Which new agent or platinum combination regimen is best for treatment of 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.
New agent or platinum combination regimens
Several meta-analyses and numerous RCTS have evaluated this question either as their primary endpoint or as part of secondary analyses. New agents making up so – called “third generation” regimens include gemcitabine, vinorelbine, docetaxel, paclitaxel and irinotecan.
Baggstrom et al, meta-analysed results from twelve RCTs from 1994 – 2004 (n= 3995 patients) comparing response rate (RR) and overall survival (OS) with 3G combination regimens including platinum-based compounds with second generation (2G) platinum-based regimens. The estimated absolute risk difference (RD) in RR in favour of 3G regimens was 12% (95% CI: 10 -15%), corresponding to a number need to treat (NNT) of eight for one patient to benefit. Owing to a high degree of heterogeneity across the studies, analysis of OS could not be undertaken.
Grossi et al, evaluated the relative impact of different 3G drugs (vinorelbine, gemcitabine, paclitaxel, docetaxel) on the activity of first-line chemotherapy in advanced NSCLC by considering RR and progressive disease (PD), in 45 RCTs (N = 11,867 patients). They found the odds of obtaining an objective response to treatment similar across the different regimens. Different rates of disease control were observed, with gemcitabine chemotherapy associated with a significant 14% lower risk for immediate progression, whereas patients receiving paclitaxel-based treatment appear to be at a higher risk for having PD as their best response. However, OS was not assessed in this meta-analysis.
Gao et al, examined whether platinum plus gemcitabine or vinorelbine are equally effective in the treatment of advanced NSCLC. This publication only meta-analysis evaluated nine RCTs involving 2186 patients, and found that no differences in RR or one-year OS. Vinorelbine plus platinum regimens led to more frequent grade 3 or 4 neutropaenia, nephrotoxicity, constipationand phlebitiswhile gemcitabineplus platinum chemotherapy was associated with more grade 3 or 4 thrombocytopaenia.
These meta-analyses collectively confirm better RR with 3G regimens compared with 2G but with differing toxicity profiles across the regimens and uncertainty or no difference in OS. A RCT of 1155 patients, evaluating four commonly used 3G platinum based regimens (vinorelbine, docetaxel, paclitaxel and gemcitabine) similarly failed to demonstrate superiority (in OS and RR) of one regimen over another although toxicity differences were observed.
In the setting of first-line empirical chemotherapy, the study by Scagliotti et al compared the effectiveness of cisplatin and pemetrexed to cisplatin and gemcitabine in a RCT of 1,725 patients. This study confirmed non-inferiority of cisplatin/pemetrexed compared with cisplatin/gemcitabine for the overall population, but also confirmed (in pre-planned analyses), superiority of cisplatin/pemetrexed for OS compared with cisplatin/gemcitabine in patients with non-SCC histology (HR 0.81, 95% CI 0.70 - 0.94), with median OS 12.6 versus 10.9 months for adenocarcinoma histology (n = 847, and 10.4 versus 6.7 months for large cell carcinoma (n = 153). Conversely, in patients with SCC, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; median OS 10.8 versus 9.4 months, respectively, HR 1.23 (95% CI 1.00 – 1.51, p = 0.05)). For cisplatin/pemetrexed, rates of grade 3/4 neutropaenia, anaemia, and thrombocytopaenia (p = 0.001); febrile neutropaenia (p = 0.002); and alopecia (p = 0.001) were significantly lower, whereas grade 3 or 4 nausea (p = 0 .004) was more common.
Gronberg et al compared carboplatin/pemetrexed to carboplatin/gemcitabine in a RCT of 436 patients with the primary endpoint of health-related quality of life. Compliance with completion of health-related QOL questionnaires was 87%. There were no significant differences for the primary health-related QOL endpoints, or in OS between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P=0.63). Multivariate analyses and interaction tests did not reveal any significant associations between histology and survival. As in the Scagliotti study, rates of Grade ¾ haematologic toxicity were less with carboplatin/pemetrexed.
Evidence summary and recommendations
| 3G platinum-based chemotherapy (vinorelbine, paclitaxel, docetaxel or gemcitabine) is associated with higher response ratio than older 2G platinum-based chemotherapy.
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| No 3G platinum-based chemotherapy regimen (vinorelbine, paclitaxel, docetaxel or gemcitabine) has been shown to be superior to another.
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| In first-line empirical treatment of advanced NSCLC, chemotherapy with cisplatin and pemetrexed is superior to cisplatin/gemcitabine in patients with non-squamous cell carcinoma histology.
| In first-line empirical treatment of advanced NSCLC, chemotherapy with cisplatin and pemetrexed is inferior to cisplatin/gemcitabine in patients with SCC histology.
3G platinum-based chemotherapy (with vinorelbine, paclitaxel, docetaxel or gemcitabine) is a standard of care as first-line chemotherapy in fit patients with stage IV NSCLC.
In the first-line setting, chemotherapy with cisplatin and pemetrexed is recommended in preference to cisplatin and gemcitabine in patients with non-squamous cell carcinoma histology.
In the first-line setting, chemotherapy with cisplatin and gemcitabine is recommended in preference to cisplatin and pemetrexed in patients with squamous cell carcinoma histology.
The choice of first-line platinum combination chemotherapy in a given patient may consider patient performance status and co-morbidities, the proposed treatment toxicity, treatment scheduling and individual patient preferences.
- Baggstrom MQ, Stinchcombe TE, Fried DB, Poole C, Hensing TA, Socinski MA. Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis. J Thorac Oncol 2007 Sep;2(9):845-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17805063.
- Gao G, Jiang J, Liang X, Zhou X, Huang R, Chu Z, et al. A meta-analysis of platinum plus gemcitabine or vinorelbine in the treatment of advanced non-small-cell lung cancer. Lung Cancer 2009 Sep;65(3):339-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19144444.
- Grossi F, Aita M, Defferrari C, Rosetti F, Brianti A, Fasola G, et al. Impact of third-generation drugs on the activity of first-line chemotherapy in advanced non-small cell lung cancer: a meta-analytical approach. Oncologist 2009 May;14(5):497-510 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19423674.
- Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002 Jan 10;346(2):92-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11784875.
- Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008 Jul 20;26(21):3543-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18506025.
- Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2009 Jul 1;27(19):3217-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19433683.