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Assistant Professor of Medicine
University of Pittsburgh
University of Pittsburgh Cancer Institute
The treatment of nonsmall-cell lung cancer (NSCLC) has undergone major changes in the past few years, which has led to modest improvements in outcome for patients at all stages of the disease. The availability of novel cytotoxic agents, new drugs that modulate molecular targets in the cancer cell and better supportive care measures for management of treatment-related toxicities have all contributed to a brighter outlook for patients with NSCLC. This article discusses some of the recent advances in the treatment of NSCLC.
The majority of patients with NSCLC are at an advanced stage at the time of diagnosis. Systemic chemotherapy remains the treatment mainstay for advanced stage NSCLC. Platinum-based two-drug combination regimens are considered optimal for patients who have a good performance status.(1) Paclitaxel, docetaxel, gemcitabine, vinorelbine or irinotecan have all been tested in combination with a platinum compound for the treatment of advanced NSCLC in randomised clinical trials. Such combination regimens result in a median survival of 8–11 months with a one-year survival rate of 30–40%.(2–4) These regimens have comparable efficacy but distinct toxicity profiles. Therefore, treatment is chosen for individual patients based on factors such as side-effects, cost and schedule. There has been a long-standing debate regarding the choice of the platinum agent to be used for the treatment of advanced-stage disease. In the USA, carboplatin is preferred over cisplatin due to its ease of administration and favourable tolerability profile. In Europe, cisplatin-based regimens continue to be commonly used. A recent meta-analysis that compared the outcomes for advanced NSCLC with cisplatin vs carboplatin-based therapy demonstrated a slight advantage in favour of the former (response rate), although no significant differences in overall survival were noted.(5)
Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), has recently been shown to improve the outcome of chemotherapy for advanced-stage NSCLC.(6) Formation of new blood vessels is critical for cancer and therefore has become an important target for cancer therapy.(7) VEGF, a key mediator of angiogenesis, can be inhibited by a monoclonal antibody or a small-molecule inhibitor of the VEGF receptor. In a phase III study conducted by the Eastern Cooperative Oncology Group (ECOG), administration of carboplatin and paclitaxel with bevacizumab resulted in improved survival over chemotherapy alone for advanced NSCLC patients (see Table 1).(6) The study excluded patients with squamous cell histology, brain metastasis, major haemoptysis or history of recent thromboembolic events. Adverse events associated with bevacizumab/chemotherapy combination included hypertension, bleeding and a slight increase in myelosuppression. This was the first randomised study to demonstrate improved survival with the addition of a third drug to combination chemotherapy for patients with advanced NSCLC. The exciting results from this study have led to the adoption of this regimen as the new reference regimen for future ECOG trials for advanced nonsquamous NSCLC. In Europe, a large confirmatory study is ongoing that randomises advanced nonsquamous NSCLC patients to treatment with the regimen of cisplatin/gemcitabine alone or in combination with bevacizumab. Bevacizumab is also being tested in combination with the other commonly used chemotherapy regimens and for treatment of earlier stages of NSCLC.
There have also been new developments in the management of patients with recurrent/refractory disease following first-line chemotherapy. Docetaxel and pemetrexed are two chemotherapeutic agents that have been approved in this setting. Both agents are associated with a response rate of approximately 10% and disease stabilisation rate of 45%.(8) The median time to progression and overall survival are three months and eight months, respectively. Pemetrexed, which is a novel multitargeted antifolate compound, is associated with a favourable haematological toxicity profile compared with docetaxel. Interestingly, supplementation of vitamin B12 and folic acid alongside pemetrexed therapy results in a very low incidence of myelosuppression and diarrhoea. Pemetrexed is now being evaluated in combination with a platinum compound for first-line treatment of advanced NSCLC by a large randomised clinical trial underway in Europe.
Inhibitors of the EGFR pathway
The epidermal growth factor receptor (EGFR) pathway is aberrant in a majority of NSCLC patients, based on receptor overexpression, gene amplification or mutations. This has led to the evaluation of agents that inhibit EGFR as a therapy for NSCLC. Erlotinib, a small-molecule inhibitor of the EGFR tyrosine kinase (TKI), was compared with placebo for patients who progressed following one or two prior chemotherapy regimens for advanced NSCLC.(9) There was a significant improvement in overall survival and progression-free survival for patients treated with erlotinib. Skin rash and diarrhoea were the most common adverse events and could be managed with appropriate supportive care measures and dose reductions. Based on this study, erlotinib is now routinely used for either second- or third-line therapy of advanced NSCLC. Gefitinib, another small-molecule inhibitor of the EGFR, is associated with comparable response rates as erlotinib but failed to demonstrate survival advantage over placebo in a large randomised clinical trial for patients with progressive NSCLC.(10) Monoclonal antibodies against the EGFR are currently under evaluation, based on single-agent activity noted in recurrent NSCLC.(11) Clinical trials are currently underway to test the utility of EGFR inhibitors in earlier stages of NSCLC, particularly in combination with external beam radiation for patients with locally advanced NSCLC.
Recent efforts have focused on the identification of predictive markers that will allow for selection of patients for therapy with targeted agents such as the EGFR inhibitors. Clinical characteristics such as female gender, adenocarcinoma and bronchioloalveolar histology, never-smokers and Asian ethnicity have all been linked with higher likelihood of response to EGFR inhibitors. Certain mutations in the ATP-binding domain of the receptor tyrosine kinase predict for higher likelihood of response to EGFR TKI therapy, although the impact on overall survival remains to be firmly established.(12,13) Other molecular markers such as EGFR gene amplification have been noted to predict for improved survival with EGFR inhibitors.(14) These observations, if confirmed in prospective clinical trials, will help with patient selection in routine clinical practice.
Although the need for systemic therapy for patients with earlier stages of NSCLC has been recognised for a long time, it was only recently that clinical trials established survival benefit with adjuvant chemotherapy (see Table 2). Administration of three to four cycles of cisplatin-based chemotherapy following surgery results in approximately 5–15% improvement in the five-year survival rate compared with surgical resection alone.(15–17) The magnitude of benefit with adjuvant chemotherapy compares favourably to breast and colon cancer, where it is routinely used. Vinorelbine was used in combination with cisplatin in the majority of the clinical trials that evaluated the role of adjuvant chemotherapy. Newer agents such as gemcitabine and the taxanes have a favourable tolerability profile in combination with cisplatin and are also suited for evaluation in the adjuvant therapy setting.
The role of carboplatin in the adjuvant setting remains to be proven, as a recent randomised trial that evaluated carboplatin/paclitaxel combination for adjuvant therapy of stage IB NSCLC failed to demonstrate survival benefit.(18) A large intergroup trial is currently being planned to study the utility of the addition of bevacizumab to adjuvant
Although adjuvant chemotherapy has become the new standard of care for early-stage NSCLC (stages II and IIIA), the delivery of planned doses of chemotherapy continues to be a challenge, since only about 60–75% of the patients are able to complete the scheduled therapy. Use of appropriate supportive care measures and dose reductions are often required to complete adjuvant chemotherapy. This limitation can potentially be overcome by administration of chemotherapy in the preoperative setting. Clinical trials have already suggested the feasibility and safety of preoperative chemotherapy.(19) Based on these results, studies to compare preoperative chemotherapy with postoperative therapy are currently underway.
The treatment paradigms for NSCLC have changed considerably in recent years. The availability of newer chemotherapeutic and molecularly targeted agents has expanded the therapeutic options available for NSCLC patients. In order to build upon these advances, there is a critical need to develop not only newer agents but also patient selection methods for targeted agents. Since NSCLC is a very heterogeneous disease, it is unlikely that any therapeutic modality will be successful for all patients. Individualised therapy and the development of novel combinations of targeted agents and chemotherapeutic agents are the focus of research efforts at the present time.