Head of Department
Maria Grazia Ghi
SS Giovanni e Paolo Hospital
This article aims to provide a general overview of the recent advances in the medical treatment of nonsmall-cell lung cancer (NSCLC), with special emphasis on the use of adjuvant therapy in early disease, chemotherapy with third-generation drug combinations in advanced disease (first- and secondline) and targeted therapies.
In the 1980s and early 1990s, multiple studies of adjuvant chemotherapy for NSCLC showed conflicting results. In 1995, the Non-Small Cell Lung Cancer Collaborative Group meta-analyses showed a non‑significant improvement in five-year survival (p=0.08) with platinum-based adjuvant chemotherapy(1) and chemotherapy was not justified after complete resection until the introduction of third-generation drugs (taxanes, vinorelbine, gemcitabine).
Since 2003, several trials from Europe and North America in stages I-IIIA NSCLC have been reported.(2–7) The studies using second-generation platinum-based regimens showed no benefit from adjuvant chemotherapy while the four trials using third-generation combinations showed a significant advantage in overall survival (OS) (approximately 10% absolute improvement at four to five years; see Table 1).
A lower but significant survival advantage was also observed in Japanese trials with UFT (tegafur/uracil), an oral drug widely used in Japan because of its mild toxicity but with no clear activity in Caucasian NSCLC patients. A specific meta-analysis on 2,003 patients from six Japanese trials has recently been published.(8) The OS benefit of adjuvant UFT administered for one to two years was of 7% at seven years (p=0.001). It is important to note that more than 80% of the patients were stage I adenocarcinoma. It is difficult to translate these data to Caucasian populations and the hypothesis of a particular genetic sensitivity to UFT in the Japanese population remains an unanswered question.
Recent adjuvant studies suggest that in medically fit patients with adequate performance status and resected stage IB–IIIA NSCLC, four cycles of platinum-based third-generation doublets should be considered. For Japanese patients with stage I adenocarcinoma, one to two years of oral UFT is an acceptable option.
Recent meta-analyses have shown that:
- Doublets (platinum plus a third-generation drug) are superior to single agents.(9,10)
- Platinum-based doublets are marginallysuperior to nonplatinum, third-generation doublets (ie, paclitaxel/gemcitabine,gemcitabine/vinorelbine).(11,12)
- Platinum-based triplets are superior to doublets in response rate (RR) but not in OS.(9)
Third-generation platinum-based doublets (cisplatin/carboplatin plus paclitaxel/docetaxel or gemcitabine or vinorelbine) are usually employed as firstline chemotherapy for advanced NSCLC. A series of randomised phase III studies showed similar results for platinum-based third-generation doublets in terms of RR (20–25%), time to progression (TTP; three to four months) and OS (eight months), as well as minimal differences in toxicity.
The first trial showing significant survival superiority with a third-generation triplet over doublet has recently been published.(13) A total of 324 stage IIIB–IV patients were randomised to receive paclitaxel/carboplatin (PC) or paclitaxel/carboplatin/gemcitabine (PCG). The RR (43.6% vs 20.2%; p<0.0001), the median survival time (10.8 vs 8.3 months: p=0.044), the one- and two-year OS were significantly superior in the PCG arm (45% and 19% vs 34% and 11%, respectively). The RR and median survival time observed with the control PC regimen are consistent with literature data.(14)
As expected, haematological toxicity was higher in the PCG arm. No difference was observed in non-haematological toxicities and in toxic/early death. Due to the clinical relevance of the improvement in OS, we suggest the PCG regimen as a treatment option for fit patients with advanced disease.
Before 2000 there was no evidence that secondline chemotherapy was able to improve survival in NSCLC. Two chemotherapy drugs (docetaxel and pemetrexed) and two antiepidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – gefitinib and erlotinib – have recently been approved for secondline therapy in platinum pretreated patients.
Docetaxel was the first drug approved by the FDA and by the European Agency. Although the RR was low (7–10%), approval was based on the results of two phase III studies showing an improvement in one-year OS (32% vs 10%) and in quality of life when compared with ifosfamide, vinorelbine or best supportive care alone.(15,16) Recently, a large randomised trial comparing pemetrexed, a multitargeted antifolate, with docetaxel showed similar RR and OS, with better toxicity profile in favour of pemetrexed.(17) Secondline therapy is currently suggested by international treatment guidelines for good performance status patients.(18)
Bevacizumab is a humanised monoclonal antibody directed against vascular endothelial growth factor (VEGF). At the 2005 ASCO meeting, the Eastern Cooperative Oncology Group presented the preliminary results of a randomised phase III trial (E4599) comparing the effectiveness of firstline carboplatin/paclitaxel with or without bevacizumab in advanced disease.(19) The trial was limited to adenocarcinoma histology due to the higher incidence of severe tumour-related bleeding episodes observed during previous phase II trials in squamous histology. In addition, patients with brain metastases, gross hemoptysis or hypertension were excluded. A total of 878 patients were randomised. Preliminary results showed an advantage in median survival time (12.5 vs 10.2 months; p=0.0075), progression-free survival (4.5 vs 4.0 months; p<0.0001) and RR (27% vs 10%; p<0.0001) for the bevacizumab arm. A higher incidence of bleeding was also observed (4.5% vs 0.7%) in the same group.
These data should be interpreted with caution. Confirmatory studies are required and the conclusion of a similar phase III trial comparing cisplatin/gemcitabine with or without bevacizumab is expected.
The anti-EGFR monoclonal antibody cetuximab and the oral TKIs gefitinib (ZD1839) and erlotinib (OSI 774) have been evaluated in first-, second- and thirdline therapy. In a phase II randomised study, cetuximab combined with cisplatin/vinorelbine failed to demonstrate any advantage over cisplatin/vinorelbine alone in firstline setting.(19)
The clinical activity of anti-EGFR-/TKIs is evident when used as a single agent in secondline treatment, while no advantages were observed when combined with chemotherapy.(20–22) Subgroup analyses showed the best activity in Japanese, female, nonsmoking, adenocarcinoma histology, probably related to somatic mutations in the EGFR gene frequently observed in this population. Although gefitinib and erlotinib have a similar mechanism of action, the most promising results are evident in the erlotinib studies. At the 2004 ASCO meeting, Canadian investigators presented the first randomised trial showing that this EGFR inhibitor prolongs survival in second- and thirdline setting over placebo (6.7 vs 4.7 months; p=0.001).(24)
Adjuvant chemotherapy after radical surgery and secondline therapy in advanced disease is now proposed by international NSCLC treatment guidelines. For the first time, two studies have recently shown the superiority of firstline therapy with three drugs (three chemotherapy drugs or two chemotherapy drugs plus a target agent) over doublets chemotherapy in advanced disease. However, confirmatory studies are required to change the current treatment guidelines in advanced disease. When targeted therapy is a treatment option, a careful patient selection is mandatory.
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