Latest options for advanced NSCLC

teaser

Davide Tassinari
MD
Associate Professor
Department of Oncology
City Hospital
Rimini
Italy
E:[email protected]

Nonsmall-cell lung cancer (NSCLC) is one of the most frequent tumours in industrialised countries, and its incidence is increasing in Europe and North America.(1) The mortality and lethality rates are quite impressive, with an overall five-year survival rate (ranging from over 60% in limited disease to less than 1% in metastatic disease).(2) Two reasons determine such an unfavourable outcome:

• The difficulty of a praecox diagnosis, even in high-risk population (eg, smokers).
• The limited efficacy of medical treatments in advanced disease.

For many years, surgery represented the only approach to improve survival of patients with limited disease, and few options existed for patients with locally advanced or metastatic disease, generally with disappointing results. However, many recent data suggest improvement in the outcome of medical treatment of NSCLC. Two concepts can now be assumed as primary milestones in the clinical approach to the disease:

• Polychemotherapy represents the treatment of choice for advanced disease.
• Platinum-containing regimens are the most effective treatments in advanced disease.(3)

On the basis of the pivotal meta-analysis carried out by the NSCLC Collaborative Group,(3) it is interesting to examine the medical approach to locally advanced or metastatic disease and the recent controversial data about the role of adjuvant chemotherapy in radically resected disease.

Discussion
The NSCLC Collaborative Group meta-analysis, published in 1995, is undoubtedly one of the most important papers about the treatment of NSCLC, as it demonstrated that platinum-containing regimens can improve overall survival of patients with locally advanced or metastatic disease.(3) In the following years, many authors tried to define either the most effective or the best-tolerated schedule combining one or more drugs with cisplatin in the treatment of advanced disease. The reasons favouring such an impressive number of randomised trials can be summarised as follows:

• Although the meta-analysis demonstrated improvement in overall survival in patients treated with platinum-containing regimens from a statistical point of view, improvement of only a few months in expected survival was disappointing from a clinical point of view.
• The schedules used in the trials examined in the meta-analysis were already obsolete when the paper was published, and none of the promising new drugs (gemcitabine, taxanes, vinorelbine or irinotecan) had been investigated in those trials.
• In addition to the lack of data about the new drugs in cisplatin combinations, a further question was related to the number of drugs that could be combined to cisplatin to obtain the best therapeutic index.

The results of the main randomised clinical trials that followed the meta-analysis of the NSCLC Collaborative Group can be summarised as follows:

• Two-drug combinations are the treatment of choice for advanced NSCLC. Three-drug combinations do not improve the main outcomes, and worsen safety data.
• Vinorelbine, docetaxel, paclitaxel or gemcitabine are the partners of choice in cisplatin combinations. No difference in outcome has been observed among these four molecules.(4)

The identification of platinum-based doublets as the treatment of choice in chemotherapy-naive advanced NSCLC patients has opened three fundamental dimensions:

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• Do the different platinum compounds present equivalent effectiveness and safety profiles?
• What is the gold standard (if any) in the treatment of elderly or frail patients?
• Is any second-line treatment to be carried out in patients with resistant or relapsed disease after a first-line treatment with platinum-containing regimens?

Many authors tried to answer these questions. Until 2004, carboplatin and cisplatin were considered two alternatives with comparable efficacy and different safety profile (carboplatin has greater haematological toxicity, but lower nausea–vomiting and renal toxicity) in the treatment of NSCLC. However, at the last ASCO meeting in June 2004, Zojwalla et al presented the results of a meta-analysis suggesting a modest but significant survival benefit of cisplatin in stage III and IV NSCLC.(5) Conversely, at present, no conclusive data comparing oxaliplatin and cisplatin have been reported in the literature.(6,7)

Monochemotherapy with vinorelbine or gemcitabine can improve the main outcomes in elderly cancer patients with acceptable safety profile. Neither polychemotherapy nor platinum-containing regimens can be recommended in elderly patients because of significant occurrence of side-effects.(8–10)

Docetaxel is the only agent that has been demonstrated to improve overall survival in pretreated cancer patients. Gefitinib, a biological agent, has been shown to give an interesting response rate and improvement in quality of life as third-line treatment after relapse or progression in patients pretreated with platinum compounds and docetaxel.(11–13)

On the basis of the evidence of activity and efficacy of cisplatin-based chemotherapy in advanced NSCLC, such a treatment has also been tested in patients with locally advanced disease (stage IIIA) and in high-risk resected patients (neoadjuvant and adjuvant approaches, respectively).(14) The rationale of neoadjuvant chemotherapy in stage IIIA NSCLC is the reduction of tumoural mass, to favour surgical approach and improve disease-free interval and overall survival. However, the randomised clinical trials have some methodological limits that make the neoadjuvant approach interesting, but at least questionable in clinical practice.(15,16) In particular, the data appear inconclusive, and enrolling patients with stage IIIA NSCLC into clinical trials still represents the strategy of choice.

Regarding the role of adjuvant chemotherapy in radically resected NSCLC, four trials – the Adjuvant Lung Project Italy (ALPI) trial,(17) the International Adjuvant Lung Cancer Trial Collaborative Group trial,(18) and two trials (JBR.10 and Cancer and Leukemia Group B [CALGB] 9633 trials) presented at the 2004 ASCO annual meeting(19,20) – have recently reported some new interesting (although questionable) data that could change the standard approach in the near future. The results of these trials have been widely commented on in the last months, and a definitive conclusion is probably still far from being reached.(21–25) The deep differences between the former, negative trial (the ALPI trial) and the more recent, positive trials (the IALC, JBR.10 and CALGB 9633 trials) have been analysed by different groups of researchers and, at present, adjuvant chemotherapy in locally resected NSCLC appears as a new, interesting option for this disease, the outcome of which remains poor despite improvement in locally advanced or metastatic disease. Although results from recent phase III trials cannot be considered conclusive,(25) platinum- containing chemotherapy is likely to play a role in such a subset of patients, and after the ASCO 2004 meeting it may be difficult to assert that adjuvant chemotherapy is not the standard strategy in radically resected NSCLC.

Finally, in addition to the role of chemotherapy in metastatic, locally advanced or radically resected NSCLC, biological treatments, in particular epithelial growth factor receptor (EGFR) inhibitors, have a role to play. Apart from preclinical experiences, most clinical experiences are currently related to the role of gefitinib in the treatment of platinum- and docetaxel-resistant patients (Iressa Dose Evaluation in Advanced Lung cancer  [IDEAL] 1 and 2 trials), and its use combined with chemotherapy (Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 1 and 2 trials). (12,13,26,27) Data on the use of gefitinib can be summarised as follows:

• Gefitinib may represent an interesting option in platinum- and taxane-resistant patients, although the design or the outcomes of IDEAL 1 and 2 trials are questionable, as both trials are randomised phase II trials with quality of life as efficacy index.
• The addition of gefitinib to chemotherapy does not seem to improve the outcome of first-line chemotherapy. A biological characterisation of patients should probably be performed to select the subset of patients with good chances of response to such an association.(28–31)
• Besides the need of a biological characterisation of the disease, nonsmoker women and patients with bronchioloalveolar carcinoma probably represent the groups with the highest probability of response.(28–31)

Conclusion
In addition to the role of platinum-containing regimens in the treatment of advanced disease, different trials have suggested a role of chemotherapy in both adjuvant and neoadjuvant setting, widening the indications to chemotherapy from the palliative setting to a comprehensive dimension of treatment. Moreover, data on second-line chemotherapy  and biological treatments seem to hold promise for the treatment of this disease.

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