New options in the treatment of non-small cell lung cancer

The options for treating non-small cell lung cancer (NSCLC) were expanded by the introduction of the taxanes. As a single agent, docetaxel produced response rates ranging from 15 to 22% in evaluable patients in the second-line setting, with median duration of responses ranging from 5.6 to 7.5 months. To confirm the results observed in the phase II studies, a phase III trial was conducted. Three-hundred and seventy-three patients with advanced NSCLC who had failed prior platinum-based chemotherapy were randomized to receive docetaxel 100 mg/m2, docetaxel 75 mg/m2 or a reference arm consisting of vinorelbine or ifosfamide. Efficacy, safety and quality of life (using the Lung Cancer Symptom Scale) were assessed. Data from this study are forthcoming and may confirm the benefits provided by the inclusion of docetaxel in the second-line treatment of NSCLC. Docetaxel is also an active single agent in the first-line setting, with response rates ranging from 24 to 38% in evaluable patients, with a median survival of 6-13 months. Based on the single-agent activity, it was logical to evaluate the efficacy of docetaxel in combination with other active agents. As such, docetaxel has been studied in with numerous other agents such as vinorelbine, gemcitabine, platinums, etc. Notably cisplatin and carboplatin has shown promising rates of response and response duration in phase II trials. These combinations have now entered randomized phase III study.     

The current status of docetaxel for advanced non-small cell lung cancer

Docetaxel is an active single agent in both first- and second-line therapy of patients with advanced non-small cell lung cancer (NSCLC). Randomized trials versus best supportive care have documented an improvement in overall survival for docetaxel therapy in both settings. Docetaxel also produced a significant 1-year survival rate improvement when compared with vinorelbine or ifosfamide as second-line therapy. Docetaxel has been extensively investigated in phase I/II studies in combination with cisplatin, carboplatin, irinotecan and gemcitabine. Substantial activity has been demonstrated. In a randomized phase II trial comparing docetaxel plus cisplatin with docetaxel plus gemcitabine, the efficacy of the two regimens was almost identical (response rates 32 and 34%; 1-year survival rates 42 and 38%). However, the combination of docetaxel with gemcitabine was associated with significantly less grade III/IV neutropenia, diarrhea and nausea/vomiting. Three drug regimens combining docetaxel with, for example, gemcitabine and carboplatin or with ifosfamide and cisplatin, are producing very high response rates in phase II trials. Whether three-drug combinations including docetaxel will result in an improved outcome for patients with advanced NSCLC remains to be determined.     

Docetaxel: a review of its use in non-small cell lung cancer

Docetaxel, a semisynthetic member of the taxoid class of antineoplastic agents, is effective in the treatment of patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). In noncomparative trials in patients with NSCLC, docetaxel 75 or 100 mg/m2 produced objective response rates of 20 to 38% and 14 to 25% as a first-line or second-line monotherapy, respectively. In Japan, docetaxel 60 mg/m2 produced objective response rates of 19 to 25% in previously untreated patients. Docetaxel 100 or 75 mg/m2 produced significantly higher response rates than either vinorelbine or ifosfamide in previously treated patients; patients treated with docetaxel 75 mg/m2 had an improved 1-year survival rate compared with those who received vinorelbine or ifosfamide. Docetaxel monotherapy in chemotherapy-naive patients produced survival rates that are similar to those reported for most platinum-containing standard combinations such as cisplatin plus vinorelbine. Combination of docetaxel with one other antineoplastic resulted in objective response rates of 20 to 54% in chemotherapy-naive patients; triple chemotherapy combinations produced responses in 51 and 60% of patients. Promising results from a few small studies and one large phase II study have also indicated a potential role for docetaxel as neoadjuvant therapy. The main dose-limiting adverse event associated with docetaxel is neutropenia, and fluid retention is common in many patients. The tolerability profile is generally acceptable in the majority of patients, although extra care has to be taken in patients with impaired liver function to minimise the risk of severe or febrile neutropenia. Conclusions. Docetaxel is generally well tolerated by patients receiving treatment for locally advanced and metastatic NSCLC, and produces response and survival rates equivalent to many current standard treatment options. Comparative studies have shown that docetaxel monotherapy provides significant survival benefits over best supportive care or treatment with vinorelbine or ifosfamide. Response and 1-year survival rates with docetaxel monotherapy are particularly encouraging in patients refractory or resistant to cisplatin or carboplatin, for whom treatment options are few. Neoadjuvant docetaxel has produced improved survival compared with local treatment alone. Combinations of docetaxel with other antineoplastic agents have produced relatively high response and 1-year survival rates; however, further comparative studies are required to confirm these benefits. In the meantime, docetaxel is a welcome addition to the options available for patients with advanced NSCLC.     

Docetaxel: new indication. First-line treatment of non small-cell lung cancer: no advance

(1) The reference first-line drug therapy for patients with non-operable non small-cell lung cancer is a combination of two cytotoxic agents, one of which is a platinum compound. The survival benefit is no more than a few months. (2) The docetaxel + cisplatin combination has now been authorised in France for first-line treatment of locally advanced and metastatic non small-cell lung cancer. Evaluation data includes the results of three comparative trials. (3) In one trial the docetaxel + cisplatin combination was no more effective than the docetaxel + carboplatin combination or the vinorelbine + cisplatin combination on either the survival time (9.4 to 11.3 months) or on other endpoints. (4) Similar results were obtained in a trial versus paclitaxel + cisplatin and gemcitabine + cisplatin (median survival time 8 months in each group). (5) In a trial versus vindesine + cisplatin, the median survival time was longer with docetaxel + cisplatin (11.3 versus 9.6 months). (6) It is difficult to analyse adverse effects in these unblinded trials. Globally, the docetaxel + cisplatin combination did not appear to be safer than the comparator combinations, particularly with regard to serious events. (7) Docetaxel, like paclitaxel, is infused intravenously every three weeks. The comparator combinations tested in the three clinical trials are infused once a week. (8) In practice, for first-line treatment of inoperable non small-cell lung cancer, the docetaxel + cisplatin combination is simply one of several options, and offers no advantages in terms of survival or adverse effects.     

Advanced Non-Small Cell Lung Carcinoma: The Emerging Role of Docetaxel

The treatment of advanced non-small cell lung carcinoma(NSCLC) has improved greatly over the past decade. With theadvent of new agents, in particular taxanes, gemcitabine, vinorelbine,and topoisomerase I inhibitors, response rates have improved from15–20% to 25–35%, with commensurate improvement in median and one year survival rates to 8–10 months and 35–45%, respectively. These improvements have proven statistically significant in multiple studies [1–4].Docetaxel, either alone or in combination with platinols, hasshown particular promise; and, in some arenas, it has become a standard component of our therapeutic armamentarium. We will review the preclinical data and single agent activity of docetaxel in treatment-naïve and previously treated NSCLC patients, its activityin combination with cisplatin and carboplatin, as well as othernew agents, and finally focus on ongoing studies evaluating itsrole in locally advanced disease.     

Gemcitabine in Non-Small Cell Lung Cancer (NSCLC)

The role of chemotherapy in the treatment of non-smallcell lung cancer (NSCLC) has increased greatly in the past fewyears. While cytotoxic drugs are currently used both as singleagents and in combination for palliation in locally advanced andmetastatic disease, they have also been incorporated intomulti-modality treatment strategies of Stage I to Stage IIINSCLC. One of the main reasons for the increased acceptance ofchemotherapy is the development of new substances.Among the most promising of these new drugs is theantimetabolite gemcitabine. Several single-arm gemcitabine PhaseII studies involving more than 400 patients show validatedresponse rates in more than 20% of the patients. Thesepositive results have also been confirmed in randomized Phase IIstudies. Gemcitabine's unique mechanism of action, its lack ofoverlapping toxicity with other agents, and its favorabletoxicity profile also define it as an ideal candidate forcombination therapy.The activity seen with single-agent gemcitabine therapy canbe compared with that of cisplatin-etoposide combination therapy.Gemcitabine-cisplatin combination response rates range from31% to 54%, with a median survival time between 8.4and 15.4 months and a 1-year survival rate between 30% and59%. In addition to the clinical research ofgemcitabine-cisplatin combinations, gemcitabine has also beentested in various double and triple combinations withcarboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide.Investigations combining gemcitabine with radiation therapy areon-going. The following review will summarize results fromrepresentative Phase I/II and III studies using gemcitabine forNSCLC patients.     

Chemoresistance in non-small cell lung cancer

The treatment of advanced non-small-cell lung cancer (NSCLC is based on the combination of platin and one of the following agents: taxanes, gemcitabine, vinorelbine or irinotecan. There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.     

晚期非小细胞肺癌个体化化疗的研究进展

非小细胞肺癌(NSCLC)全球发病率高、死亡病例多。第三代化疗药物(长春瑞滨、吉西他滨、紫杉醇、多西他赛)联合铂类的两药化疗方案仍是目前NSCLC一线治疗的常规方案。与化疗疗效相关的新靶标基因(切除修复交叉互补基因1与铂类耐药、核苷酸还原酶调节因子1与吉西他滨耐药、β微管蛋白与紫杉类耐药等)有可能作为预测化疗反应的生物标记。本文结合分子病理分型综述临床个体化化疗方案研究。     

Gemcitabine and vinorelbine (GV) versus cisplatin, gemcitabine and vinorelbine (CGV) as first-line treatment in advanced non small cell lung cancer: Results of a prospective randomized phase II study

The objective of this study was to assess whether adding cisplatin to gemcitabine/vinorelbine combination improves the clinical outcome in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-na?ve patients with advanced NSCLC; age < or = 75 years: Karnofsky performance status > or = 60%, and with adequate hematological, renal and hepatic function, were randomized into 2 treatment groups to receive Gemcitabine 1250 mg/m2 + vinorelbine 30 mg/m2 (GV group), or cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 (CGV group). All drugs were administered on days 1 and 8 every three weeks: From September 1999 to March 2003, 114 patients were enrolled. No statistically significant difference was observed in GV vs CGV group in objective response (37 versus 47%, respectively; P = 0.5), median time to progression (5 versus 5.8 months; P = 0.6), overall survival (9 versus 10 months; P = 0.9) and 1-year survival (26 versus 28%; P = 0.9). Conversely, toxicities were significantly higher for CGV, including grade 3-4 neutropenia (24 versus 45%); neutropenic fever (4 versus 14%, including one toxic death); grade 3-4 thrombocytopenia (2 versus 14%); and grade 3-4 emesis (2 versus 14%). Our results suggest that the combination of gemcitabine and vinorelbine is less toxic than three-drug combination with cisplatin while showing similar efficacy.     

Vinorelbine: a review of its use in elderly patients with advanced non-small cell lung cancer

Vinorelbine is a semisynthetic vinca alkaloid that is effective as monotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC). In the large comparative Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), patients receiving vinorelbine monotherapy achieved an objective response rate of 19.7%. The median survival time and the 1-year survival rate were significantly higher in recipients of vinorelbine plus best supportive care than in recipients of best supportive care alone. Vinorelbine recipients generally scored better than recipients of best supportive care on quality-of-life (QOL) functioning scales and experienced significantly fewer lung cancer-related symptoms; however, QOL scores were worse with vinorelbine for parameters relating to drug tolerability. Comparative phase III trials investigating the efficacy of combination therapy with vinorelbine and other agents specifically in elderly patients with advanced NSCLC have been conducted only for the combination of vinorelbine and gemcitabine [the Southern Italy Cooperative Oncology Group (SICOG) trial and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)]. Objective response rates for vinorelbine/gemcitabine combination therapy in these phase III trials were 22 and 20%, respectively. The SICOG trial was closed early when an interim analysis demonstrated a significant survival advantage for combination therapy with vinorelbine plus gemcitabine over vinorelbine monotherapy. However, a survival advantage for combination therapy versus vinorelbine monotherapy was not demonstrated in the larger MILES trial. The main adverse effect of vinorelbine monotherapy in the elderly is myelosuppression. Adverse events associated with most antineoplastic agents, such as mild alopecia, nausea, vomiting and mucositis, were reported in clinical trials; however, these events were rarely severe. Mild-to-moderate neurotoxicity, including constipation (presumably from autonomic neuropathy), was also reported. The addition of gemcitabine to vinorelbine increased the incidence of both haematological and nonhaematological adverse events. However, there was no significant increase in the incidence of life-threatening toxicity. Vinorelbine as a single agent is effective in elderly patients with NSCLC and is associated with improved survival and at least a trend towards improved QOL parameters compared with best supportive care alone. Vinorelbine was associated with a generally manageable tolerability profile. The benefit of adding gemcitabine to vinorelbine for the treatment of NSCLC in the elderly is equivocal; improved survival was reported in one comparative trial, but not in another larger one. Vinorelbine is an effective and well tolerated palliative treatment option for elderly patients with advanced NSCLC.     

Phase II study of docetaxel alternating with cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.     

Biweekly administration of docetaxel and vinorelbine as second-line chemotherapy for patients with stage IIIB and IV non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 013-02)

The current report aims to evaluate the efficacy and safety profile of a biweekly administration of docetaxel and vinorelbine to patients with advanced non-small cell lung cancer, who had previously been treated for this disease. In a prospective, multicenter, open-label, phase II trial, patients received 40 mg/m of docetaxel and 20 mg/m of vinorelbine on days 1 and 15, every 28 days. Treatment continued for up to a maximum of six cycles, unless disease progression or unacceptable toxicity occurred, or consent was withdrawn. Fifty patients were enrolled in the study and they received 174 cycles of chemotherapy, with a median of three cycles per patient. All patients were evaluated for efficacy and toxicity in an intention-to-treat analysis. The overall response rate was 10% [95% confidence interval (CI): 1-19], including one complete response (2%) and four partial responses (8%). Previous chemotherapy of 80% of the responders included paclitaxel. Median time to disease progression was 2.7 months (95% CI: 2.2-4.3) and median overall survival was 6.5 months (95% CI: 2.5-9.2). The survival rates at 1 and 2 years were 18% (95% CI: 7-29) and 4% (95% CI: 0-10), respectively. The most frequent severe toxicities were neutropenia (20% of patients) and leukopenia (8% of patients). Other toxicities appeared in 4% or fewer of the patients. Biweekly administration of docetaxel and vinorelbine is feasible as a second-line treatment for non-small cell lung cancer patients, but its level of activity and toxicity does not suggest any advantage compared with the results obtained with single-agent docetaxel in the same setting.     

吉西他滨联合长春瑞滨用于转移性鼻咽癌二线治疗的临床观察

目的评价吉西他滨联合长春瑞滨二线治疗晚期鼻咽癌的近期疗效和毒性反应。方法 38例均为含顺铂方案一线化疗失败的晚期鼻咽癌患者,接受吉西他滨联合长春瑞滨方案治疗,吉西他滨1000mg/m2静脉滴注30min,d1、d8,长春瑞滨25mg/m2静脉推注,d1、d8,每21d重复一次。结果 38例共完成167个周期的治疗,中位数4周期,范围2~6周期,均可评价疗效,其中CR5例,PR20例,SD9例,PD4例,客观有效率(CR+PR)65.8%,中位缓解时间5.6个月。中位疾病进展时间6.2个月,中位生存期16.2个月;1年生存率65.8%,2年生存率44.7%。不良反应主要为Ⅰ~Ⅱ度骨髓抑制、末梢神经毒性及胃肠道反应。结论吉西他滨联合长春瑞滨二线治疗转移性鼻咽癌患者,初步观察疗效可,毒副作用可耐受,值得临床进一步研究。     

奥沙利铂加多西紫杉醇与奥沙利铂加长春瑞宾治疗43例老年晚期NSCLC的对照研究

目的评价奥沙利铂加多西紫杉醇与奥沙利铂加长春瑞宾方案治疗晚期非小细胞肺癌的临床疗效和安全性。方法可评价疗效的NSCLC患者以1：1比例随机分为治疗组与对照组。奥沙利铂联合多西紫杉醇组（治疗组）23例,奥沙利铂联合长春瑞宾组（对照组）20例。治疗组为多西紫杉醇75mg/m^2,静脉滴注2h,第1天;奥沙利铂（OXA）200mg/m^2,静脉滴注2h,第2天。每3周重复一次,行3周期（9周）治疗后判定临床效果。对照组为长春瑞滨25mg/m^2静脉推注,第1、8天;奥沙利铂用法同治疗组。结果治疗组总有效率（RR）为56.52%（13/23）;对照组总有效率（RR）为55%（11/20）。治疗组和对照组两组患者临床疗效和各项生活质量评分差异无统计学意义（P≥0.05）。治疗组恶心呕吐反应以及血红蛋白下降均较对照组轻。未出现治疗相关性死亡。结论奥沙利铂加多西紫杉醇治疗晚期非小细胞肺癌患者临床疗效高,不良反应轻微。     

A cost-utility analysis of second-line chemotherapy in metastatic breast cancer. Docetaxel versus paclitaxel versus vinorelbine

The aim of this study was to determine the incremental effectiveness, the incremental health-related quality of life (differences in quality-adjusted progression-free survival between treatments), the incremental cost and the incremental cost-effectiveness and cost-utility ratios, for docetaxel, paclitaxel and vinorelbine, when these drugs were used as second-line treatment in patients with metastatic breast cancer. In the absence of comparative direct evidence of the relative efficacy of docetaxel, paclitaxel and vinorelbine in this setting, a model was designed to determine the effects of the 3 interventions on health outcome and cost. A Markov process model, based on 53 disease states, was thus constructed to evaluate the socioeconomics of the 3 treatment regimens. The model allows assessments from the start of second-line chemotherapy until death. Costs were evaluated from the combined view of the healthcare system and the patient. Direct nonmedical and indirect costs were excluded. Consumption per episode of care was estimated by retrospective analysis of 153 medical reports from 5 different hospitals. Hospital costs were allocated values from the national accounting costs by diagnosis-related group (DRG). The content of the health states was based on the multiattribute health states classification system (MASH). Preference values were assigned by application of a standard reference lottery using 20 oncological nurses as proxies for the patients. The health-related quality-of-life score was used as a quality adjustment weighting factor to calculate quality-adjusted progression-free survival associated with the 3 different regimens. Docetaxel reduces the time spent in progression, decreases the number of complications due to progressive disease and thereby provides better quality of life. It provides a benefit of 57 disease- and discomfort-free days compared with vinorelbine and 22 days compared with paclitaxel. Docetaxel may be thought of as self-financing as a result of savings in hospital admissions, providing net savings of 6800 French francs (FF; 1993 values) compared with expenditure associated with vinorelbine treatment and FF700 compared with the equivalent figures for paclitaxel.     

Cost effectiveness of treatment with new agents in advanced non-small-cell lung cancer: a systematic review

In past decades, studies focusing on new chemotherapeutic agents for patients with inoperable non-small-cell lung cancer have reported only modest gains in survival. These health gains are achieved at considerable cost, but economic evidence is lacking on superiority of one agent in terms of cost effectiveness. The objective of this systematic review was to assess fully published cost-effectiveness studies comparing the new agents docetaxel, paclitaxel, vinorelbine, gemcitabine and pemetrexed, and the targeted therapies erlotinib and gefitinib with one another. We performed systematic searches in the bibliographic databases PubMed, EMBASE and Health Economic Evaluations (HEED) [via the Cochrane Library] for fully published studies from the past 10 years. Studies were screened by two independent reviewers according to a priori inclusion criteria. The methodological quality of the included studies was evaluated by two independent reviewers using standardized assessment tools. A total of 222 potential studies were identified; 11 studies and six reviews were included. The methodological quality of the full economic evaluations was fairly good. Transparency in costs and resource use, details on statistical tests and sensitivity analysis were points for improvement. In first-line treatment, gemcitabine+cisplatin was cost effective compared with other platinum-based regimens (paclitaxel, docetaxel and vinorelbine). In one study, pemetrexed+cisplatin was cost effective compared with gemcitabine+cisplatin in patients with non-squamous-cell carcinoma. In second-line treatment, docetaxel was cost effective compared with best supportive care; erlotinib was cost effective compared with placebo; and docetaxel and pemetrexed were dominated by erlotinib. We found indications of superiority in terms of cost effectiveness for gemcitabine+cisplatin in a first-line setting, and for erlotinib in a second-line setting.     

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.     

Gemcitabine and carboplatin in combination for the treatment of advanced,metastatic, non-small cell lung cancer

The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent, gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile. Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.     

Phase I/II trial of gemcitabine plus docetaxel in advanced non small cell lung cancer (NSCLC)

INTRODUCTION: The poor prognosis of non small cell lung cancer (NSCLC), as well as the significant toxicity from many conventional cytotoxic regimens warrants the investigation of combinations of new active agents for treatment. This is a phase I-II (dose-finding, efficacy, and toxicity) study of docetaxel + gemcitabine in patients with stage IIIB-IV NSCLC without prior systemic therapy. Patients were treated in cohorts of 3 with alternating increasing doses of docetaxel and gemcitabine at each level. Patients: Fifty patients were entered, of which 49 were eligible including 28 males and 21 females; 15 stage IIIB and 34 stage IV; median age 57 yrs (35-74). RESULTS: The Maximum Tolerated Dose (MTD) was docetaxel 60 mg/m(2) day 1 and gemcitabine 750 mg/m(2) d1 & 8, every 21 days. The overall response rate is 20%. Eight patients are not formally assessable for response due to early discontinuation or loss to follow-up and are considered to have progressive disease. The median time to progression (TTP) is 3.5 months (1-25), with 11 pts with at least 7 months TTP. There were 10 pts (20%) with a partial response (PR); 18 (37%) maintained stable disease; 21 (43%) had progressive disease (PD) or were not assessable. Toxicity: Forty-nine patients are evaluable for assessment for toxicity: Grade (Gr) 3/4 toxicity was documented thus: 14 with neutropenia, 1 with anemia, 1 with nausea, 2 liver function, 2 dyspnea, 2 fatigue, 1 allergy, 1 neurologic. CONCLUSION: This regimen is well tolerated and results in phase I-II testing in this patient population warrant further consideration of the study of docetaxel + gemcitabine for advanced NSCLC.