Lung and mediastinum: Edited by Cesare Gridelli
The majority of patients affected by nonsmall cell lung cancer (NSCLC) have advanced disease at diagnosis, and medical treatment is the cornerstone of management. Platin-based doublets including a third-generation drug such as gemcitabine, docetaxel, paclitaxel and vinorelbine have shown superimposable efficacy with different toxicity profiles . With this background, the choice of a chemotherapy regimen was until not long ago based on the oncologist's preference according to his or her clinical practice. Today, the decision scenario is more complicated due to the recent improvements in medical treatment. The major advancements in understanding cancer biology and the mechanisms of oncogenesis have allowed the development of several potential molecular targets for the treatment of cancer, which are components of signalling pathways or metabolic processes contributing to the acquisition of cancer phenotype. Several targeted agents and chemotherapy agents have been introduced in clinical trials, and recently a number of drugs have been approved for use in clinical practice. Bevacizumab, an antiangiogenetic monoclonal antibody, combined with chemotherapy showed superior efficacy as compared with chemotherapy alone. A randomized phase III trial (study E4599) comparing the combination of bevacizumab plus carboplatin plus paclitaxel versus chemotherapy alone in advanced nonsquamous NSCLC showed progression-free survival (PFS) and survival advantage favouring the bevacizumab arm . In the AVAiL (AVAstin in Lung) trial, a randomized phase III study in nonsquamous histology, cisplatin plus gemcitabine chemotherapy was compared with chemotherapy plus two different doses of bevacizumab, 7.5 and 15 mg/kg. The primary endpoint was PFS, and statistically significant differences favouring both bevacizumab combinations were reported, with no survival difference . The main issue with bevacizumab is that it needs patient selection, as in fact, to date, the drug can be used only in nonsquamous histology due to a high risk of pulmonary bleeding in squamous carcinoma. To date, bevacizumab is licensed for advanced nonsquamous NSCLC.
Recently, a phase III randomized trial in advanced NSCLC patients compared the new chemotherapy combination of cisplatin plus pemetrexed versus cisplatin plus gemcitabine . In the whole patient population the two regimens showed superimposable efficacy in terms of response rate, PFS and overall survival, with a better toxicity profile favouring the pemetrexed arm. A preplanned subgroup analysis showed a statistically significant advantage in all outcomes for cisplatin plus pemetrexed as compared with cisplatin plus gemcitabine in nonsquamous histology. On the contrary, the advantage of the cisplatin plus gemcitabine combination in squamous carcinoma was clear. This observation has its biological explanation in the higher protein level of thymydilate-synthase, the primary target of pemetrexed, observed in squamous cell carcinoma . After this study, pemetrexed was licensed for first-line treatment of advanced nonsquamous NSCLC.
Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment and patients outcome over the last several years. Recently, a phase III randomized trial, comparing, in a first-line setting, never- or very light smoking Asian patients affected by advanced pulmonary adenocarcinoma, gefitinib to carboplatin plus paclitaxel chemotherapy, showed no difference in terms of PFS and survival in the overall patients population . A subset analysis of patients with tumour EGFR mutation showed a large benefit in PFS for gefitinib compared with chemotherapy. The European Medicines Agency (EMEA) approved the drug for use as first-line treatment of advanced NSCLC with EGFR mutation. Cetuximab is an anti-EGFR monoclonal antibody approved for use in the treatment of colorectal carcinoma and head and neck cancer. Very recently, in the FLEX (first-line in lung cancer with Erbitux) phase III randomized trial, the combination of cisplatin and vinorelbine plus cetuximab demonstrated superiority in terms of response rate and overall survival (6 weeks median survival gain) compared with the same chemotherapy alone in the first-line treatment of advanced EGFR expressing NSCLC . On July 2009, EMEA did not approve the drug for the treatment of advanced NSCLC and a Merck–Serono appeal against the decision is ongoing.
Based on this scenario, in order to choose an optimal treatment, a general NSCLC diagnosis is not enough and we should always try to obtain a sample of tumour tissue. After a specific diagnosis we should keep in mind a possible algorithm for front-line treatment decision (Fig. 1).
For squamous carcinoma a platin-based doublet including a third-generation drug (i.e. gemcitabine, docetaxel, paclitaxel, vinorelbine) excluding pemetrexed, waiting for a regulatory final decision for cetuximab should be considered. For nonsquamous carcinoma, mainly in never-smokers and adenocarcinoma patients, we should assess EGFR mutation, and in the case of a mutated tumour, an EGFR tyrosine kinase inhibitor should be the first-treatment option. If we have an EGFR wild-type tumour or EGFR mutation was not assessed, platin-based chemotherapy plus bevacizumab, if patient is eligible for bevacizumab according to safety selection criteria, or cisplatin plus pemetrexed should be considered the preferred option. However, in this case a platin-based doublet including a third-generation drug may be taken into account, with cetuximab as a further opportunity if licensed.
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