Back Back
NSCLC in Elderly Patients
Managing Elderly Patients With Advanced NSCLC

Released: January 30, 2017

Expiration: January 29, 2018

Activity Information

Activity

Progress
1
Course Completed
Continue

With a median age of approximately 70 years at diagnosis for metastatic NSCLC, the elderly comprise the predominant subgroup of patients with advanced NSCLC. Even so, treatment of elderly patients with advanced NSCLC is a major area of therapeutic confusion. As a result of misperceptions about the tolerability and efficacy of treatments in the elderly and underestimates of their expected longevity, elderly patients commonly are undertreated. In reality, chronologic age cutoffs without regard to physiologic age are poor predictors of treatment tolerance and benefit. Furthermore, actuarial life tables predict that a 70-year-old man and a 70‑year‑old woman are expected to have approximately 14 and 16 additional years of life, respectively. Therefore, the major factor strongly influencing the expected survival of most elderly patients with metastatic NSCLC is the cancer itself, not comorbidities, and not age alone.

Defining “Elderly Patients”
The more effective way to define “elderly patients” is by their physiologic age, which can be accomplished through geriatric assessment. Geriatric assessments measure both physical and mental capacity and often include evaluation of performance status and comorbidities. There is no one standard way to conduct a geriatric assessment; each geriatric specialist will choose the formal assessment methods based on his or her preference. There is an argument to be made that perhaps all elderly patients should undergo geriatric assessment to identify inconspicuous limitations that might not be obvious from a simple conversation. However, more geriatric-savvy oncologists might first ask their elderly patients a few screening questions to see if a full geriatric assessment is necessary, for example: Do you do your own bills? How many times have you fallen in the last month? If, from this conversation, the patient is clearly 70 going on 30 years of age, most clinicians will treat them like a younger patient rather than request a consult for a full geriatric assessment.

Targeted Therapy for Advanced NSCLC With Actionable Mutations
For an older NSCLC patient with an actionable mutation in EGFR (10% to 15% of all NSCLC patients in North American and 50% of patients in Asia), ALK (2% to 7% of all NSCLC patients), or ROS1 (1% to 3% of all NSCLC patients), the first choice of treatment should be targeted therapy. When matched with an actionable mutation, oral targeted therapies are more effective, less toxic, and more convenient than conventional IV chemotherapy for patients. As such, targeted therapies can be considered more geriatric friendly, both from the perspective of limiting toxicity and from preventing suffering from the cancer itself. For example, first-line gefitinib was shown to be less toxic and more effective than carboplatin/paclitaxel for patients with EGFR-mutation-positive NSCLC in the phase III IPASS trial. Furthermore, for patients with ALK rearrangement–positive NSCLC, first-line and second-line crizotinib achieved a superior PFS vs chemotherapy in the phase III PROFILE 1014 trial (10.9 vs 7.0 months; HR: 0.45; P < .001) and the phase III PROFILE 1007 trial (7.7 vs 3.0 months; HR: 0.49; P < .001), respectively.

Immune Checkpoint Inhibitors for Advanced NSCLC
For the 25% to 30% of patients with newly diagnosed metastatic NSCLC without actionable mutations that is positive for high PD-L1 expression and for those patients who failed previous platinum-based doublet chemotherapy, immune checkpoint inhibitors are the preferred choice of treatment regardless of age. These agents are extremely tolerable as compared with cytotoxic alternatives and may be considered geriatric friendly. The PD-1 inhibitor pembrolizumab is FDA indicated as the first-line therapy for patients with at least 50% PD-L1 tumor staining and as second-line treatment following doublet chemotherapy for patients with at least 1% PD-L1 tumor staining. The PD-1 inhibitor nivolumab and PD-L1 inhibitor atezolizumab are FDA approved for the second-line treatment of advanced NSCLC following doublet chemotherapy regardless of PD-L1 expression. 

Chemotherapy in Elderly Patients With Advanced NSCLC
Most patients diagnosed with advanced NSCLC are PD-L1 negative and lack driver mutations, and therefore should receive chemotherapy in the frontline. Chemotherapy is associated with considerable adverse events (eg, nausea, alopecia, fatigue, and infections), especially in elderly patients. Although elderly patients with advanced NSCLC might contemplate foregoing chemotherapy as a way to maximize quality of life, metastatic lung cancer is highly symptomatic and causes a great deal of suffering. Cancer growth in the brain causes headaches, confusion, nausea and vomiting; cancer growth within the lungs causes coughs and shortness of breath; and cancer growth that presses on a nerve causes pain. With advanced NSCLC, we do not have the luxury of ignoring these sources of suffering. Our goal in achieving quality of life with chemotherapy is to find a balance between symptom control and toxicity—good chemotherapies control suffering from the disease while causing a minimum of adverse events.

Platinum-Based Doublet Chemotherapy vs Monotherapy
When cytotoxic therapy is used, the standard of care for younger patients with advanced NSCLC is platinum-based doublet chemotherapy, typically some combination of cisplatin or carboplatin with paclitaxel, albumin-bound paclitaxel, pemetrexed, gemcitabine, vinorelbine, or docetaxel. Until recently, there was substantial controversy about whether platinum-based doublet chemotherapy could also be used in elderly patients or if it would be better to use a single agent. The phase III IFCT-0501 trial, which randomized patients 70-89 years of age with a performance status (PS) of at least 2 to carboplatin/paclitaxel doublet chemotherapy vs gemcitabine monotherapy, showed that both PFS (HR: 0.51) and OS (HR: 0.64) were better with doublet chemotherapy (P < .0001 for both), even in a subgroup analysis of less-fit, elderly patients with a PS of 2. Similar results were obtained for carboplatin/pemetrexed doublet chemotherapy vs pemetrexed monotherapy in a phase III trial of advanced NSCLC patients with a PS of 2, even in a subset analysis of elderly patients. Thus, it appears that even for elderly patients, 2 drug regimens are better than single agents.

Choice of Geriatric-Friendly Chemotherapeutic Agents
Regarding the choice of platinum agent, cisplatin is a very geriatric-unfriendly drug, whereas carboplatin is much more geriatric friendly. Cisplatin is very toxic, causing otopathy, nephropathy, neuropathy, and nausea and vomiting. It is mostly cleared in the urine, which can be a problem for older patients that enter treatment with preexisting age‑related decline in kidney function. Although carboplatin is also mostly excreted in the urine, it is much less nephrotoxic and its AUC dosing formula inherently accounts for preexisting decline in the glomerular filtration rate. Furthermore, nausea, vomiting, neuropathy and otopathy are less frequent with this agent, but it is more myelosuppressive than cisplatin.

Of the approved taxanes, nab-paclitaxel, a solvent-free, albumin-bound form of paclitaxel, has been shown to be quite geriatric friendly. In a subgroup analysis of a phase III trial comparing first-line carboplatin/nab-paclitaxel vs carboplatin/paclitaxel in advanced NSCLC, nab-paclitaxel was shown to have superior efficacy in the elderly. Among elderly patients aged 70 years or older, nab-paclitaxel significantly improved OS vs paclitaxel (19.9 vs 10.4 months, respectively; HR: 0.583; P = .009), as well as had significantly lower rates of neutropenia, neuropathy, and arthralgia but higher rates of thrombocytopenia. A phase IV trial comparing 2 schedules of first-line nab-paclitaxel in combination with carboplatin and a phase II trial of second-line nab-paclitaxel in patients aged 70 years or older support these results.

Paclitaxel is a moderately geriatric-friendly drug, especially when it is given on a weekly schedule that allows for dose adjustments or treatment cessation in patients who are having difficulty with tolerance. Gemcitabine is mostly renally cleared. Gemcitabine tends to be a gentler agent for patients with good renal function. Docetaxel is more difficult on older patients—they just do not feel well on it. When I do consider docetaxel for older patients, I often consider reducing the dose from the standard of 75 mg/m2 to 60 mg/m2. Finally, taxanes are all mostly excreted through feces, so renal dysfunction—at low levels, at least—is not much of a problem.

Pemetrexed is another geriatric-friendly cytotoxic agent with limited toxicity, but its indication is restricted to patients with nonsquamous NSCLC, whether in combination in the frontline or as a single agent as maintenance therapy or in the second line. In a phase III trial of patients unselected by age, first-line cisplatin/pemetrexed achieved a superior OS in patients with nonsquamous histology vs cisplatin/gemcitabine (12.6 vs 10.9 months; HR: 0.84; P = .03), findings that held in a subgroup analysis of patients aged 65 years and older (HR: 0.88). Furthermore, in the phase III JMEN trial, maintenance pemetrexed was well tolerated and showed a superior PFS and OS vs placebo, with a post hoc subgroup analysis of patients at least 65 years of age showing similar results. Finally, second-line, single-agent pemetrexed achieved a superior OS vs docetaxel in patients at least 70 years of age (HR: 0.86), even though OS was comparable between these 2 agents in younger patients.

The phase III ELVIS trial showed that first-line vinorelbine more than doubled survival vs placebo in elderly patients with advanced NSCLC: At 1 year, 32% of patients were alive with vinorelbine vs 14% with placebo. Furthermore, robust quality-of-life measurements showed that patients who received vinorelbine had better global health status and physical, role, emotional, cognitive, and social functioning vs placebo. However, not all drugs are superior in the elderly. The ECOG 4599 trial, which randomized patients unselected by age to carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab, showed a slight improvement in OS with the addition of bevacizumab for NSCLC patients younger than 75 years of age, but not 75 years of age or older.

Concluding Remarks
In summary, older patients with lung cancer are more resilient and have more life expectancy than is commonly thought. Geriatric assessment is useful for defining the fitness level of and identifying interventions for older patients. However, many elderly patients are candidates for standard therapies for advanced NSCLC. In general, when an EGFR-sensitizing mutation, ALK rearrangement, or ROS1 rearrangement is found, the first choice of therapy should be targeted therapy. When indicated, an immune checkpoint inhibitor is recommended for elderly patients with advanced NSCLC. Finally, when cytotoxic therapy is indicated, carboplatin based doublets are preferred over single-agent therapy or no therapy in fit patients with a PS of 0-2. Individual treatment decisions should always consider the values, comorbidities, and PS of each individual patient.

Please share your thoughts or questions on the care of elderly patients with advanced NSCLC in the comment box below.

Continue

Poll

1.
Approximately how often do you perform geriatric assessment of your patients with advanced NSCLC who are at least 70 years of age?
Submit