What is the optimal systemic therapy regimen for patients with poor performance status 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 this question is the evidence in support of the old practice paradigm for empirical chemotherapy for stage IV NSCLC. Empirical therapy here refers to therapy given to all patients with poor performance status.

Poor performance status patients

Most studies with cytotoxic chemotherapy have been evaluated in “fit” patients, predominantly with PS 0 or 1. Patients with PS 2 are generally considered a poor prognostic group and at higher risk of toxicity, particularly from cytotoxic chemotherapy. Attempts to improve outcomes in this poor performance group population (PS 2) of patients with advanced NSCLC have been challenging with trials focused on the use of less toxic regimes or monotherapy with 3G agents or anti-EGFR TKIs.

Liu et al undertook a systematic review of phase II and II studies to examine the safety and efficacy of EGFR TKI monotherapy versus single-agent chemotherapy using third-generation cytotoxics as first-line treatment for patients with advanced non-small cell lung cancer and poor performance status.[1] No randomised controlled trials (RCTs) were identified. Fifteen single arm phase II studies (1425 patients) were evaluated to determine pooled estimates for RR and safety. The pooled RR (95% CI) to EGFR TKIs for unselected populations was 6% (3–8%), which compares with 9% (6–13%) reported by single-agent 3G chemotherapy trials. By summary comparison only, toxicity profiles were more favourable for the EGFR TKIs than chemotherapy. This study confirms the feasibility of treatment in the poor PS population but does not provide information on the overall benefit of such treatment.

Baggstrom et al reported a meta-analysis of five trials (n =1029 patients) compared 3G single agents with BSC. Four of the trials included a BSC control arm, and one trial included 5-fluorouracil (5FU)/ leucovorin as the control arm.[2] Response rates for the 3G agents ranged from 12% to 20%. One-year survival favored the 3G agents over BSC with risk difference of 7% (95% CI: 2% to 12%).[2] The number needed to treat for one patient to realise a benefit in the probability of one-year survival was 14.[2] These five trials evaluated single agent vinorelbine, paclitaxel, docetaxel and gemcitabine.[3][4][5][6][7] The study by Crawford et al of single agent vinorelbine included 50% of patients with low PS, the vinoerlbine study by Gridelli et al in patients over 70 included 24% of patients with PS 2, the paclitaxel study by Ranson et al included 15% PS 2 patients, the docetaxel study by Roszkowski et al, included 20% PS 2 patients whilst the gemcitabine study by Anderson et al was mainly in low PS patients.[3][4][5][6][7] The study by Anderson et al of gemcitabine versus best supportive care evaluated QOL as its primary endpoint and confirmed better QOL and reduced disease-related symptoms compared with those receiving best supportive care alone, although breathlessness was least well palliated and OS was no different.[5] Quality of life was also in favour of paclitaxel, docetaxel and vinorelbine (versus best supportive care) in the respective studies.[4][6][7]

In the second-line setting, several of the key RCTs that evaluated the efficacy of EGFR TKIs have included PS 2 or greater patients.[8][9][10] Both the placebo controlled trials of gefitinib and erlotinib enrolled > 30 % of patients with PS 2, whilst the study by Kim et al comparing gefitinib to docetaxel included 11% of PS 2 patients. In the BR21 study, analysis of benefit by the PS 2 and 3 subgroups that received erlotinib versus placebo demonstrated a benefit in OS (HR 0.8; 95% CI 05-1.1 (PS 2); 0.4-1.3 (PS 3)), which compares with OS HR 0.7 for the overall population. (0.6-0.9).[8] Thatcher et al, demonstrated the direction of benefit to be in favour of gefitinib over placebo in the OS analysis by sub-populations (30% of patients with PS2).[9]. In the small PS2 sub-population in the study by Kim et al comparing gefitinib with docetaxel, the direction of benefit favoured gefitinib but the confidence limits were wide.[10] Overall. confident conclusions cannot be made for benefit from gefitinib in unselected PS 2 or more patients. However, given the magnitude of benefit observed with gefitinib in first line patients with activating EGFR gene mutations (GMT+, ,described in the section below)[11], it would be reasonable to expect that EGFR GMT + "selected" patients may still potentially benefit from an EGFR TKI , even if of poor performance status, given the size of the observed benefit and relatively low toxicity.

Evidence summary and recommendations

Evidence summary Level References
In patients with poor performance status (PS 2), first-line monotherapy with 3G chemotherapy (vinorelbine, gemcitabine, paclitaxel or docetaxel) may improve survival and/or quality of life.

Last reviewed December 2015

I, II [3], [4], [5], [6], [7], [2]
Evidence-based recommendationQuestion mark transparent.png Grade
First-line monotherapy with 3G chemotherapy could be offered to selected patients with PS2 for symptom improvement and possible survival gain, who are willing to accept treatment toxicity.

Last reviewed December 2015

B


Evidence summary Level References
There is evidence for benefit with erlotinib 150 mg daily as second or third-line therapy in unselected poor performance status patients (PS2 or 3) .

Last reviewed December 2015

II [8]
Evidence-based recommendationQuestion mark transparent.png Grade
Poor performance status patients having received 1 or 2 lines of prior therapy, may be offered erlotinib 150 mg daily.

Last reviewed December 2015

B


Practice pointQuestion mark transparent.png

Decision-making on treatment in poor performance status patients may weigh up benefits against toxicity and patient preferences. Whilst a single agent 3G chemotherapy is an option in unselected patients, patients with known activating EGFR MTs should be considered for first line EGFR TKIs as the magnitude of benefit is greater and toxicity profile more favourable.
Last reviewed December 2015

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References

  1. Liu S, Wang D, Chen B, Wang Y, Zhao W, Wu J. The safety and efficacy of EGFR TKIs monotherapy versus single-agent chemotherapy using third-generation cytotoxics as the first-line treatment for patients with advanced non-small cell lung cancer and poor performance status. Lung Cancer 2011 Jan 4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21211862.
  2. 2.0 2.1 2.2 2.3 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. 3.0 3.1 3.2 Crawford J, O'Rourke M, Schiller JH, Spiridonidis CH, Yanovich S, Ozer H, et al. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol 1996 Oct;14(10):2774-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8874339.
  4. 4.0 4.1 4.2 4.3 Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999 Jan 6;91(1):66-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9890172.
  5. 5.0 5.1 5.2 5.3 Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer--a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer 2000 Aug;83(4):447-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10945489.
  6. 6.0 6.1 6.2 6.3 Ranson M, Davidson N, Nicolson M, Falk S, Carmichael J, Lopez P, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000 Jul 5;92(13):1074-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10880550.
  7. 7.0 7.1 7.2 7.3 Roszkowski K, Pluzanska A, Krzakowski M, Smith AP, Saigi E, Aasebo U, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000 Mar;27(3):145-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10699688.
  8. 8.0 8.1 8.2 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005 Jul 14;353(2):123-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16014882.
  9. 9.0 9.1 Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005 Oct;366(9496):1527-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257339.
  10. 10.0 10.1 Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008 Nov 22;372(9652):1809-18 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19027483.
  11. Bria E, Milella M, Cuppone F, Novello S, Ceribelli A, Vaccaro V, et al. Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. Ann Oncol 2011 Oct;22(10):2277-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21325444.

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Appendices

Further resources

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