxicity and survival and 46 for response rate. Out of 46 evaluable patients, 19 achieved partial response (41.3%), 17 had stable disease (37%) and 10 (21.7%) experienced disease progression. The median duration of response was 6 months (range 2-9+ months). The main adverse reactions were myelotoxicity (grades 3 and 4) in 10 (19.2%) patients and diarrhoea (grade 3) in four (7.7%) patients. Irinotecan combined with paclitaxel, administered every 2 weeks, appears to be an effective treatment for advanced-stage NSCLC.     

A phase II study of oxaliplatin and paclitaxel in patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin and paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The treatment regimen was given as defined in a phase I investigation in patients with previously treated ovarian cancer. It consisted of paclitaxel 175 mg/m(2) (1-h infusion) and oxaliplatin 130 mg/m(2) (2-h infusion) given every 21 days. Eligible patients had stage IIIB (pleural effusion)/IV NSCLC, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic function. RESULTS: A total of 38 patients were enrolled with the following characteristics: 29% male (n = 11); 71% female (n = 27); median age 64.5 years (range 37-78); performance status of 0-1 84% (n = 32); stage IIIB 8% (n = 3); stage IV 92% (n = 35). One hundred and eighty-one cycles were administered, with a median of four per patient (range one to 12). The overall objective response rate for all 38 patients was 34.2% [95% confidence interval (CI) 19.6% to 51.4%]. This response rate includes 13 patients who met criteria for a partial response. No complete responses were observed. Median overall survival time was 9.2 months (95% CI 6-12.4) and median progression-free survival time was 4.3 months (95% CI 2.1-6.5). The 1- and 2-year overall survival rates were 37% and 21%, respectively. Hematological toxicity included six patients with grade 4 neutropenia. Non-hematological toxicity consisted mainly of grades 1 and 2 neurosensory toxicity. Laryngodysesthesia was observed in two patients following oxaliplatin infusion. No grade 4 non-hematological toxicities were encountered. CONCLUSION: This regimen is well tolerated, and demonstrates activity in patients with advanced NSCLC.     

Sequential therapy in advanced non-small-cell lung cancer with weekly paclitaxel followed by cisplatin-gemcitabine-vinorelbine. A phase II study.

Objectives:New effective therapies are needed to improvethe outcome of patients with advanced non-small-cell lung cancer(NSCLC). The aim of this study was to assess the response rate andsurvival obtained with a sequential regimen of chemotherapy. Patients and methods:Patients with newly diagnosed stageIIIb–IV NSCLC were included. They all had measurable disease and agood performance status (0–2 in the Eastern Cooperative OncologyGroup scale). Chemotherapy consisted of weekly paclitaxel 150mg/m² × 6, followed two weeks later by cisplatin 100mg/m² on day 1, gemcitabine 1000 mg/m² on days 1and 14, and vinorelbine 25 mg/m² on days 1 and 14 (CGV). CGVwas administered every 28 days for a maximum of six courses. Results:Fifty-two patients were included, 19 (37%)with stage IIIb and 33 (63%) with stage IV disease. After therapywith weekly paclitaxel, 29 partial responses were obtained (56%,95% confidence interval (95% CI):38%–67%), whereas 15 patients had stable disease(29%) and eight had a progression (15%). After CGV, therewere four complete remissions (8%) and 24 partial responses(46%), for an overall response rate of 54% (95% CI:37%–65%). Eight patients had stable disease(15%) and 16 had a progression (31%). No patientprogressing after paclitaxel responded to CGV, whereas 5 out of 15patients with stable disease reached a partial response with CGV(33%). On the contrary, 5 out of 29 patients with a partialresponse to paclitaxel progressed after CGV (17%). Mediansurvival has not been reached after a median follow-up of 14 months.Median time to progression was nine months. Fifty-six percent ofpatients remain alive at one year. Two hundred eighty-nine courses ofpaclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 perpatient, respectively (ranges 2–6 and 0–6, respectively).WHO grade 3–4 toxicities for paclitaxel were: neutropenia in twopatients (4%) and peripheral neuropathy in five (10%). Twopatients had allergic reactions requiring paclitaxel withdrawal, whereasfour (8%) had hyperglycemia >250 mg/ml. Grade 3–4toxicities for CGV were: neutropenia in ten patients (20%),peripheral neuropathy in six (12%), anemia in four (8%),nausea/vomiting in five (10%), thrombocytopenia in two(4%), and fatigue in four (8%). Conclusion:Our results suggest that sequential chemotherapy with weeklypaclitaxel followed by CGV is highly active in patients with advancedNSCLC and has an acceptable toxicity. This schedule deserves furtherevaluation in a phase III study.     

Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer.

BACKGROUND: A phase II trial of alternating i.v. and oral vinorelbine in combination with cisplatin was designed to determine the response rate, safety profile, progression-free survival, overall survival and quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-six chemotherapy-na?ve patients received cisplatin 100 mg/m(2) and i.v. vinorelbine 25 mg/m(2) on day 1, followed by oral vinorelbine 60 mg/m(2) on days 8, 15 and 22, every 28 days. RESULTS: After an independent review, the response rate was 33% [95% confidence interval (CI) 20% to 46%]. Median progression-free and overall survival were 5.5 months (95% CI 3.7-6.4) and 8.9 months (95% CI 8.8-11.7), respectively. The most frequent hematological toxicities were neutropenia (grade 3-4 in 73% of patients) and anemia (grade 3-4 in 11% of patients). Grade 3-4 infections and non-hematological toxicities occurred occasionally. QoL for lung cancer related symptoms was stable or improved. CONCLUSIONS: The efficacy and safety of the alternating vinorelbine schedule (i.v. on day 1, oral on days 8, 15 and 22) in combination with cisplatin in advanced NSCLC are similar to those of the standard regimen using exclusively i.v. vinorelbine, whereas ease of administration and patient comfort may favor the novel approach.     

Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.     

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.     

异长春花碱单药化疗高龄晚期非小细胞肺癌

目的：评价高龄NSCLC患者用异长春花碱单药化疗的生存率,生活质量及能否耐受。方法：治疗高龄晚期非小细胞肺癌40例,治疗组20例予以持续深静脉输注异长春花碱（NVB）24小时7．5mg/m^2第1－5天,同时第一天快速静滴异长春花碱7．5mg/m^2,三周后重复;对照组20例运用中药薏芯仁提取物200ml/天静滴20天1疗程辅以其他支持治疗,每1月为1疗程,所有病例至少完成两个疗程,除非治疗中发现病情进展,结果：治疗组有效率35％（7／20）,患者中位生存期 7．2个月,一年生存率25％,对照组有效率10％（2／20）,患者中位生存期4．8个月,一年生存率5％,结论：对高龄晚期非小细胞癌患者,异长春花碱单药治疗较中药薏芯仁为主的支持治疗有更好的疗效,生活质量,更长的生存期,且毒副反应轻微,可以耐受。     

Paclitaxel and carboplatin in combination with gemcitabine: a phase I-II trial in patients with advanced non-small-cell lung cancer. Gruppo Studio Tumori Polmonari Veneto (GSTPV).

Background:The combination of paclitaxel (P) and carboplatin (C)is an effective treatment for advanced NSCLC. Gemcitabine (G) is an active newdrug. We planned a phase I study to find the maximum tolerated dose (MTD) ofthe PCG combination. A phase II study was subsequently conducted to evaluatethe activity and toxicity of PCG. Patients and methods:Forty-five patients entered the study.Twenty-eight had stage IIIA–B disease, 17 stage IV. In the phase Istudy, with a fixed dose of C at AUC = 6 on day 1, P was escalated usingincrements of 25 mg/m² starting from 175 mg/m² on day1 and G with increments of 200 mg/m² starting from 800mg/m² on day 1 and 8. Results:Fourteen patients entered the phase I study. The MTD wasreached at P 200 mg/m², C AUC = 6 and G 1000 mg/m².Neutropenic fever and grade 3 diarrhea were the dose limiting toxicities.Thirty-one patients were treated in the phase II study with P 175mg/m², C AUC = 6 and G 1000 mg/m². Response rate was57% (68% in stage III and 47% in stage IV).Myelosuppression was the main toxicity, with grade 3–4 leukopeniaoccurring in 35% of cases. Grade 3 anemia was observed in 24%of cases and grade 3–4 thrombocytopenia occurred in 34% ofpatients. Non-hematological toxicity was mild. Median survival and one-yearactuarial survival were 20.5 months and 74% for stage III and 11.5months and 47% for stage IV. Conclusions:PCG is a promising regimen for treating advancedNSCLC. A phase III study comparing PCG to paclitaxel plus carboplatin inadvanced NSCLC is ongoing. On the other hand, we are planning to introduce thePCG regimen in the treatment of stage II–III patients in the setting ofa multimodality treatment.     

Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study.

BACKGROUND: Oxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study. PATIENTS AND METHODS: Twenty-eight chemotherapy-na?ve patients (22 men and six women: median age 58 years, range 33-70), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure. RESULTS: A total of 117 cycles were given, for a median of three per patient (range 1-8). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25 cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed. CONCLUSIONS: The oxaliplatin-vinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.     

Vinorelbine alternating oral and intravenous plus carboplatin in advanced non-small-cell lung cancer: results of a multicentre phase II study.

BACKGROUND: Vinorelbine and carboplatin are both active agents in the treatment of non-small-cell lung cancer (NSCLC). Vinorelbine has recently been developed in an oral formulation, which is as active as the intravenous (i.v.) form. PATIENTS AND METHODS: Fifty-two chemonaive patients with unresectable localised or metastatic NSCLC received i.v. vinorelbine 25 mg/m(2) plus carboplatin (AUC 5) on day 1 and oral vinorelbine 60 mg/m(2) on day 8 (or day 15 if neutrophils <1500/mm(3)) every 3 weeks in an open-label, multicentre phase II study. RESULTS: A total of 224 cycles were given, with the median number per patient of four (range one to eight). Eight responses out of 52 enrolled patients were documented and validated by an independent panel review, yielding a response rate of 18.2% [95% confidence interval (CI) 6.8-29.6%] in the evaluable population. This response rate was balanced by a high rate of disease control (78.9% in the intention-to treat population and 90.9% in the evaluable population). The median progression-free and median survival were 5.1 months (95% CI 4.3-8.1) and 9.3 months (95% CI 6.8-11.4), respectively. Overall, the safety profile of the combination regimen alternating i.v. and oral vinorelbine appeared similar to that expected for each individual agent. Some lung cancer-specific items (pain, dyspnoea) improved or were stabilised by assessment using the EORTC QLQ-C30 and QLQ-LC13 questionnaires. CONCLUSIONS: The combination of carboplatin with an alternating regimen of i.v./oral vinorelbine is a well tolerated regimen with a low level of toxicity and a low rate of serious adverse events. A high rate of disease control (partial response + no change) was achieved. Progression-free survival and overall survival fell within the expected range. This regimen is convenient and safe for the treatment of patients with locally advanced or metastatic NSCLC patients.     

长春瑞滨治疗27例高龄晚期非小细胞肺癌

目的:探讨单药长春瑞滨治疗70岁以上高龄晚期非小细胞肺癌患者的疗效及毒副反应。方法:2002年9月至2004年9月采用长春瑞滨治疗70岁以上高龄晚期非小细胞肺癌(NSCLC)27例,长春瑞滨25~30mg/m2 60ml生理盐水稀释,静注第1、8天,21天为1个周期,一般3~4周期,共进行了92周期。观察近期疗效、远期疗效、不良反应、中位缓解期和中位生存期。结果:PR9例,NC10例,PD8例,总有效率33.3%。中位缓解期4.1个月,中位生存期10.3个月。白细胞减少发生率为55.4%(51/92),Ⅲ/Ⅳ度为18.5%(17/92),血小板减少率为8.7%(8/92),静脉炎发生率为6.5%(6/92)。结论:长春瑞滨在治疗高龄晚期NSCLC患者中,有较好的近期疗效,毒副反应可耐受,临床应用安全,可以作为高龄晚期非小细胞肺癌的治疗方案选择之一。     

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.     

长春瑞滨联合奥沙利铂治疗老年晚期非小细胞肺癌

目的:评价长春瑞滨(NVB)联合奥沙利铂(OXA)治疗老年晚期非小细胞肺癌的疗效和毒副反应。方法:对住院治疗的老年晚期肺癌患者28例,用NVB联合OXA方案化疗,NVB25mg/m2ivd1、8,OXA130mg/m2ivd1,4周重复。结果:全组28例共完成78周期化疗,PR11例,有效率39.29%,中位生存期10.3个月,1年生存率32.14%,主要毒副反应为骨髓抑制和周围神经炎。结论:长春瑞滨联合奥沙利铂治疗老年晚期非小细胞肺癌有较好疗效,毒副反应可以耐受。     

Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan.

BACKGROUND: To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer (NSCLC) by a non-inferiority design. PATIENTS AND METHODS: A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m(2) on day 1 plus irinotecan 60 mg/m(2) on days 1, 8, 15 every 4 weeks (IP) carboplatin AUC 6.0 min x mg/mL (area under the concentration-time curve) on day 1 plus paclitaxel 200 mg/m(2) on day 1 every 3 weeks (TC); cisplatin 80 mg/m(2) on day 1 plus gemcitabine 1000 mg/m(2) on days 1, 8 every 3 weeks (GP); and cisplatin 80 mg/m(2) on day 1 plus vinorelbine 25 mg/m(2) on days 1, 8 every 3 weeks (NP). RESULTS: The response rate, median survival time, and 1-year survival rate were 31.0%, 13.9 months, 59.2%, respectively, in IP; 32.4%, 12.3 months, 51.0% in TC; 30.1%, 14.0 months, 59.6% in GP; and 33.1%, 11.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated. CONCLUSION: The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.     

长春瑞滨加顺铂治疗48例晚期非小细胞肺癌

目的：观察长春瑞滨加顺铂联合中治疗晚期非小细胞肺癌的临床疗效。方法：48例Ⅲ-Ⅳ期非小细胞肺癌（22例初治、26例复治）,采用长春瑞滨25mg/m^2,静注,第1,5天,顺铂35mg/m^2,静注,第1－3天,联合化疗。结果：初治22例中CR＋PR14例,有效率63．6％,复治26例中CR＋PR10例,有效率38．5％,总有效率50％。中位缓解期5．5个月,中位生存期11个月。主要副反应为骨髓抑制及静脉炎,采用深静脉给药可减轻静脉炎发生。结论：长春瑞滨加顺铂联合化疗治疗晚期非小细胞肺癌疗效较高,副反应可耐受,值得临床进一步观察。     

Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group.

BACKGROUND: This phase III study was designed to compare the combination paclitaxel (Taxol)-gemcitabine (PG) versus carboplatin-gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. METHODS: Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m(2) on days 1 and 8 plus either paclitaxel 200 mg/m(2) on day 1 (arm A) or carboplatin at an area under the concentration-time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. RESULTS: A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74-12.0] for group A and 10.49 (95% CI 9.04-11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. CONCLUSION: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.     

A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Purpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m² intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.