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Advanced Non-Small-Cell Lung Cancer in the Elderly

Chapter 13 – Lung Cancer in the Elderly

When choosing a treatment strategy in elderly patients with advanced NSCLC, several options are available such as palliative care without chemotherapy, single-agent chemotherapy with a third-generation drug, non-platinum-based combination chemotherapy, platinum-based combination chemotherapy, and new biological agents.

First-line Treatment in Epidermal-Growth Factor Non-Mutated Cancer

Single-Agent Chemotherapy
Single-agent chemotherapy with vinorelbine, gemcitabine, and taxanes (paclitaxel and docetaxel) are first-line treatment options supported by prospective, elderly-specific clinical data (Table below).

Randomised Trials in Elderly Patients with Advanced Non-Small Cell Lung – First-line treatments

Author (yr)TreatmentNumber of patientsResponse rate (%)Median overall survival (wk)Quality of life/Toxicity
Elvis (99)Best supportive care7821
Elvis (99)Vinorelbine762028Better with vinorelbine
Frasci (00)Vinorelbine601518Better with vinorelbine + gemcitabine
Frasci (00)Vinorelbine + gemcitabine602229
Gridelli (03)Vinorelbine2231836No difference
Gridelli (03)Gemcitabine2231628No difference
Gridelli (03)Vinorelbine + gemcitabine2322130No difference
Quoix (11)Vinorelbine + gemcitabine22620Doublet more toxic
Quoix (11)Carboplatin + paclitaxel22543

Single-agent vinorelbine prolonged OS and improved the control of tumour-related symptoms compared with best supportive care (BSC) in patients aged ≥70 years and induced low toxicity.

Gemcitabine was equally effective compared to vinorelbine or the combination of gemcitabine and vinorelbine in terms of response rate (RR) and median OS.

Docetaxel improved RR and progression-free survival (PFS) compared with vinorelbine, but at the cost of higher grade 3 and 4 neutropenia. In phase II studies, paclitaxel given either in a weekly or 3-weekly schedule also showed efficacy in the elderly population compared to younger patients.

Based on these findings, single-agent therapy (docetaxel, gemcitabine or vinorelbine) is recommended as first-line NSCLC treatment in most elderly patients.

Combination Chemotherapy
To improve the results obtained with single-agent chemotherapy in elderly patients, combination therapy with different agents were tested.

Non-platinum-based combinations
Non-platinum doublets have been compared with single agent schedules in predominantly elderly patients (generally ≥70 years) and showed either significant advantages for doublet therapy or no significant differences compared to single-agent therapy.

A meta-analysis of trials including patients aged 65–79 years indicated a significantly increased RR with gemcitabine-based regimens over single-agent chemotherapy but a non-significant improvement in 1-year survival. However, single agent gemcitabine is not registered for this indication.

Platinum-based combinations
Several trials of cisplatin- and carboplatin-based chemotherapy, comparing the outcomes in younger and elderly patients (generally aged ≥70 years) with NSCLC showed the feasibility of these schedules in the elderly with similar findings in relation to outcome.

Randomised trials of platinum-based regimens have also been conducted in elderly patients. A combination of carboplatin and paclitaxel in fit patients aged 70–89 years with NSCLC was compared with single agent vinorelbine or gemcitabine and showed a longer median OS of 10.3 months compared to 6.2 months for monotherapy but at a cost of more toxicity.

A recent systematic review and meta-analysis that evaluated outcomes with doublet chemotherapy versus single agent cytotoxic treatment in patients aged ≥65 years with NSCLC, confirmed platinum-based doublet therapy to be superior to single-agent therapy in terms of OS, time to progression, 1-year survival rate and objective RR. Grade 3/4 anaemia, thrombocytopenia and neurotoxicity were seen more frequently in the doublet therapy group.

Based on these findings, single-agent therapy (docetaxel, gemcitabine or vinorelbine) is recommended as first-line treatment of Epidermal growth factor receptor (EGFR) non-mutated NSCLC in the elderly. The combination of carboplatin and paclitaxel might be considered in fit elderly patients.

Second-line Treatment in Epidermal-Growth Factor Non-Mutated Cancer

Retrospective analysis of a randomised phase III trial comparing pemetrexed in combination with folic acid and vitamin B12 with docetaxel in pre-treated patients with NSCLC showed that objective RRs, median PFS, median OS and toxicity findings were not significantly different between younger and elderly (aged ≥70 years) patients in either treatment group. Pemetrexed was superior compared to docetaxel in non-squamous histologies.

Targeted Therapy

Anti-angiogenic agents
Elderly patients (> 75 years) appear not to benefit from the addition of bevacizumab to carboplatin/paclitaxel based on subgroup analysis of clinical trials evaluating these combinations with increased toxicity with the addition of bevacizumab.

Tyrosine kinase inhibitors
The use of Tyrosine kinase is indicated as first-line treatment in patients with EGFR Gene-mutated tumours. Both gefitinib and erlotinib have been used in elderly patients and there are no comparative data to recommend one or the other, while gefitinib appears to have a slightly more favourable toxicity profile.

Second- or third-line treatment with gefitinib or erlotinib may be beneficial in older patients with advanced, non-EGFR-mutated NSCLC but elderly patients have more grade ≥3 toxicity and were more likely to stop treatment earlier that younger patients. This may be due to concomitant medications that interfere with Cytochrome P450 3A4 activity.

Immunotherapy - Immune checkpoint inhibitors
Recently, drugs targeting the programmed death-1 (PD-1) pathway, inhibiting the immunosuppressive activity of cancer cells have been developed in the treatment of metastatic non-small cell lung cancer.

Nivolumab, a human immunoglobulin G4 (IgG4) Monoclonal antibody (HuMAb), which binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 has been registered in Europe as a second-line treatment to be given after prior chemotherapy. Nivolumab use in second-line treatment is based on an open label phase 3 randomised study comparing nivolumab with docetaxel in 272 patients of whom 44% were ≥65 years of age and 11% ≥75 years of age. There was a consistent OS benefit in favour of nivolumab (hazard ratio 0.59; 96.85% confidence interval 0.43- 0.81); p 0.0002).

This study included a limited number of patients ≥ 75 years, in this age group nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76-4.51), Because of the small sample size, no definitive conclusions can be drawn from these data.

In elderly patients, no dose adaption of nivolumab is necessary and no overall differences in safety were reported between elderly (≥ 65 years) and younger patients (< 65 years). Data from patients 75 years of age or older are too limited to draw conclusions.

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