Is monotherapy with new third generation (3G) agents as effective as platinum combination therapy for treatment of stage IV inoperable NSCLC?

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Introduction

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.

Monotherapy with new agents versus platinum combination therapy

A meta-analysis by Hotta et al, examined the question of how treatment with single agent 3G agents (vinorelbine, paclitaxel, docetaxel, gemcitabine and irinotecan) compares with the same agent and a platinum agent.[1] This meta-analysis evaluated 2374 patients from eight RCTs between 1994 – 2003. A greater than two-fold higher overall response rate (RR) was seen with platinum combination than the new agent alone [odds ratio = 2.32; 95% CI 1.68–3.20]. Platinum-based doublet therapy was associated with a 13% prolongation of overall survival (OS) (HR = 0.87; 95% CI = 0.80–0.94,P <0.001).[1] Despite significant increases in the frequencies of various toxicities in patients receiving platinum-based doublets, no significant difference in treatment-related mortality was observed.[1]

Baggstrom et al in their meta-analsysis examined the effectiveness of 3G agents (vinorelbine, paclitaxel, docetaxel and gemcitabine) as first-line monotherapy compared with best supportive care in five RCTS of 1029 patients from 1996 – 2000.[2] One trial used 5-fluorouracil (5FU)/leucovorin as the control arm. RR for the 3G regimens ranged from 12-20%. One-year survival favored the 3G agents over best supportive care with a summary absolute risk difference of 7% (95% CI: 2 - 12%). They calculated that the NNT for one patient to realise a benefit in the probability of one-year survival was 14.

Delbaldo et al examined the effectiveness of two-drug platinum combination chemotherapy compared with single agent therapy.[3][4] This study evaluated 7175 patients from 29 RCTs but also included studies using older agents such as etoposide, vindesine and mitomycin C, as well as the modern 3G agents previously listed. Some of the studies included used a non-platinum combination in the comparator arm. Two-drug combination therapy was found to have a higher RR (OR, 0.42; 95% CI 0.37-0.47; p <.001). The absolute benefit was 13%, which corresponds to a two-fold increase in RR from 13% with a single-agent regimen to 26% with a doublet regimen.[4] The benefit was higher when the control arm was an older drug (OR, 0.35) than when it was a newer drug (OR, 0.52) (P=.001). Two-drug combination therapy was associated with a significant increase in one-year survival (OR, 0.80; 95% CI, 0.70-0.91; P<.001)[4] The absolute benefit was 5%, which corresponds to an increase in one-year survival from 30% with a single agent regimen to 35% with a doublet regimen. The benefit was higher when the control arm was an older drug than newer drug for both one-year survival rate (p=.03) and median survival (p=.007).[4]

Evidence summary and recommendations

Evidence summary Level References
3G platinum-based combination chemotherapy (vinorelbine, paclitaxel, docetaxel, irinotecan or gemcitabine) is superior to 3G agent monotherapy.

Last reviewed December 2015

I [1], [4]
3G platinum-based monotherapy (vinorelbine, paclitaxel, docetaxel, or gemcitabine) improves survival compared with best supportive care.

Last reviewed December 2015

I [2]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients fit for chemotherapy should be offered 3G platinum-based combination chemotherapy (vinorelbine, paclitaxel, docetaxel, irinotecan or gemcitabine) in preference to 3G agent monotherapy, as it is more effective.

Last reviewed December 2015

A
Evidence-based recommendationQuestion mark transparent.png Grade
Patients unfit for combination chemotherapy could be considered for 3G monotherapy with vinorelbine, paclitaxel, docetaxel or gemcitabine.

Last reviewed December 2015

A


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References

  1. 1.0 1.1 1.2 1.3 Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 2004 Oct 1;22(19):3860-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15326194.
  2. 2.0 2.1 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.
  3. Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. JAMA 2004 Jul 28;292(4):470-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15280345.
  4. 4.0 4.1 4.2 4.3 4.4 Delbaldo C, Michiels S, Rolland E, Syz N, Soria JC, Le Chevalier T, et al. Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev 2007 Oct 17;(4):CD004569 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17943820.

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Appendices

Further resources

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