What is the optimal systemic therapy regimen for elderly patients for treatment of stage IV inoperable NSCLC?

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Introduction

The majority of patients treated with systemic therapy for 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 elderly patients as defined below.

Systemic therapy for elderly patients

The age criterion for designation of “elderly” has varied somewhat across NSCLC studies with the elderly groups commonly defined as those patients either 65 or 70 years of age or older. Several randomised controlled trials (RCTs) have been conducted within this subgroup. As a group elderly patients are considered at higher risk of treatment related toxicity, due to possible age physiologic effects on drug handling and high proportion of co-morbidities. Gridelli et al first reported findings to indicate benefit from monotherapy with vinorelbine in patients over 70, with improvement seen in OS 0.65 (95% CI = 0.45–0.93) and fewer reported lung cancer related symptoms in a RCT of 161 patients[1] Kudoh et al, subsequently compared docetaxel 60 mg/m2 (day one) to vinorelbine 25 mg/m2 (days one and eight) every 21 days for four cycles, in a RCT of 182 Japanese patients over 70 years of age.[2] There was no statistical difference in the primary endpoint of median OS with docetaxel versus vinorelbine (14.3 months versus 9.9 months; HR 0.780; 95% CI 0.561 - 1.085; P = 0.138).[2] However, median PFS (5.5 months versus 3.1 months; P = 0.001), RR (22.7% versus 9.9%; P = 0.019) and disease-related symptoms favoured docetaxel over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 - 3.20). Docetaxel was associated with more grade 3/4 neutropaenia (82.9% for docetaxel; 69.2% for vinorelbine; P = 0.031).[2]

Hainsworth et al, randomised 350 patients over 65 years of age to first line single-agent weekly docetaxel versus the combination of docetaxel and gemcitabine.[3] There was no difference in OS with the combination treatment compared with single agent weekly docetaxel.[3] Russo et al reported a literature-based meta-analysis of RCTs that compared a gemcitabine based doublet regimen with a 3G single agent in elderly patients (> 65).[4] This meta-analysis included the study by Hainsworth et al. Four trials evaluating 1436 patients were included in the meta-analysis. A significant difference in RR was seen favouring gemcitabine doublet therapy over single 3G agents (OR 0.65; 95% CI 0.51-0.82, p < .001), whereas one-year survival rate was not significantly different (OR, 0.78; 95% CI, 0.57-1.06, P = 0.169). Only Grade ¾ thrombocytopaenia was greater with combination therapy (OR, 1.76; 95% CI, 1.12-2.76, P= 0.014).

More recently, Quoix et al reported findings from a RCT of that compared a carboplatin and paclitaxel doublet chemotherapy regimen with 3G monotherapy in 451 elderly patients (age 70-89) with advanced NSCLC.[5] Patients were treated with carboplatin AUC 6 on day one and 90 mg/m. paclitaxel on days 1, 8, and 15 Q4 weekly or 3G monotherapy with either 25 mg/m2. vinorelbine on days one and eight or 1150 mg/m2 gemcitabine on days one and eight, Q3 weekly.[5] Overall survival was in favour of the combination (median 10.3 months for doublet chemotherapy versus 6.2 months for 3G monotherapy (HR 0.64, 95% CI 0.52–0.78; p<0.0001)).[5] Toxicity was more frequent in the doublet chemotherapy group than in the monotherapy group (neutropaenia (48.4% vs 12.4%); asthenia (10.3% versus 5.8%)[5]

Evidence summary and recommendations

Evidence summary Level References
First-line single agent vinorelbine (30 mg/m2 on days one and eight, Q3 weekly) in patients over 70 years of age improves survival and reduces disease related symptoms.

Last reviewed December 2015

II [1]
In patients over 70 years of age, first line single agent docetaxel 60 mg/m2 (day one) compared to vinorelbine 25 mg/m2 (days one and eight) every 21 days, improves response rate, progression free survival and disease related symptoms, but not overall survival and is associated with more G3/4 neutropaenia.

Last reviewed December 2015

II [2]
In patients over 65 years of age, gemcitabine doublet chemotherapy improves response rate compared with single agent 3G chemotherapy, but does not improve survival and is associated with greater thrombocytopaenia.

Last reviewed December 2015

I [4]
In patients over 70 years of age, first-line carboplatin/weekly paclitaxel combination improves survival compared with 3G monotherapy (weekly vinorelbine or gemcitabine) but, is associated with more neutropaenia.

Last reviewed December 2015

II [5]
Evidence-based recommendationQuestion mark transparent.png Grade
Suitably fit patients over 65 years of age, can be offered first-line mono-chemotherapy with a 3G single agent (vinorelbine (25-30 mg/ m2 day one, eight Q3 weekly), docetaxel (60 mg/m2 day one, Q3 weekly) or gemcitabine (1150 mg/m2 days one and eight, Q3 weekly).

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
In elderly patients, first-line gemcitabine doublet chemotherapy is not recommended.

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
In fit elderly patients, first-line carboplatin/weekly paclitaxel may be offered instead of 3G monotherapy, but at the expense of greater neutropaenia.

Last reviewed December 2015

B


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References

  1. 1.0 1.1 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.
  2. 2.0 2.1 2.2 2.3 Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006 Aug 1;24(22):3657-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16877734.
  3. 3.0 3.1 Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, et al. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer 2007 Nov 1;110(9):2027-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17823908.
  4. 4.0 4.1 Russo A, Rizzo S, Fulfaro F, Adamo V, Santini D, Vincenzi B, et al. Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer: a Literature-based Meta-analysis. Cancer 2009 May 1;115(9):1924-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19235250.
  5. 5.0 5.1 5.2 5.3 5.4 Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavolé A, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011 Sep 17;378(9796):1079-88 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21831418.

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Appendices

Further resources

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