Treating elderly with lung cancer
With the European continent aging faster than any other region, evaluation of new drugs in the elderly is becoming a major issue. Dr. Ilona Rousalova, Pulmonologist & Thoracic Surgeon, Czech Lung Cancer Cooperative Group, studies the problems in treating geriatric cancer patients and says criteria for clinical trials should be carefully reconsidered to help better pharmacological developments
The elderly population is the fastest-growing portion of the population in western countries.
Lung cancer is the third most common cancer type and the leading cause of cancer-related deaths in Europe. This is an increasingly common problem in older individuals since more than 50% of cases of advanced non-small cell lung cancer (NSCLC) are diagnosed in patients over the age of 65 years. (1)
Biological changes associated with aging
Risk of cancer development in the aging population can be mainly linked to two processes; first, DNA damage caused by cumulative exposure to carcinogens, radiation, and viruses and second, decline in different host defenses against tumor growth.
Aging has a significant effect on the responses to pharmacological interventions. Age-related physiological and pathological changes play a major role in altering pharmacological actions of drugs. Most important coexisting pathologies are changes involving metabolism, cardiovascular, respiratory, renal, and hepatic systems as they adversely affect the patient’s functional status and treatment outcome. It has been reported that individuals aged 65-77 years have at least six chronic diseases on average. Comorbidities and functional status are key factors in the overall survival of patients as well as the benefits and toxicity of therapy.
Performance status (PS) is the major prognostic factor in lung cancer, but it cannot accurately predict outcome in elderly patients. However, there are other tests which demonstrate treatment tolerance and survival in elderly, such as Activities of Daily Living (ADL) or Instrumental Activities of Daily Living (IADL). But, at the present time, Comprehensive Geriatric Assessment (CGA), though criticised for being time-consuming and non-standardised, remains the most useful tool for evaluating the elderly who are fit and most likely to benefit from standard therapy.
Treatment of the elderly is particularly challenging because of the coexistence of variable comorbidities, which predispose them to less toleration of toxicity of medical treatments compared to their younger counterparts. This patient population is at risk of both empirical under treatment, resulting in poor survival, or excessive toxicity from standard therapy. Therefore, treatments designed to address the special needs of this population are critical.
Elderly patients with metastatic NSCLC and epidermal growth factor receptors (EGFR) and non-mutated tumors should be considered for treatment with chemotherapy. The choice between monotherapy and a platinum-based (preferably carboplatin) doublet should be based on considerations such as PS and geriatric assessment.
Elderly fit patients or PS 0–1 (asymptomatic or symptomatic but completely ambulatory) and some cases of PS 2 (symptomatic, 50% in bed during the day) should be treated with a platinum-based doublet, whereas those who are more vulnerable and the majority of PS 2 patients should be considered for a reduced-dose carboplatin-based doublet or monotherapy. (2, 3)
Newer regimens – anti-angiogenic treatment, targeted therapy
Combination of first line platinum-based chemotherapy with bevacizumab, the anti-VEGF monoclonal antibody, could offer the same benefit in patients aged >65 years as are seen in younger patients, to be used cautiously due to higher toxicity, although there is no compelling evidence to support its use in patients older than 65-70 years of age. (4)
Among targeted therapies, tyrosine kinase inhibitors (TKI) associated with the EGFR (erlotinib and gefitinib) are involved in many cellular processes such as proliferation, growth, migration, invasion and survival. Erlotinib was the first target agent approved for the treatment of NSCLC in second and third line, in patients unselected for EGFR mutations. Gefitinib was the first EGFR TKI approved for the treatment of NSCLC in all lines of setting in patients harbouring EGFR mutations. In elderly patients, with a poor prognosis, and different co-morbidities, erlotinib and gefitinib is recommended as valid therapeutic options (5, 6).
While there is little data about elderly patients with adenocarcinoma harbouring EML4-ALK translocation, there is no reason to believe that this group would derive less benefit from ALK TKI therapy (crizotinib, cerinib).
Clinical trials design
Elderly patients are the majority of the users of many medicines despite being poorly represented in clinical trials. Although persons aged ≥65 years represent only about 13% of the population, they consume nearly one-third of all medications. (7) Moreover, the overall proportion of older oncologic patients (> 65 years of age) in trials conducted by the Southwest Oncology Group was 25%. Hence, the evaluation of new drugs in the elderly is a major issue. The lack of data on octogenarians suggests that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years.
Moreover, the evaluation of promising therapies (immunotherapy such as PD-1/PD-1L checkpoint inhibitors – nivolumab, pembrolizumab) should continue, with comprehensive analyses of patient selection, efficacy, toxicity, and quality of life. In fact, there are multiple physician-related, patient-related and trial-related barriers in recruiting elderly patients to clinical trials. Furthermore, with an ageing population in Europe, medical oncology is becoming geriatric oncology, hence the criteria for recruitment of the elderly to clinical trials should be carefully reconsidered.
1. Maione M et al. Ther Adv Med Oncol 2010; 2 (4): 251-260.
2. Blanco R et al., Annals of Oncology, 2015; 26 (3): 451-463.
3. DaweDE and Ellis PM, Frontier in Oncology 2014; 4: 174.
4. Zhu J et al. JAMA 2012; 307: 1593–1601.
5. Lin CC and Yang CH. Targ Oncol 2009; 4: 37–44.
6. Unger JM et al. J Clin Oncol. 2006; 24(1):141–144.
7. Shenoy P and Harugy A. Perspect Clin Res 2015; 6 (4): 184-189.