Chemotherapy is the established standard of care in nonsmall-cell lung cancer (NSCLC). The range of chemotherapy indications has recently been widened, including adjuvant chemotherapy in early stages (I–III) and chemotherapy in the elderly or unfit (Eastern Cooperative Oncology Group [ECOG]/Zubrod performance status 2) patients. Chemotherapy doublet is the standard recommendation; alternatively, a platinum-free combination may be used. Second-line therapy has become standard in good-performance-status patients. Targeted therapy with small molecules is effective in advanced stages following chemotherapy, and is now under investigation for the early stages of the disease.
The advent of adjuvant chemotherapy
Although curative surgery is the cornerstone of early-stage lung cancer therapy, the five-year overall survival rates for NSCLC stage IB–IIIA patients are <50%, with the majority of relapses occurring in distant sites. Postoperative platinum- based chemotherapy improves survival in 4–5% of patients. This was first indicated by a meta-analysis of adjuvant cisplatin-based trials performed between 1965 and 1991.(1) A European trial could not show a survival advantage, probably due to insufficient dose intensity and compliance.(2)
However, survival benefit with adjuvant chemotherapy was demonstrated in two large randomised studies in 2003, and was confirmed by results presented at the ASCO 2004 Annual Meeting in New Orleans (LA, USA). The European International Adjuvant Lung Cancer T (IALT) study(3) and a Japanese study,(4) both published in 2003, demonstrated a significant survival benefit with adjuvant chemotherapy. Two recent studies presented at ASCO 2004 confirmed these positive results in stage IB and II patients.(5,6) The National Cancer Institute of Canada (NCIC) study in NSCLC stage IB and II patients used four cycles of cisplatin–vinorelbine. The five-year survival in the chemotherapy group was 69% compared with 54% in the control group, showing a significant reduction (30%) of death risk with adjuvant chemotherapy. The Cancer and Leukemia Group B (CALGB) study in NSCLC stage IB patients following complete resection used four cycles of carboplatin–paclitaxel, resulting in a mortality rate reduction of 12% in the chemotherapy group. In conclusion, adjuvant chemotherapy using a platinum-based regimen (cisplatin or carboplatin) should be recommended following surgery in NSCLC stage IB and III in patients with good performance status and low comorbidity.
Preoperative chemotherapy in locally advanced stages
A German multicentre study in stage IIIA/B patients compared preoperative chemotherapy (consisting of cisplatinum–etoposid [PE]) alone with preoperative chemoradiotherapy using a hyperfractionated radiotherapy (hfRT) schedule (hfRT/CT).(7) Results showed that addition of hfRT/CT to PE before planned surgery had no impact on progression-free survival or survival but contributed to significantly higher rates of grade 3/4 oesophagitis. In addition, in this setting, preoperative chemotherapy is less toxic than preoperative chemoradiotherapy.
Chemotherapy doublet with or without platinum
In the 1990s, cisplatin-based combination chemotherapy was shown to improve survival and quality of life in patients with advanced NSCLC. Chemotherapy is indicated in individuals with good performance status (ECOG status 0 or 1, and possibly 2).(8)
Many different two-drug combinations, including cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine and vinorelbine, provide similar efficacy results,(9) response rates, one-year survival rates and toxicity.(10,11) Evolving data also suggest that two-drug combinations are superior to single-drug therapy, irrespective of which of the six single drugs is used.(9) ASCO 2004 guidelines(8) recommend that nonplatinum-based chemotherapy regimens may be used as an alternative to platinum-based regimens in first-line treatment. Single-agent chemotherapy is recommended only in elderly patients or in patients with an ECOG performance status of 2.
Second-line chemotherapy is currently the established standard of care in good-performance patients. Docetaxel monotherapy showed a significant survival benefit and symptom improvement when compared with the best supportive care.(12) Updated ASCO guidelines 2003 recommend docetaxel following platinum-based first-line therapy.(7) Weekly docetaxel may be better tolerated and as effective as docetaxel three times a week.(13) Alimta (pemetrexed), a new multitarget antifolate, seems to be as effective as docetaxel, with the same response rate (9%), time to progression and survival rate, but with a more favourable toxicity profile.(14)
Efficacy in second- or third-line therapy following chemotherapy
Small molecules such as gefitinib and erlotinib are orally available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) that display antitumour activity in patients with previously treated advanced NSCLC. Two large studies with gefitinib (IDEAL1 and 2) have demonstrated response rates between 11% (in American patients) and 18% (in Japanese patients) with improved disease-related symptoms and quality of life.(15,16)
Comparing the TKI erlotinib with placebo in patients following failure of first- or second-line therapy(17) showed a significant advantage in response (9% vs 0%), median survival and one-year survival (31% vs 22%) in the erlotinib group. Toxicity was mild, with mild diarrhoea and acne-like exanthemas being observed.
In conclusion, TKI therapy may prolong survival following standard first-line chemotherapy, compared with placebo. The ASCO recommendation is to use gefitinib after failure of both platinum-based and docetaxel chemotherapies.(8)
Lack of efficacy in first-line combination with chemotherapy
Although gefitinib and erlotinib are effective following chemotherapy, these drugs failed to show effectiveness when given concomitantly and in combination with standard chemotherapy. Four large studies combining two-drug platinum-based chemotherapy with TKI (gefitinib or erlotinib) led to negative results. INTACT (INnovaTive Agents in lung and ColorecTal cancer) I and III, in which gefitinib was combined with gemcitabine–cisplatin or paclitaxel– carboplatin, also showed negative results.(18,19) The TALENT and TRIBUTE studies(20,21) compared cisplatinum–gemcitabine(20) and carboplatin–paclitaxel(21) with erlotinib or placebo; no survival benefit was demonstrated in any of the four studies.
Predictive factors for response to treatment
Although most patients with NSCLC have no response to gefitinib, 10% of patients treated with this drug present a rapid and often dramatic clinical response. Somatic mutations of the EGFR may be predictive for this response to gefitinib,(22) shown to be present in nine out of 10 responding patients. Clinical response predictors include adenocarcinoma histology with bronchioloalveolar features and being a nonsmoker.(23)
Chemotherapy is the standard treatment in advanced NSCLC, in stage III patients (in combination with surgery and/or radiotherapy) and now also in adjuvant therapy of NSCLC patients. Second-line chemotherapy is currently the established standard of care in good-performance patients. Finally, TKIs are effective in pretreated patients, and future investigations will define prognostic factors for response to TKIs.
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