Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.

PURPOSE: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy. PATIENTS AND METHODS: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC). RESULTS: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL. CONCLUSION: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.     

多西紫杉醇联合长春瑞滨二线治疗晚期非小细胞肺癌的临床研究

Objective:To evaluate the efficacy and toxicity of docetaxel and vinorelbine as second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).Methods:48 histologically or cytologically confirmed NSCLC patients with progressive or recurrent disease after first-line treatment were treated with docetaxel and vinorelbine.The chemotherapy included vinorelbine (25 mg/m2) on days 1,5 and docetaxel (60 mg/m2) on day 1.The treatment was repeated every 3 weeks.Patients receiving at least two cycles were evaluated for efficacy and toxicity.Results:Of 48 patients,1 patient achieved complete response and 16 achieved partial response.Overall response rate for all 48 patients was 35.4% (17/48).Main hematologic toxicities included neutropenia (60.4%) and febrile neutropenia (29.2%) and non-hematologic toxicities were mild.Conclusion:The combination of docetaxel-vinorelbine as second-line chemotherapy is an effective regimen with manageable toxicity for the treatment of advanced NSCLC.Further studies may confirm these results.     

Treatment of unresectable non-small-cell lung cancer

Current progress in the treatment of unresectable non-small-cell lung cancer (NSCLC) is reviewed. Several new agents including vinorelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan have been shown to have distinct activity for NSCLC. Combinations of a new agent with cisplatin or carboplatin were highly active for advanced NSCLC, and randomized trials are in progress to establish the standard chemotherapy regimen for advanced NSCLC. The effectiveness of concurrent chemoradiotherapy has been established in Japan, while that of induction chemotherapy has yet to be confirmed. Induction chemoradiotherapy may be useful and randomized trials comparing chemotherapy alone with chemoradiotherapy as an induction therapy are needed.     

培美曲塞联合顺铂与长春瑞滨联合顺铂一线治疗晚期NSCLC的对比研究

目的 比较培美曲塞或长春瑞滨联合顺铂一线治疗晚期非小细胞肺癌（NSCLC）的疗效及毒副反应。方法 回顾性分析我院2008年1月至2010年12月收治的68例晚期NSCLC患者,分别接受培美曲塞联合顺铂（PC方案组,32例）或长春瑞滨联合顺铂（NP方案组,36例）一线治疗。PC方案组：培美曲塞500mg／m2,d1;顺铂 25mg／m²,d₁～d₃。NP方案组：长春瑞滨 25mg／m²,d₁、d₈,顺铂25mg／m²,d₁～d₃。每3周为1周期,每2个周期评价疗效。结果 所有患者均可评价近期疗效。两组均无完全缓解病例,PC方案组与NP方案组的有效率（RR）分别为40.6%（13/32）和36.1%（13/36）,疾病控制率（DCR）分别为71.9%（23/32）和61.1%（22/36）,两组RR和DCR的差异均无统计学意义（P＞0.05）。两组中位疾病进展时间（TTP）分别为6.2和5.2个月,组间差异无统计意义（P＞0.05）。NP方案组3～4级白细胞减少、中性粒细胞减少的发生率高于PC方案组（P＜0.05）。 结论 培美曲塞联合顺铂与长春瑞滨联合顺铂一线治疗晚期NSCLC的疗效相当,但培美曲塞的毒副反应较少。     

Weekly vinorelbine and docetaxel as second-line chemotherapy for pretreated non-small cell lung cancer patients: a phase I-II trial

Docetaxel was proven to be effective as second-line therapy for patients with advanced NSCLC after failure of platinum-based front-line chemotherapy. We designed this phase I/II study to define the Maximum Tolerated Dose of weekly docetaxel combined with weekly vinorelbine, and subsequently evaluate tolerability and activity of this schedule in NSCLC patients who were progressive after treatment with either cisplatin and gemcitabine or carboplatin and paclitaxel regimens. To be eligible for the study, patients were required to have a WHO performance status < or =2, failure after at least two cycles of first platinum-based chemotherapy, and no prior treatment with docetaxel and vinorelbine. A total of 27 patients were enrolled in this phase I/II study. A weekly docetaxel dose of 25 mg/m2 was recommended in combination with fixed vinorelbine dose of 20 mg/m2, and 24 patients were treated at this dose level. Severe neutropenia (62%) and febrile neutropenia (29%) were the most frequent toxicities, with 83% of patients requiring dose modification or delay. In the phase II study, 5 (21%) patients obtained a partial response, 8 (33%) patients had stable disease, whereas 10 (42%) patients progressed. After a median follow-up of 18.7 months, median survival was 8 months, with 30% surviving at 1 year. Regardless of the use of weekly docetaxel schedule, this regimen was highly myelosuppressive, and did not seem to improve response rate and survival compared to single-agent docetaxel. No further developments of this schedule are warranted.     

A case of advanced large cell lung carcinoma for whom fourth-line chemotherapy of cisplatin and gemcitabine proved effective for the first time

CASE: A 56-year-old Japanese man who was suffering from dry cough and right neck mass visited our hospital. Chest X-ray revealed a lung mass shadow in the lower left lung field. We diagnosed it as an advanced large cell carcinoma after conducting transbronchial lung biopsy and neck lymphnode biopsy. A right neck mass enlarged after three chemotherapy regimens of carboplatin and vinorelbine for first-line, docetaxel for second-line, and TS-1 and cisplatin for third-line. Finally, cisplatin (80 mg/m(2), day 1) and gemcitabine (800 mg/m(2), day 1, 8) were administered as fourth-line therapy. Partial response was observed after completing four chemotherapy cycles. CONCLUSION: In this case, the fourth-line chemotherapy, consisting of cisplatin and gemcitabine, proved effective for refractory NSCLC. Further research should be conducted regarding third-line chemotherapy for NSCLC patients with good performance status.     

Non-cisplatin based chemotherapy in advanced non-small cell lung cancer

Platinum-based, especially cisplatin-based chemotherapy is still the backbone of combination chemotherapy for advanced non-small cell lung cancer (NSCLC). Several combinations of cisplatin-or carboplatin-based chemotherapy are widely used in the treatment of advanced NSCLC. However, cisplatin is associated with considerable toxicity and large amount of fluid infusion that may lead to reluctance on the part of both physicians and patients to accept cisplatin-based chemotherapy for incurable NSCLC. Carboplatin has also been a widely used agent in the treatment of NSCLC instead of cisplatin. However, it is controversial whether carboplatin has the same activity as cisplatin or not. Several reports showed that carboplatin was not superior but almost equal to cisplatin in terms of survival. Third generation agents have been developed in the past decades including gemcitabine, paclitaxel, docetaxel, vinorelbine and irinotecan. All of them have promising levels of anti-tumor activity for NSCLC and the development of non-platinum-based chemotherapy was expected. Several randomized trials and meta-analysis have compared platinum-based combination chemotherapy with non-platinum chemotherapy based on various combinations of these third generation agents. The analysis of these trials indicated that non-platinum based chemotherapy was not superior to platinum-based chemotherapy for survival time but less toxicity. Third-generation-based non-platinum combinations are still treatment options for advanced NSCLC patients who are not eligible for platinum-based chemotherapy.     

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century—that is, two‐drug combinations consisting of either cisplatin or carboplatin plus a third‐generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)—remain the primary treatment option for advanced non‐small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin–pemetrexed over cisplatin–gemcitabine as first‐line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single‐agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta‐analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy‐naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.     

The role of irinotecan combined with Cisplatin or Carboplatin in the treatment of advanced non-small-cell lung cancer

Since the 1980s, cisplatin therapy for advanced non-small-cell lung cancer (NSCLC) has shown improvement in patient outcome with respect to overall survival. In the past decade, several new agents, such as the taxanes (paclitaxel and docetaxel), gemcitabine, vinorelbine, and irinotecan, have also shown promising single-agent efficacy in the treatment of advanced NSCLC. Superior efficacy was observed when these 5 agents were used in combination with cisplatin as compared to cisplatin alone for treatment of patients with NSCLC. The toxicity profiles of these 5 agents were found to be largely nonoverlapping with cisplatin. The results of recent randomized trials with different cisplatin-based chemotherapy regimens have shown that platinum-based therapy is still the mainstay for treatment of NSCLC; however, it appears that a chemotherapy efficacy plateau has been reached. Moreover, it has also been shown that for patients unable to tolerate cisplatin, nonplatinum doublets consisting of gemcitabine with either taxanes or vinorelbine are equivalent in efficacy and can be alternatives for first-line treatment of advanced NSCLC. Thus, the development of new and novel strategies is essential for treatment of NSCLC patients. Ongoing trials with vaccines, signal transduction modulators, antiangiogenic agents, and gene therapy in combination with chemotherapy     

Weekly Vinorelbine and Docetaxel as Second-Line Chemotherapy for Pretreated Non-Small Cell Lung Cancer Patients: a Phase I-II Trial

Abstract

Docetaxel was proven to be effective as second-line therapy for patients with advanced NSCLC after failure of platinum-based front-line chemotherapy. We designed this phase I/II study to define the Maximum Tolerated Dose of weekly docetaxel combined with weekly vinorelbine, and subsequently evaluate tolerability and activity of this schedule in NSCLC patients who were progressive after treatment with either cisplatin and gemcitabine or carboplatin and paclitaxel regimens. To be eligible for the study, patients were required to have a WHO performance status ≤2, failure after at least two cycles of first platinum-based chemotherapy, and no prior treatment with docetaxel and vinorelbine. A total of 27 patients were enrolled in this phase I/II study. A weekly docetaxel dose of 25 mg/m² was recommended in combination with fixed vinorelbine dose of 20 mg/m², and 24 patients were treated at this dose level. Severe neutropenia (62%) and febrile neutropenia (29%) were the most frequent toxicities, with 83% of patients requiring dose modification or delay. In the phase II study, 5 (21%) patients obtained a partial response, 8 (33%) patients had stable disease, whereas 10 (42%) patients progressed. After a median follow-up of 18.7 months, median survival was 8 months, with 30% surviving at 1 year. Regardless of the use of weekly docetaxel schedule, this regimen was highly myelosuppressive, and did not seem to improve response rate and survival compared to single-agent docetaxel. No further developments of this schedule are warranted.     

TC与NP方案治疗晚期非小细胞肺癌的疗效对比观察

目的 比较紫杉醇（PTX）加卡铂（CBP）（TC方案）与长春瑞滨（NVB）加顺铂（DDP）（NP方案）治疗晚期非小细胞肺癌（NsCLC）的疗效和不良反应。方法 56例初治晚期NSCLC依照患者就诊化疗的先后顺序随机分入TC组和NP组，化疗2周期后进行评价。结果 TC组完全缓解率为10．7％，部分缓解率为42．9％，总有效率为53．6％，NP组完全缓解率为7．1％，部分缓解率为42．9％，总有效率为50．0％，2组疗效无显著性差异（P〉0．05）。TC组胃肠道反应、肾毒性和肌肉关节疼痛发生率均比NP组低，有显著性差异（P〈0．05）。结论 TC方案和NP方案均可作为治疗晚期NSCLC的一线化疗方案。     

Gemcitabine and carboplatin regimens in advanced non-small-cell lung cancer: focus on randomized phase III trials

In the past decade unequivocal evidence regarding the benefit of platinum-based chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has emerged. Several regimens consisting of either cisplatin or carboplatin combined with agents such as paclitaxel, docetaxel, gemcitabine, vinorelbine, or irinotecan have demonstrated superiority over older combinations or single-agent platinums. These regimens have roughly equivalent activity in terms of response and survival. The major differences have been in terms of toxicities and expense. Gemcitabine/carboplatin is a combination with clear activity in advanced disease and excellent tolerability. Unlike taxane-based therapy, there is minimal neuropathy and little alopecia. For registration purposes, gemcitabine was initially combined with cisplatin. Regimens combining gemcitabine with carboplatin reported a similar rate of myelotoxicity (primarily thrombocytopenia) as gemcitabine/cisplatin. The observation that a 21-day schedule in which carboplatin is administered on day 1 and gemcitabine on days 1 and 8 could substantially reduce this toxicity provided a preferred schedule for administration. The major factor limiting acceptance of this regimen was the absence of phase III data. This year a number of phase III trials were presented, which coupled with the results of large, multicenter phase II studies (including one from a US cooperative group), has now established gemcitabine/carboplatin as a standard regimen for the treatment of advanced NSCLC. Its excellent toxicity profile has also led several groups to utilize the regimen as a platform for combination with newer drugs.     

紫杉醇联合顺铂及长春瑞滨联合卡铂治疗老年晚期非小细胞肺癌的临床对照研究

为了探讨紫杉醇联合顺铂及长春瑞滨联合卡铂方案对老年晚期非小细胞肺癌(non-smallcelllungcancer,NSCLC)的疗效和毒副反应,选取初治晚期NSCLC65例,分别应用TP(紫杉醇 顺铂)、NE(长春瑞滨 卡铂)方案治疗。每例均完成2个周期化疗后评价疗效及毒副反应。结果两组患者近期有效率TP组为41·9%(13/31),NE组为41·2%(14/34),差异无统计学意义,P>0·05。中位生存期TP组8·1个月,NE组7·2个月,差异无统计学意义,P>0·05。两组毒副反应均以骨髓抑制、脱发及恶心呕吐为主,TP组恶心呕吐发生率为87·1%,NE组为73·5%,白细胞减少TP组为74·9%,NE组为85·3%。两组病例均无化疗相关死亡发生。初步研究结果提示,TP、NE联合方案是治疗老年晚期NSCLC有效且耐受性较好的方案。     

老年晚期非小细胞肺癌一线含铂两药化疗方案的疗效与安全性分析

目的评价老年晚期非小细胞肺癌一线含铂两药化疗方案的疗效和安全性。方法对2007年1月至2009年12月在中国医学科学院肿瘤医院一线接受含铂两药方案化疗的73例老年晚期非小细胞肺癌(NSCLC)患者的临床治疗情况进行回顾性分析。结果 73例老年晚期NSCLC患者,化疗方案含紫杉醇、吉西他滨、长春瑞滨和培美曲塞的患者分别为47例、21例、3例和2例;含顺铂或卡铂者分别为27例和46例。疗效评价完全缓解(CR)0例,部分缓解(PR)31例(42.5%),稳定(SD)28例(38.4%),进展(PD)14例(19.2%),疾病控制率为80.9%。化疗方案中,含顺铂或卡铂以及含紫杉醇或吉西他滨对客观有效率和疾病控制率的影响差异无统计学意义(P>0.05)。13例(17.8%)患者未出现明显的不良反应,32例(43.8%)出现1/2级的血液学或非血液学毒性,24例(32.9%)出现3/4级血液学毒性,4例(5.5%)出现3/4级非血液学毒性。在评价为PR或SD的59例患者中,中位化疗周期数为4个周期,有43例(72.9%)患者完成了≥4个周期的含铂两药方案化疗。中位无进展生存时间为6.8个月。结论三代化疗药物的含铂两药化疗方案对一般状态好的老年晚期非小细胞肺癌患者有较好的疗效和耐受性,可以作为其一线化疗的治疗选择。     

Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non-small-cell lung cancer?

Elderly patients and younger "unfit" patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (> or = 2) suffering from advanced non-small-cell lung cancer (NSCLC) are two different populations--both of which require palliative treatments. Elderly patients frequently experience progressive decline of organ function and multiple comorbidities, which need to be considered when choosing therapy. ECOG 1594 showed that advanced NSCLC patients with an ECOG PS of 2 did not tolerate platinum-based chemotherapy (cisplatin/paclitaxel, carboplatin/paclitaxel, cisplatin/docetaxel, carboplatin/paclitaxel). These data confirm that treatments designed specifically for this patient subset are needed. Single-agent chemotherapy seems to be a reasonable approach, and non-platinum-based combination chemotherapy should also be investigated. The oncology community has become increasingly aware of the magnitude of the problem of cancer in the elderly. More than 30% of lung cancers arise in patients > or = 70 years old. Elderly patients tolerate chemotherapy poorly, according to the few published papers, and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. A phase III randomized trial (ELVIS [Elderly Lung Cancer Vinorelbine Italian Study]) demonstrated survival and quality-of-life benefits with single-agent vinorelbine versus best supportive care. Among the newer drugs, gemcitabine has demonstrated activity and low toxicity in phase II studies. With this background, we performed a randomized, multicenter phase III trial (MILES [Multicenter Italian Lung Cancer in the Elderly Study]) in 707 advanced NSCLC elderly patients. The MILES study compared single-agent chemotherapy with vinorelbine or gemcitabine versus polychemotherapy with gemcitabine plus vinorelbine. Results showed no benefit in response rate, time to progression, survival, and quality of life for the combination. Single-agent chemotherapy remains the standard treatment approach for elderly NSCLC patients with advanced disease.     

Lung cancer

Aging society is coming now, the ratio of elderly patients among all lung cancer patients has currently been increasing. It is necessary for elderly patients who are under-represented in clinical trials to study their suitable regimen. Thus, phase II and III clinical trials have been performed specifically for elderly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients all over the world. As for single agent chemotherapy, there is a strong rationale for docetaxel and vinorelbine in elderly patients with advanced NSCLC. Recently, there are phase I and II clinical trial for CPT-11 monotherapy, and gefitinib and TS-1 are reasonable options for elderly patients. Alimta is tolerable for elderly, and subset analysis is performed for the elderly with recurrent NSCLC. As platinum-based chemotherapy, there are several elderly subset analyses and JCOG 0207, which is a phase III trial now in progress comparing weekly cisplatin+weekly docetaxel and weekly docetaxel. In SCLC, there is no evidence of single agent chemotherapy but combination chemotherapy such as carboplatin+etoposide is recommended. A phase III study of carboplatin+etoposide versus amrubicin under way. These studies should aim to optimize several agents for elderly patients and prolong survival, palliative care.     

Randomized phase II trial of two different schedules of docetaxel plus cisplatin as first-line therapy in advanced nonsmall cell lung cancer

BACKGROUND: There is increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. The purpose of the current randomized study was to evaluate the toxicity and efficacy of docetaxel plus cisplatin combination on 2 schedules in patients with previously untreated, advanced nonsmall-cell lung cancer (NSCLC). METHODS: Consenting patients with advanced NSCLC were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) on Day 1, plus 3-weekly (75 mg/m(2) on Day 1) or weekly (35 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle) docetaxel, for up to 6 cycles. RESULTS: Of 86 patients accrued, 41 patients were treated with 3-weekly and 43 with weekly docetaxel plus cisplatin. The most frequent grade 3/4 toxicity in the 3-weekly arm was neutropenia (56% of patients). In those receiving the weekly regimen, the frequent grade 3/4 toxicities were fatigue (44%) and nausea/vomiting (35%). The overall response rate was 40% with the 3-weekly and 39% with the weekly arm (P = .74). The median progression-free survival was 4.3 months in the 3-weekly arm and 3.9 months in the weekly arm (P = .08) and the median survival was 10.3 and 10.0 months, respectively (P = .76). Quality of life data showed no relevant difference between the arms. CONCLUSIONS: The weekly schedule of docetaxel plus cisplatin combination as first-line chemotherapy for advanced NSCLC, while feasible, has no clear advantage over the standard 3-weekly regimen.     

Chemotherapy regimens in advanced non small-cell lung cancer: recent randomized trials

The four chemotherapy regimens evaluated in Eastern Cooperative Oncology Group study 1594 (paclitaxel/ cisplatin, gemcitabine/cisplatin, docetaxel/cisplatin, and paclitaxel/carboplatin) are effective treatment options for the therapy of advanced non small-cell lung cancer (NSCLC). Only numerical differences have been noted in overall survival with these regimens, probably due to the fact that total therapy received by these patients was the same. There was an improved median time to progression with the gemcitabine/ cisplatin doublet. Choice of a chemotherapy regimen in practice is being based on the tolerability and side-effect profile of these doublets. In the foreseeable future, we will see the use of selective and individualized therapy in addition to chemotherapy in the management of advanced NSCLC.     

Is there a preferred combination chemotherapy regimen for metastastic non-small cell lung cancer?

Since over 70% of patients with non-small cell lung cancer (NSCLC) have advanced (locally advanced or metastatic) disease, the majority of NSCLC patients might benefit from chemotherapy. During the past decade, a number of new agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, and topotecan) have been found to be effective against lung cancer. These agents have been combined with cisplatin, carboplatin, and nonplatinum drugs to treat NSCLC. They, in general, produce median survival times of 8-10 months and 1- and 2-year survival rates of 35%-40% and 10%-15%, respectively. Based on this review, there is not a preferred combination chemotherapy regimen to treat advanced NSCLC patients. However, there are a number of different regimens from which to choose.