Place des thérapeutiques biologiques ciblées

Two targeted therapies are approved by the FDA-for the treatment of non-small cell lung cancer (NSCLC). Bévacizumab (Avastin®) is an anti-angiogenic drug; it is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Combined with standard first-line chemotherapy in two phase III studies in advanced or metastatic, non squamous non-small cell lung cancers, it induced an improvement in response rates and progression-free survival compared to chemotherapy alone, and a significant advantage as regards survival in combination with a carboplatin paclitaxel-based chemotherapy. Toxic effects limit its use. Erlotinib (Tarceva®), the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrated a benefit in survival in a randomized phase III trial comparing Erlotinib to best supportive care in second or third line treatment after failure of a platinum-based chemotherapy in patients with advanced or metastatic NSCLC. Its toxicity profile is more favourable and its use needs to be better defined compared to the two other drugs approved as second line treatment for advanced or metastatic NSCLC.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Neglected and underrepresented subpopulations: elderly and performance status 2 patients with advanced-stage non-small-cell lung cancer

Elderly patients and those with performance status (PS) of 2 with non-small-cell lung cancer (NSCLC) have been habitually underrepresented in clinical trials. Therapeutic neglect and legitimate concerns about toxicity are responsible. Yet randomized phase III data in the elderly have demonstrated a survival benefit for single-agent chemotherapy compared with best supportive care, and retrospective analyses of fit elderly patients enrolled on platinum agent-based trials have shown similar survival rates, albeit more toxicity, compared with younger counterparts. To date, however, there are no phase III trials specific to the elderly population demonstrating a survival benefit for platinum agent-based combinations compared with the constituent nonplatinum single agent; such efforts are ongoing. Performance status is a critical prognostic factor in advanced-stage NSCLC. Retrospective analyses of multiple trials conducted before 1995 suggested that patients with advanced-stage NSCLC and compromised PS experienced substantial toxicity and virtually no benefit from systemic chemotherapy, leading most cooperative groups to suspend research in this cohort. But this trend has changed. A subset analysis of patients with a PS of 2 enrolled on a recent Cancer and Leukemia Group B trial showed a significant survival benefit for carboplatin in combination with paclitaxel compared with paclitaxel alone, and recent randomized phase II efforts evaluating platinum agent-based combinations have yielded median survival times of > 6 months with acceptable toxicity rates. Although the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction trials testing polyglutamated paclitaxel failed to show a survival advantage compared with standard agents, interest in testing new, less toxic agents continues. Future efforts will need to differentiate the reasons for compromised PS, be it tumor burden, comorbidity, or both.     

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.     

Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer

BACKGROUND: In phase II trials, paclitaxel has been shown to have antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). However, the survival and quality-of-life (QOL) benefits of paclitaxel used as a single agent compared with supportive care alone have not been assessed in a randomized clinical trial. METHODS: A total of 157 patients with stage IIIB or IV NSCLC who had received no prior chemotherapy were randomly assigned to receive either best supportive care alone (78 patients) or paclitaxel plus supportive care (79 patients). Paclitaxel was administered as a 3-hour intravenous infusion every 3 weeks. Supportive care included palliative radiotherapy and supportive therapy with corticosteroids, antibiotics, analgesics, antiemetics, transfusions, and other symptomatic therapy as required. The primary end point of the study was survival. Time to disease progression, response rate, adverse events, and QOL were secondary end points. RESULTS: Pretreatment characteristics were evenly distributed between the two arms. Survival was statistically significantly better in the paclitaxel plus supportive care arm than in the supportive care alone arm (two-sided P =.037) (median survival = 6.8 months versus 4.8 months). Cox multivariate analysis showed paclitaxel plus supportive care to be statistically significantly associated with improved survival (two-sided P =.048). QOL was similar for both treatment arms, except for the functional activity score of the Rotterdam Symptom Checklist, where QOL data statistically significantly favored the paclitaxel plus supportive care arm (two-sided P =.043). CONCLUSION: The addition of paclitaxel to best supportive care significantly improved survival and time to disease progression compared with best supportive care in patients with advanced NSCLC and may improve some aspects of QOL.     

The Optimal Chemotherapy for Stage III Non–Small Cell Lung Cancer Patients

Nearly one third of non–small cell lung cancer (NSCLC) patients at diagnosis have stage III disease. Concurrent chemoradiation has emerged as the standard of care for patients with unresectable stage III NSCLC. Meta-analyses of studies comparing concurrent with sequential therapy showed that there was a relative improvement of about 20% with concurrent therapy over sequential therapy in these patients and that concurrent chemoradiation is more toxic than the sequential approach, particularly with regard to esophagitis. The incidence of pneumonitis is not significantly higher with concurrent therapy. All the phase 3 trials comparing concurrent with sequential therapy included cisplatin-based therapy. In addition, patients enrolled in these studies were required to have good performance status and some studies mandated limited weight loss. Some patients are also treated with lower doses of chemotherapy, particularly carboplatin and paclitaxel, concurrently with radiation followed by full-dose chemotherapy. Randomized studies have failed to show benefit of induction or consolidation chemotherapy. For patients who have a poor performance status or significant weight loss, a sequential approach of chemotherapy followed by radiation may be appropriate. Ongoing clinical trials are evaluating the utility of integrating some of the newer agents such as pemetrexed and cetuximab into the treatment plan for stage III patients.     

Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline

This evidence-based practice guideline on the use of paclitaxel (Taxol^®) or docetaxel (Taxotere^®) as first-line treatment for patients with advanced non-small cell lung cancer who are candidates for palliative first-line chemotherapy is based on a systematic search and review of literature published in full or in abstract form between 1985 and April 2005. Forty-five randomized trials, including 11 abstracts, were reviewed and clinicians in the province of Ontario, Canada, provided feedback on a draft version of the guideline. Two phase III trials detected a statistically significant survival advantage for a taxane (paclitaxel or docetaxel) with best supportive care versus best supportive care alone. Among the nine fully published phase III trials comparing platinum-based chemotherapies, taxane-platinum combinations achieved higher response rates compared with older chemotherapy combinations, although significantly longer survival was observed only for docetaxel-cisplatin compared with vindesine-cisplatin. Response rates and survival were generally not significantly different for taxane-platinum combinations compared with other current chemotherapy combinations, although the toxicity profile of the regimens varied. However, in one large trial, improved tumor response and modest survival and quality of life benefits were associated with docetaxel-cisplatin compared with vinorelbine-cisplatin. No statistically significant survival differences were detected in the three fully published phase III trials comparing a taxane-gemcitabine combination with a taxane-platinum regimen.

Recommendations: (i) paclitaxel or docetaxel combined with cisplatin is recommended as one of a number of chemotherapy options for the first-line treatment of advanced non-small cell lung cancer in patients with a good performance status; (ii) carboplatin may be combined with a taxane if a patient is unable or unwilling to take cisplatin; (iii) a taxane-gemcitabine combination may be considered for patients with a contraindication to cisplatin and carboplatin; (iv) no firm recommendation can be made on the optimal dose and schedule of taxane-based chemotherapy; however, commonly used regimens include cisplatin 75 mg/m² combined with either docetaxel 75 mg/m² or paclitaxel 135 mg/m² (24-h infusion) and carboplatin AUC 6 combined with paclitaxel 225 mg/m² (3-h infusion); (v) a single-agent taxane may be used if combination chemotherapy is considered inappropriate.     

Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax)

Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.     

Are chemotherapy response rates related to treatment-induced survival prolongations in patients with advanced cancer?

PURPOSE: Patients with incurable cancer are faced with difficult decisions regarding whether to take chemotherapy in an attempt to preserve the quality and/or prolong the quantity of their lives. The average prolongation in survival with chemotherapy compared with best supportive care has not been well described. METHODS: We performed a literature search using PUBMED combined with expert inquiry to identify trials comparing cytotoxic chemotherapy with best supportive care. Twenty-five randomized, controlled clinical trials comparing cytotoxic chemotherapy with best supportive care were identified. Sixteen trials (64%) were in patients with non-small-cell lung cancer (NSCLC). Data were extracted and analyzed. RESULTS: Sufficient data for statistical modeling were available for NSCLC trials. The mean sample size of the NSCLC trials was 175 patients. Response rates in the treatment arms for NSCLC ranged from 7% to 42%. A relationship between response rate and survival was observed for NSCLC. The estimated relationship for NSCLC suggested that each 3.3% increase in response rate correlated, on average, with a 1-week increase in median survival, and each 2% increase in response rate correlated, on average, with a 1% increase in 1-year survival. The mean increase in 1-year survival for trials of agents with at least a 20% response rate in NSCLC was 16%. Formulas are provided to help estimate how a given response rate may effect median and 1-year survival relative to best supportive care alone for NSCLC. CONCLUSION: We found a relationship between response rate and both median and 1-year survival in NSCLC. This information may help oncologists estimate how an NSCLC chemotherapy regimen with a given response rate can, on average, impact survival relative to supportive care alone.     

Current standards of care in small-cell and non-small-cell lung cancer

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.     

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.     

Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions

Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of first-line therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen.     

Second-line Treatment for Non–Small-Cell Lung Cancer: One Size Does Not Fit All

After progression following first-line treatment, many patients with advanced non–small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC.     

Incorporating novel agents with gemcitabine-based treatment of NSCLC

First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing.     

Chemotherapy in metastatic and locally advanced non-small cell lung cancer

The majority of patients with non-small cell lung cancer have locally advanced and metastatic disease at diagnosis. Combination platinum-based chemotherapy is the standard treatment for patients with advanced disease who have a performance status of 0-1. Chemotherapy is superior to supportive care alone in terms of survival, palliation of symptoms, and in many studies, improving quality of life. Newer third generation therapies such as paclitaxel, docetaxel, vinorelbine, and gemcitabine have been proven effective as single agents with minimal toxicity, compared with supportive care alone. In combination with platinum, these agents produce higher response rates than older platinum-based regimens, are associated with additional survival benefits, and are generally more convenient and less toxic for patients. Newer nonplatinum doublets appear equivalent to newer platinum-regimens and have expanded the options available for patients. Targeted agents are promising and may soon offer patients more effective and less toxic therapies. Progress in treatment in the advanced setting has led to advances in the care of locally advanced disease. Combination chemoradiotherapy is a standard treatment for locally advanced disease, and studies with newer agents are in progress.     

Lung Cancer Highlights from ASCO 2005

Exciting news regarding lung cancer was presented at the American Society of Clinical Oncology (ASCO) 2005 Annual Meeting held in Orlando, FL. Last but not least among the big killers, after breast cancer and colorectal cancer, non-small cell lung cancer (NSCLC) can now benefit from the addition of a molecularly targeted agent to standard first-line chemotherapy. The Eastern Cooperative Oncology Group 4599 phase III trial showed superior survival in patients with advanced nonsquamous NSCLC when the angiogenesis inhibitor bevacizumab was added to standard first-line chemotherapy with carboplatin and paclitaxel, compared with the same chemotherapy alone. Careful patient selection is mandatory to avoid fatal bleeding following bevacizumab administration. The role of surgery in the multimodality treatment of stage III NSCLC was further defined by the North American Intergroup 0139 trial and the European Organization for the Research and Treatment of Cancer Lung Cancer group 08941 trial. The final results of the Adjuvant Navelbine International Trialist Association trial add further support to adjuvant platinum-based chemotherapy following radical surgery in early-stage NSCLC. Interesting studies further addressed the correlation between molecular tumor profiling and clinical outcome with molecularly targeted agents in NSCLC, in particular gefitinib and erlotinib. Still, the Southwest Oncology Group 0023 randomized trial of maintenance gefitinib after definitive chemoradiation in unresectable NSCLC failed to demonstrate an advantage for maintenance gefitinib over placebo. Unfortunately, no striking results have been reported for small cell lung cancer and pleural malignant mesothelioma. The results of the studies in this report are updated with the data presented at the 2005 ASCO Annual Meeting.     

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.     

The place of targeted therapy in the patient management of non-small cell lung cancer

There is much interest in the use of targeted therapies for the management of non-small cell lung cancer (NSCLC). To date, four targeted therapies - bevacizumab, cetuximab, erlotinib and gefitinib - have been investigated in randomised trials, in the treatment of advanced NSCLC. In the first-line setting, bevacizumab has been shown to significantly prolong survival when added to carboplatin/paclitaxel, as demonstrated in a large phase III study. However, issues of toxicity limit this treatment regimen to selected patients. The addition of bevacizumab to gemcitabine/cisplatin will be reported at ASCO 2007. The addition of cetuximab to cisplatin/vinorelbine has also been shown to improve survival in a randomised phase II study. Erlotinib has been investigated as monotherapy in first-line chemo-na?ve patients and has demonstrated objective response rates of 10-23%. However, in a study comparing erlotinib versus chemotherapy, the outcome was less favourable for patients who had received erlotinib. Erlotinib monotherapy has also been investigated in recurrent disease, and has been shown to improve overall survival over that achieved with placebo. The greatest benefit was observed in never-smokers with epidermal growth factor receptor-positive tumours. In a further phase II randomised study, the effect of combining two targeted therapies has been investigated. This study compared erlotinib/bevacizumab versus bevacizumab/chemotherapy versus chemotherapy alone. Both regimens including targeted therapy were comparable and superior to chemotherapy alone. However, these are preliminary data and further research is required to clarify the role of targeted therapies in the management of advanced NSCLC.     

Single-agent chemotherapy for non-small cell lung cancer

The survival and quality of life benefits of combination chemotherapy in patients with non-small cell lung cancer (NSCLC) are now well recognized. Since many clinical trials have been conducted in relatively young patients with good performance status, many elderly patients and patients with poor performance status are not offered chemotherapy because of concerns about higher risks of toxicity. The newer agents, including topotecan, are active as single agents in NSCLC, achieving response rates of up to 30%. Overall survival and symptoms may be improved when these agents are added to best supportive care. They are well tolerated in both elderly patients and patients with poor performance status. The major toxicity with the standard 5-day administration schedule of topotecan is myelosuppression, but weekly schedules may offer reduced toxicity while maintaining efficacy. Thus, single-agent therapy with newer agents is generally considered in elderly and poor performance status patients. However, combination chemotherapy may also be appropriate for some patients in these subgroups. Future studies of chemotherapy in NSCLC should not exclude elderly patients and patients with poor performance status.     

A systematic overview of chemotherapy effects in non-small cell lung cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy for non-small cell lung cancer (NSCLC) is based on 53 scientific publications including six meta-analyses based on 65 prospective randomised trials comprising 15,607 patients and an additional 32 prospective randomised studies including 8,902 patients. The conclusions reached can be summarised into the following points: In stage IIIB-IV disease, published data demonstrate that cisplatin-based chemotherapy confers a modest, median 1.5-3 months, prolongation of survival. The closely related compound carboplatin seems to provide similar effects. Randomised studies indicate symptomatic relief and improvement of indices of quality of life (QoL) for patients who receive platinum-based combination chemotherapy or single drug therapy with more recent compounds. Data supporting the use of chemotherapy are not available for patients in poor general condition (WHO performance status 3 4) and evidence is limited for elderly patients (above 70-75 years). Platinum-based chemotherapy can be recommended for selective use in routine care of advanced NSCLC although patients should be encouraged to participate in controlled clinical trials to further elucidate the role of chemotherapy in advanced disease. In advanced disease, recent data suggest that the newer agents gemcitabine, paclitaxel, irinotecan and vinorelbine, in combination with cisplatin, provide an additional survival benefit compared with earlier cisplatin-based regimens. Furthermore, paclitaxel, docetaxel and vinorelbine as single agents seemingly provide a survival benefit over supportive care alone comparable to that of older cisplatin-based combinations. A standard regimen for advanced disease cannot yet be defined. Until more data are at hand, it is recommended to be platinum-based and preferably combined with one of the newer agents. At progression after platinum-based chemotherapy for advanced disease, limited data indicate a small survival benefit from docetaxel over supportive care alone. Such second-line chemotherapy of advanced disease can be recommended for selected patients but should preferably be confined to controlled clinical trials. In stage III disease, published data show that induction cisplatin-based chemotherapy before radical radiotherapy modestly prolongs long-term survival and lowers the incidence of distant metastases compared with radiotherapy alone. Furthermore, published data show that concurrent chemo- and radiotherapy with cisplatin or carboplatin may enhance local control and long-term survival. Chemotherapy in this setting can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. In stage IIIAN2 disease, data from pilot studies demonstrate that surgery after induction chemotherapy is feasible. Pathologically complete remissions have been confirmed in 10-20% of treated patients. Two small randomised studies demonstrate a significant survival advantage for induction chemotherapy followed by surgery compared with surgery alone. Induction chemotherapy can be recommended for selected patients but treatment should preferably be given within a controlled clinical trial. The superiority of induction chemotherapy plus surgery compared with combined chemotherapy and radical irradiation has not been proven in a randomised trial but currently such studies are under way. In the adjuvant setting, published data suggest that cisplatin-based chemotherapy after radical surgery may increase five-year survival from around 50% by a further 5% but the confidence interval for this estimate is too wide for firm conclusions. Large-scale prospective randomised trials are under way to resolve this important issue and adjuvant chemotherapy is, thus, not recommended for routine treatment.