Medical treatment of advanced non-small cell lung cancer in elderly patients: a review of the role of chemotherapy and targeted agents.

Lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases. Half of the patients at diagnosis of NSCLC are over seventy years old; therefore, the elderly represent a large subgroup of patients affected by advanced NSCLC in our clinical practice. Nevertheless, the elderly are under-represented in clinical trials. Given the fact that old age is frequently associated with several comorbidities, poor general conditions and physiologic reduction in organ function, clinicians must carefully choose the best treatment option for elderly patients with advanced NSCLC, always taking into account the expected risks and benefits. In this paper we perform a review of literature evidence regarding the medical treatment of elderly patients affected by advanced NSCLC, encompassing single-agent chemotherapy, doublet chemotherapy and targeted agents. We conclude that single-agent chemotherapy with a third generation agent (vinorelbine, taxanes, gemcitabine) represents a valid treatment option for elderly patients who are not eligible for a combination chemotherapy due to clinical features such as comorbidities, poor performance status and inadequate organ function. Platinum-based doublet chemotherapy shows similar efficacy in elderly patients as compared to their younger counterpart, despite greater treatment related toxicity and it is indicated in elderly patients with ECOG PS: 0-2, adequate organ function and no major comorbidities. Elderly patients affected by epidermal growth factor receptor (EGFR) mutated NSCLC benefit mostly from a tyrosine kinase inhibitor of EGFR (erlotinib, gefitinib) which is associated with a good toxicity profile. Currently there are no available data to strongly support the use of bevacizumab in combination with first line chemotherapy in the treatment of older adults. Elderly patients affected by NSCLC harboring the EML4-ALK translocation could benefit mostly from a treatment with an oral inhibitor of such a rearrangement (crizotinib).

Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer.

OBJECTIVES: Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC. MATERIALS AND METHODS: We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. RESULTS: 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated. CONCLUSION: We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.