Elderly lung cancer patients: what treatment strategies?

Who is the elderly patient & what are his main problems?

Increasing life expectancy and lower birth rates are leading to an aging population in the Western world, with the proportion of people over the age of 65 years predicted to rise steadily throughout the 21st century [1]. The incidence of malignant tumors increases progressively with age, which becomes the single most important risk factor for the development of cancer. A 20-year-old individual has approximately a one in 10,000 risk of developing a cancer per year, which increases to approximately one in 1000 at 50 years of age and approximately one in 100 per year at age 80 years [2]. The association of age and cancer could be due to a more prolonged exposure to carcinogens, an increasingly favorable environment for developing cancer, or both [3]. As a consequence, we can expect an increase in the number of older cancer patients considered suitable for chemotherapy. Unfortunately, there is a minimal participation of older patients in clinical trials, particularly those involving chemotherapy [4,5]. When discussing elderly patients, several problems arise.

The first question to address is ‘at what age a person should be defined old?’ It should be noted that it is very difficult to establish a maximum age. Within epidemiological literature, the age of 65 years is usually considered as a cut-off point to select the elderly population. On the contrary, in clinical trials, the age of 70 years is frequently used as lower limit for patient selection, while a cut-off age of 75 years is less common. In clinical practice, biological rather than chronological age should be considered. Unfortunately, to date, laboratory tests and geriatric evaluation are inadequate to define aging; therefore, at present, chronological age should be used as a frame of reference for clinical trials. A cut-off of 70 years of age seems to be the most appropriate. In fact, 70 years of age may be considered as the lower boundary of senescence, because the incidence of age-related changes starts to increase after the age of 70 years [6].

The second question is ‘what are the characteristics that accompany old age?’ Two main points should be considered: comorbid conditions and progressive physiologic reduction of organ function. Cancer patients aged 70 years and older have, on average, three comorbidities that can affect cancer risk, detection, evolution and treatment [7]. Aging brings about a progressive decrease in physiologic reserve that affects each individual and, typically, begins in the third decade of life. A number of age-related changes in drug adsorption, distribution, metabolism and excretion can contribute to differences in treatment tolerance between older and younger patients [8,9]. Therefore, elderly patients could tolerate chemotherapy poorly because of comorbid conditions and organ failure.

Another important consideration is that aging is a heterogeneous process. Within a group of elderly patients of the same chronological age, some are fit and others are frail. Thus, in order to further individualize treatment choice in elderly patients, it is important to practice a comprehensive geriatric assessment (CGA), including assessment of comorbidity, socioeconomic conditions, functional dependence, emotional and cognitive conditions, an estimate of life expectancy and recognition of frailty. However, the CGA may be too lengthy for a busy clinical practice. As alternatives to a full geriatric assessment, the evaluation proposed by the Cardiovascular Health Study (CHS) has gained particular prominence, because it correlates well with mortality and risk of functional dependence [10]. Considering that the definition of frailty is currently controversial, it is prudent to reserve this term for the specific context of CHS assessment that allows the classification of elderly patients into three groups (fit, pre-frail or frail) according to five items (unintentional weight loss, self-reported exhaustion, weakness, walking speed and level of physical activity) [10,11].

Lung cancer is the leading cause of cancer-related mortality worldwide. The majority of lung cancer cases are diagnosed in elderly patients, more than 50% in patients aged over 65 years and approximately 30% in patients aged over 70 years [12]. The most common lung cancer subtype is non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of all new diagnoses [13].

As a consequence, elderly patients with NSCLC will be an increasing population to be treated in the near future.

Elderly NSCLC patients treatment: state-of-the-art

Since most patients with NSCLC have advanced disease at diagnosis, chemotherapy is the mainstay of treatment. The main clinical data on chemotherapy for elderly NSCLC patients come from advanced disease. Two main randomized, Phase III trials stated single-agent chemotherapy as the standard treatment [14,15]. A third randomized, Phase III trial compared two single-agent (vinorelbine versus docetaxel) failing to demonstrate a survival advantage for one of them [16]. However, considering single-agent chemotherapy with a third-generation drug (a recommended option for elderly advanced NSCLC patients [17–19]), a question arises: ‘which single-agent?’ Several factors should be considered by the clinician when choosing the drug to be administered. This choice should take into account the expected toxicity profile of the agent, pharmacokinetics, organ function and comorbidities.

Third-generation, platinum-based doublets represent the standard of care for advanced NSCLC in adult patients, but they are associated with significant toxicity and evaluation of the risk versus benefit ratio should be particularly rigorous in elderly patients [17]. In retrospective analyses, treatment outcomes of platinum-based chemotherapy were compared between patients younger and older than 70 years. Globally, these analyses found no differences in survival between elderly and younger patients, with a small increase in toxicity in the elderly, and suggested that advanced age alone should not preclude platinum-based chemotherapy for NSCLC. However, elderly patients enrolled in this kind of trial are not representative of the whole elderly population, but rather of a small subgroup considered by investigators to be eligible for aggressive treatments. Prospective Phase II clinical trials of platinum-based chemotherapy employed innovative schedules and attenuated platinum doses to obtain active and well-tolerated regimens. The results are very interesting in terms of activity and tolerability but the benefit of platinum-based combination chemotherapy should be proven by large clinical trials specifically designed for elderly patients [18].

In early-stage cancer, two meta-analyses evaluating Phase III trials of surgery alone versus surgery plus adjuvant chemotherapy in the general population showed a significant survival benefit at 5 years for cisplatin-based chemotherapy. A subgroup analysis showed no evidence that any group of patients specified by age benefited more or less from chemotherapy [19,20]. Recently, a retrospective analysis was performed on 155 elderly patients (aged >65 years) out of 482 patients who were radically resected for NSCLC and randomized to receive or not receive adjuvant cisplatin plus vinorelbine regimen. Despite elderly patients receiving less total chemotherapy than younger patients, adjuvant treatment improved survival with an acceptable toxicity profile [21]. This survival advantage was lost in patients over 75 years. However, considering the risk of selection bias of retrospective analyses, prospective studies are needed to investigate adjuvant chemotherapy in elderly patients.

Several randomized trials have compared sequential and concurrent chemoradiotherapy versus radiation alone and demonstrated the superiority of combined modality approaches. Recent randomized trials have also compared sequential versus concurrent approaches, demonstrating a survival benefit in favor of concurrent chemoradiotherapy. Retrospective analyses of combined chemoradiotherapy in locally advanced NSCLC patients suggest equivalent therapeutic benefit for younger and older patients, despite heightened toxicity [22]. There have been no elderly-specific Phase III trials in this setting. To date, combined chemoradiotherapy, particularly with a concurrent approach, should be offered to highly selected elderly patients only.

Since data from retrospective analyses suffer from inherent uncontrolled biases, only specifically designed prospective studies can define the value of combined chemoradiotherapy for the broader population of elderly patients with locally advanced NSCLC.

Should new targeted therapies be considered the future in the treatment of elderly NSCLC patients?

To improve the results reached with chemotherapy, new specific approaches are needed. Knowledge of cancer biology and mechanisms of oncogenesis enabled the development of new agents able to specifically block pathways responsible for the acquisition of the cancer phenotype. Many new target agents have been tested in preclinical and clinical settings, but, to date, only two agents have been licensed for NSCLC treatment:

•	Erlotinib: an oral small molecule inhibiting EGF receptor tyrosine kinase approved worldwide for the treatment of recurrent advanced NSCLC [23]
•	Bevacizumab: a monoclonal antibody inhibiting VEGF, licensed for use in combination with carboplatin plus paclitaxel for first-line therapy of patients with advanced nonsquamous NSCLC in the USA [24]

While erlotinib was demonstrated to be active and well tolerated as first-line monotherapy in elderly patients affected by advanced NSCLC [25], bevacizumab, in a retrospective analysis, resulted in a higher incidence of toxicity without survival advantage [26]. These different results could be explained with the different drug toxicity profiles. Bevacizumab is administered to more selected patients owing to the risk of hemoptysis reported in squamous histology and its cardiovascular toxicity. The latter is the main reason for routinely contraindicating use of bevacizumab in elderly patients, in whom cardiovascular diseases are observed very often.

The treatment of elderly NSCLC patients must be carried out with respect for their quality of life; many new targeted agents are being evaluated in clinical research and some of them (e.g., ZD6474, sorafenib and sunitinib) appear to be promising due to initial evidence of their antitumor activity, good toxicity profile and oral administration.

Summary & future directions

Clinical trials that systematically include functional status and comorbidity as part of geriatric assessment are rare. Future trials specifically addressed to the elderly should include these kinds of evaluations. In unselected elderly patients with advanced disease, single-agent chemotherapy can be considered a standard treatment, while platinum-based regimens must be investigated in prospective clinical trials. Adjuvant chemotherapy for early stages and combined treatment for locally advanced disease should be evaluated in clinical studies specifically designed for the elderly population. New biologic agents could play an important role in the treatment of elderly NSCLC patients, considering that the explosion in knowledge regarding molecular biology and the development of targeted therapies is opening a new era for improving cancer therapy.

Despite a growing body of data, a great deal of work is still needed to establish optimal strategies to care for elderly patients diagnosed with lung cancer. Hence, as older lung cancer patients will be the majority of the patients that we treat, they need to become a main focus of clinical research.

Financial & competing interests disclosure

Honoraria as consultant and as Speaker bureau member for Roche Eli-Lilly and AstraZeneca. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.