What is the optimal first-line chemotherapy regimen in patients with stage IV inoperable NSCLC?
The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.
Prior to commencing first line systemic therapy, the histological subtype of the tumour should be established and adequate tissue obtained for molecular testing if possible. In particular, EGFR and ALK mutation testing should be performed on all adenocarcinoma specimens and appropriate targeted therapy given instead of chemotherapy if one of these mutations is found.  In addition, testing for PD-L1 expression should be considered and patients with expression levels ≥ 50% considered for PD-1 immunotherapy as first line therapy.
The first piece of evidence to establish a standard of practice was the meta-analysis of randomised trials until 1992 evaluating chemotherapy for non-Small Cell Lung Cancer by the Non-small Cell Lung Cancer Collaborative Group. Data from eight trials (N = 778) evaluating best supportive care versus best supportive care and cisplatin based chemotherapy showed a clear survival benefit in favour of chemotherapy with a hazard ratio of 0.73 (P<0.0001), or 27% reduction in the risk of death. This is equivalent to an absolute improvement in survival of 10% at one year, improving survival from 15% to 25%.It is important to note that empirical chemotherapy has only been formally evaluated in "fit" patients. Patient performance status (PS) has conventionally been used to standardise and quantify cancer patient’s general well-being and activities of daily life. The simplest of such scores in widespread use is the .
By Convention, “fit” patients have a low PS and in most chemotherapy trials, the predominant patient group included is that with PS 0 or 1, with a minority being PS 2 or greater (referred to as poor performance status and described separately in the section below). Furthermore, chemotherapy trials have usually only included patients with adequate organ function and excluded patients with medically unstable co-morbidities and uncontrolled brain metastases. The median age of patients on chemotherapy trials is also lower than the median of the Australian lung cancer population.
A large number of randomised controlled studies and subsequent meta-analyses have been reported addressing questions such as, which platinum agent is best (carboplatin versus cisplatin)?; which new agent paired with a platinum agent is best (often referred to as "third generation (3G)” regimens)"?; is monotherapy with new (“3G”) agents as effective as platinum combination therapy?;are three chemotherapy agents (“triplet regimens”) better than two (“doublet regimens”)?; are non-platinum doublet chemotherapy regimens as effective as platinum doublet regimens?; what is the optimal duration of chemotherapy?; and is chemotherapy and a “biologic” or “targeted“ therapy superior to chemotherapy alone?
Evidence summary and recommendations
| Platinum-based chemotherapy improves survival in stage IV NSCLC compared with best supportive care. Note that this evidence is based on clinical trials conducted in fit patients, with predominant performance status 0-1, no unstable co-morbidities, adequate organ function and without uncontrolled brain metastases.
Last reviewed September 2017
Platinum-based chemotherapy can be used to extend survival in newly diagnosed patients with stage IV NSCLC.
Last reviewed September 2017
The decision to undertake empirical platinum-based chemotherapy in a given patient should consider factors such as patient performance status (0,1 versus 2 or more) and co-morbidities, their disease extent and symptoms, proposed treatment toxicity and their individual preferences for benefit from specific treatment(s) and toxicities.
- Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 2015 Sep;26(9):1877-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26141208.
- Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014 Dec 4;371(23):2167-77 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25470694.
- Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982 Dec;5(6):649-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7165009.
- Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311(7010):899-909 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7580546.
- Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010 May 12;(5):CD007309 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20464750.