Vinicius Ernani and Taofeek K. Owonikoko

INTRODUCTION

Lung cancer is the leading cause of cancer-associated mortality worldwide, causing an estimated 1.4 million deaths per year. In the United States, lung cancer occurs in a predominantly elderly population with a median age at diagnosis of 70 years (1). Indeed, two-thirds of newly diagnosed lung cancer patients are more than 65 years old and approximately 10% to 15% are 80 years old or older at diagnosis (2). An analysis of the Surveillance, Epidemiology, and End Results (SEER) database revealed that non–small-cell lung cancer (NSCLC) accounts for 84% of lung cancer cases in patients less than 70 years old, 85% among those aged 70 to 79 years, and 90% of those aged 80 years or older (2). The prevalence of the different histologic subtypes of lung cancer also varies with age. Squamous cell carcinoma accounts for approximately 20% of all cases in each of the three elderly age groups, while adenocarcinoma accounts for 33% of cases in the less than 70-year group, 27% in those 70 to 79 years, and 23% in those greater than 80 years old.

Although lung cancer is a disease of the elderly, there is no established consensus on the management of elderly patients due to the limited representation of this group in pivotal studies that established standard management algorithms. Indeed, only 25% of older patients receive cytotoxic chemotherapy for advanced disease (3). Moreover, due to age-related declines in physical capability and organ function (Figure 12.1), treatment approaches that are deemed safe in fit younger patients may require particular care and adjustment when applied to fit elderly patients and younger patients with significant comorbid conditions.

There are also no established consensus definitions for elderly or high-risk patients, but elderly is generally defined as ≥70 years of age, while significant impairment in neurologic, cardiopulmonary, hepatic, and renal function could place a patient at high risk for specific surgical, radiotherapeutic, or systemic interventions used to treat lung cancer. Significant heterogeneity exists within elderly and high-risk populations due to differences in the impact of specific organ dysfunction and comorbid illnesses. These differences may or may not correlate directly with functional status and capacity to tolerate the increasing array of therapies employed in the management of various stages of lung cancer. For the purpose of this review, elderly patients and “unfit” younger patients are considered the high-risk patient group requiring special attention when selecting optimal therapy.

Figure 12.1 Age-Dependent Decline in Critical Organ Function Impacting Optimal Management of NSCLC in Elderly and High-Risk Patients

GENERAL CONSIDERATIONS IN ELDERLY LUNG CANCER PATIENTS

The normal aging process involves a progressive deterioration in physiologic function, especially renal and hematopoietic function. In addition, older patients often have multiple comorbidities, including cardiac and pulmonary conditions, which put them at risk for surgical intervention. The elderly also have a greater likelihood of polypharmacy, which can interfere with efficient metabolism of anticancer agents (4,5). While chronological age is not the best parameter for determining fitness, existing validated tools may not be practical for routine patient care. However, a few of these tools, such as the Charlson comorbidity index and the more detailed Cumulative Illness Rating Scale-Geriatric, have been employed as research measures (6,7).

Performance status is a major prognostic factor in lung cancer patients and is generally employed to guide the selection of the most appropriate treatment. Performance status needs to be evaluated independently from comorbidities, because there is little correlation between comorbidity and functional status in elderly patients (8). The Comprehensive Geriatric Assessment (CGA; Table 12.1) encompasses multiple domains such as functional, emotional, and nutritional status, comorbid illnesses, polypharmacy, cognitive capacity, and the patient’s social and environmental situations, and is more reliable than age alone in classifying patients as “fit,” vulnerable, or frail and in aiding selection of patients for specific therapeutic interventions (9–11). In a prospective phase III trial, CGA outperformed the traditional tools of performance status and chronological age in assigning appropriate systemic therapy (12).

EARLY STAGE NSCLC

Surgical Considerations in Elderly and High-Risk Patients

Surgery is the primary treatment for patients with early stage lung cancer and should not be withheld from elderly patients based solely on their chronological age. Performance status and comorbid illnesses should be considered when deciding for or against surgery (13). Since elderly and high-risk patients are more likely to suffer from pulmonary complications following lung resection, preoperative cardiopulmonary evaluation is recommended for every patient undergoing surgery. In a study of patients of all ages, the Lung Cancer Study Group prospectively compared sublobar resection with lobectomy and demonstrated that limited resections were associated with higher rates of death and local recurrence. Thus, lobectomy is superior to sublobar resection in patients with early stage NSCLC (14). However, some retrospective studies support more limited operations, such as wedge resection or segmentectomy, in elderly patients with lung cancer (15,16). For standard-risk patients with operable disease, sublobar resections should be reserved for pure ground-glass lesions smaller than 2 cm located in the periphery of the lung. In patients at higher risk for surgical complications, sublobar resections can be performed more liberally.

Video-assisted thoracoscopic surgery (VATS) is a minimally invasive technique that enables an optimal oncologic resection with comparable cancer-specific outcomes to open surgical approaches. VATS is also associated with shortened hospital stay and lower rate of postoperative pulmonary complications (17). However, minimally invasive surgery does not obviate the need for proper selection of patients, especially those with impaired cardiac function or limited cardiopulmonary reserve, since frail patients are more likely than fit patients to have postoperative complications following minimally invasive surgery (18,19).

Radiation for Medically Inoperable Patients With Early Stage NSCLC

Stereotactic ablative radiotherapy (SABR) is now an established alternative to surgery in medically inoperable patients, including elderly and high-risk patients with significant comorbid illnesses that render surgery unsafe. Whether SABR is a legitimate alternative to surgery in fit elderly patients who may safely undergo surgery has not been clearly established because prospective studies that attempted to compare SABR to definitive surgery in operable patients have been unable to meet accrual targets. Nonetheless, pooled data from 58 patients with clinical stage I, operable NSCLC enrolled on two randomized, phase III trials stereotactic ablative radiotherapy (SABR) in stage I non–small-cell lung cancer patients who can undergo lobectomy (STARS) and trial of either surgery or stereotactic radiotherapy for early stage (IA) lung cancer (ROSEL) that were discontinued for poor accrual showed a 3-year overall survival rate of 95% versus 79% (HR 0.14, 95% confidence interval [CI] 0.02–1.19; P = .037) and a 3-year recurrence-free survival of 86% versus 80% (HR 0.69, 95% CI 0.21–2.29; P = .54) for SABR versus surgery, respectively. This limited dataset suggests that SABR could be considered in appropriately informed elderly patients with operable stage I NSCLC (20).

Adjuvant Chemotherapy in NSCLC

The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis established that adjuvant cisplatin-based chemotherapy is associated with a 5.3% absolute increase in 5-year overall survival after complete surgical resection of NSCLC compared to no further treatment (21). Unfortunately, there are no elderly specific randomized trials in the adjuvant setting. Data supporting the use of adjuvant chemotherapy in the elderly come from two studies. The first was a pooled analysis that considered individual data from 4,584 patients enrolled in the five randomized trials registered in the LACE database. Outcome and toxicity data were compared between three age groups: less than 65 years old, 65 to 69 years old, and ≥70 years old. Elderly patients ≥70 years old received significantly fewer total doses of cisplatin and fewer cycles of chemotherapy. However, the survival benefit from cisplatin-based adjuvant chemotherapy was similar in patients in the three age groups, and there was no significant difference in treatment-related toxicity (22). Similarly, a retrospective analysis of the impact of age on survival, treatment delivery, and toxicity in 155 elderly patients (>65 years) enrolled on the JBR.10 study showed that adjuvant chemotherapy conferred a survival benefit in elderly patients that was comparable to that reported for the overall study population (23). Cisplatin-based regimens were used in the pivotal studies of adjuvant chemotherapy. However, carboplatin has a better safety profile, especially in the elderly. While there is no comparative data in this setting to establish the equivalence of carboplatin and cisplatin, extrapolation from a meta-analysis in patients with advanced-stage disease that showed no difference in efficacy between carboplatin and cisplatin (24) supports the use of carboplatin in elderly and high-risk patients with specific contraindication to cisplatin.

Postoperative Radiation Therapy in NSCLC

Patients who have undergone complete surgical resection for NSCLC and have a high risk of recurrence, especially those with mediastinal lymph node involvement, may benefit from postoperative radiation therapy (PORT) (25,26). While there is no robust prospective data regarding the impact of PORT in elderly patients, a retrospective analysis suggests a lack of benefit for PORT in the elderly (27).

LOCALLY ADVANCED NSCLC

Concurrent chemoradiotherapy (CCRT) is the standard of care for most patients with unresectable stage III NSCLC, but the majority of elderly patients with stage III disease do not receive combined modality therapy. At least three randomized phase III trials demonstrated improved survival with CCRT compared to a sequential approach in the general lung cancer population at the cost of higher toxicity (28–30). Post hoc analyses indicate that both elderly and younger patients achieve a comparable survival benefit from CCRT, but significant increases in both hematologic and nonhematologic toxicities in the elderly could potentially outweigh the benefits if patients are not carefully selected (31–33). In a phase III trial in Japanese patients, ≥70 years old with locally advanced NSCLC, CCRT using low-dose, single-agent carboplatin was superior to radiation alone (median overall survival, 22.4 vs. 16.9 months), at the expense of higher toxicity (34).

METASTATIC NSCLC

Cytotoxic Chemotherapy

Concerns regarding the risk of intolerable toxicity limited the use of cytotoxic chemotherapy in elderly patients until the European, phase III Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS) study compared single-agent vinorelbine versus best supportive care in patients ≥70 years of age and demonstrated that vinorelbine was both safe and beneficial (median overall survival, 28 vs. 21 weeks; P = .03) (35). A subsequent phase III trial comparing docetaxel to vinorelbine in 182 elderly Japanese patients ≥70 years old demonstrated a significant benefit with docetaxel in terms of progression-free survival (PFS), response rate, and disease-related symptoms (36). However, the phase III Multicenter Italian Lung Cancer in the Elderly Study (MILES) that compared single-agent vinorelbine or gemcitabine to the combination of vinorelbine plus gemcitabine in 698 patients ≥70 years old showed no survival advantage for the combination regimen (37). These trials established a role for single-agent chemotherapy as a safe and effective option for elderly patients with metastatic NSCLC.

Subsequently, a number of studies have examined the efficacy and tolerability of two-drug regimens in older and high-risk lung cancer patients. Retrospective subset analyses of randomized trials that enrolled fit patients of all ages with advanced NSCLC have generally shown similar outcomes with combination chemotherapy regardless of age (38–41). For example, a subset analysis of a study that compared cisplatin or carboplatin plus docetaxel to cisplatin plus vinorelbine showed no survival difference with age (39). Similarly, a retrospective analysis of a phase III study of gemcitabine plus carboplatin or paclitaxel versus carboplatin plus paclitaxel demonstrated no survival difference by age (40). Finally, a phase III trial that randomized 561 patients to paclitaxel alone versus carboplatin plus paclitaxel reported a nonsignificant improvement in survival with combination therapy with similar survival outcomes in elderly (≥70 years old) and younger patients (41). However, a combined analysis of data from two Southwest Oncology Group (SWOG) trials reported shorter overall survival in patients ≥70 years old who were treated with platinum-based, two-drug chemotherapy regimens (median, 7 vs. 9 months; P = .04) (42).

Recent prospective, elderly specific trials have also demonstrated a survival benefit with combination chemotherapy over single-agent therapy. (Table 12.2) Quoix et al. randomized 451 patients between 70 and 89 years of age to carboplatin plus paclitaxel × four cycles or single-agent vinorelbine or gemcitabine × five cycles, and reported improved overall survival with combination chemotherapy (10.3 vs. 6.2 months; P < .0001) (43). Another prospective study by Lilenbaum et al. in high-risk patients with advanced, untreated NSCLC and an ECOG performance status of two compared single-agent pemetrexed to the combination of carboplatin plus pemetrexed. A large proportion of the enrolled patients were elderly (median age, 65 years; range 40–91 years). All efficacy endpoints favored combination chemotherapy over single-agent therapy, including response rate (10% vs. 24%; P = .032), PFS (median, 2.8 vs. 5.8 months; HR 0.46, 95% CI 0.35–0.63; P < .001), and overall survival (median, 5.3 vs. 9.3 months; HR 0.62, 95% CI 0.46–0.83; P = .001) (44).

A recent comprehensive meta-analysis of 51 elderly focused studies evaluated the benefits of: (a) nonplatinum single-agents versus combination regimens and (b) nonplatinum combination regimens versus platinum-based combination regimens. Based on low-quality evidence from five randomized trials, nonplatinum single-agent therapy and combination regimens yielded similar overall survival (HR 0.92, 95% CI 0.72–1.17) and PFS (HR 0.94, 95% CI 0.83–1.07). In contrast, based on moderate-quality evidence, platinum-based combination therapy resulted in improved overall survival compared to nonplatinum combination regimens (HR 0.76, 95% CI 0.69–0.85), albeit at the cost of increased hematologic and nonhematologic toxicity (45).

Antiangiogenic Agents

The addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), to cytotoxic chemotherapy is a standard option for first-line treatment of advanced, non-squamous NSCLC. The benefit of bevacizumab was reported in ECOG 4599, which randomized 878 patients of all ages with advanced NSCLC to carboplatin plus paclitaxel alone versus carboplatin, paclitaxel plus bevacizumab followed by maintenance bevacizumab. Patients treated with chemotherapy plus bevacizumab demonstrated improved overall survival (median, 12.3 vs. 10.3 months; HR 0.79; P = .003) (46). Subsequently, the PointBreak trial failed to demonstrate the superiority of carboplatin, pemetrexed plus bevacizumab followed by maintenance pemetrexed plus bevacizumab over carboplatin, paclitaxel plus bevacizumab followed by maintenance bevacizumab. A combined retrospective analysis of outcome by age using individual data from patients treated with carboplatin, paclitaxel, plus bevacizumab on the E4599 and PointBreak studies showed a significant benefit with the addition of bevacizumab when compared to patients treated with carboplatin plus paclitaxel alone in E4599, but only in patients younger than 75 years of age. Elderly patients not only did not seem to benefit from bevacizumab, but also had increased toxicity when treated with it (47).

Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors

EGFR gene mutations are more commonly observed in younger patients and never-smokers. However, these alterations are also found in elderly patients and smokers, albeit at a lower frequency. Thus, molecular testing for EGFR mutations and other targetable genetic alterations should not be restricted based on patient age or other clinical or demographic factors (48). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib, gefitinib, and afatinib) are now established as the preferred front-line treatment for metastatic NSCLC harboring sensitizing EGFR mutations. There are no prospective data to suggest which EGFR-TKI might be preferred for the treatment of elderly patients. However, elderly specific studies and subgroup analyses of randomized trials comparing EGFR-TKIs to platinum-based chemotherapy have demonstrated the safety and efficacy of these agents in elderly patients (Table 12.3) (49,50). Moreover, these studies have reported no significant differences in clinical outcome between elderly and younger patients (51–53). Therefore, elderly patients with EGFR-mutated NSCLC should be treated with the same algorithms as used for younger patients.

Anaplastic Lymphoma Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) rearrangement is the second most common targetable alteration, after EGFR mutations, in NSCLC. ALK rearrangement is frequently observed in younger, never-smokers, but its presence is not dependent solely on these clinical characteristics (48). Given the relatively small number of patients with ALK-rearranged NSCLC, elderly specific studies are not feasible. Moreover, formal subset analyses based on age are also impractical since the overwhelming majority of patients are younger. Nonetheless, clinical trials that established the efficacy of crizotinib, ceritinib, and alectinib for the treatment of ALK-rearranged NSCLC did enroll some elderly patients and revealed no age-based differences in safety or efficacy (54,55).

Immunotherapy

Agents targeting the PD-1 signaling pathway are now approved for the treatment of squamous and non-squamous NSCLC that progressed after treatment with platinum-based therapy. While there is a progressive natural diminution in immunologic response with age, post hoc subset analyses of the pivotal studies leading to the approval of the PD-1 antagonists nivolumab and pembrolizumab did not suggest any differences in treatment efficacy based on age. A recent meta-analysis of nine randomized, controlled trials of immune checkpoint inhibitors enrolling 5,265 patients evaluated efficacy in both younger and older (≥65–70 years old) patients and found a consistent overall survival benefit favoring immunotherapy in both younger (HR 0.75, 95% CI 0.68–0.82) and older (HR 0.73, 95% CI 0.62–0.87) patient subgroups (56).

SMALL CELL LUNG CANCER

Small cell lung cancer (SCLC) commonly occurs in the elderly, with 43% of patients being diagnosed at 70 years of age or older (2). Patients with SCLC also frequently present with poor performance status due to preexisting comorbidities and the aggressiveness of the disease. However, few randomized trials have specifically focused on the treatment of SCLC in the elderly, and many have combined elderly and poor performance status patients without reporting outcomes separately for the two groups. Therefore, deriving appropriate treatment guidelines for the elderly and other high-risk patients is challenging.

A common theme in clinical trials for elderly patients with SCLC is to compare the efficacy and toxicity of lower intensity regimens to standard regimens (Table 12.4). In one randomized trial that enrolled only elderly patients, Ardizzoni et al. compared standard cisplatin plus etoposide (PE) to a reduced-dose PE regimen in 95 patients ≥70 years old with performance status of 0 to 2. Although reduced-dose PE was less toxic, it also yielded a lower response rate and overall survival (57). Two other randomized trials included both elderly and poor performance status patients. Okamoto et al. compared PE to carboplatin plus etoposide in 220 patients with extensive-stage SCLC. Ninety-two percent of patients were ≥70 years old with a performance status of 0 to 1 and 8% were less than 70 years old with a performance status of 3. There were no significant differences in response rate or survival between the two arms in the overall study population or in the subgroup of elderly patients (58). Souhami et al. compared single-agent etoposide to a regimen that alternated PE with CAV (cyclophosphamide, doxorubicin, vincristine) in 155 patients who were either ≥75 years old with any performance status or less than 75 years old with performance status of 2 to 3. All efficacy endpoints, including response rate, PFS, overall survival, and quality of life, were significantly worse in the single-agent etoposide arm (59). However, this trial did not report outcomes separately for elderly or poor performance status patients.

Several large clinical trials have been retrospectively analyzed to evaluate the effect of age on outcome in SCLC. Yuen et al. reported a retrospective, age-specific analysis of INT-0096 in which 381 patients with limited-stage SCLC and performance status 0 to 2 were randomized to receive standard PE with either once-daily or twice-daily radiation therapy (RT). Only 13% of patients were ≥70 years old. Response rates (88% vs. 80%; P = .11) and PFS (5 years, 19% vs. 16%; P = .18) were similar in both younger and older patients, but toxicity was greater in the elderly. Overall survival was better in younger patients (median, 22 vs. 14 months; P = .05), mainly due to a higher treatment-related death rate in elderly patients (10% vs. 1%). Among elderly patients, twice-daily radiation did result in better overall survival compared to once-daily RT, but this difference did not reach statistical significance (60). Schild et al. performed a retrospective age-specific analysis on NCCTG 89-20-52, a similar trial that randomized 263 patients with limited-stage SCLC and performance status 0 to 2 to standard PE with either once-daily or twice-daily RT. In this study, 21% of patients were ≥70 years old. Overall survival was nonsignificantly lower in elderly patients compared to younger patients (5-year, 17% vs. 22%; P = .14). Again, the treatment-related death rate (5.6% vs. 0.5%, P = .03) was significantly greater in the elderly (61).

Two recent retrospective analyses also support the use of chemotherapy and RT in appropriate elderly patients, though treatment selection-bias may confound the results of such studies. A retrospective study of the National Lung Cancer Database evaluated 8,637 patients ≥70 years of age with limited-stage SCLC who were treated with either chemotherapy alone or chemoradiotherapy. The use of chemoradiotherapy declined with increasing age, higher TNM stage, and greater comorbidities, and was associated with better overall survival (median, 15.6 vs. 9.3 months; P < .001) (62). Similarly, an analysis of 10,428 patients ≥65 years old with SCLC who were enrolled in the SEER-Medicare database reported that the use of chemotherapy and RT were both associated with better survival, even in patients ≥85 years old, with chemotherapy improving overall survival by 6.9 months (63).

In general, elderly patients with limited-stage SCLC and good performance status should be considered for treatment with platinum-based chemotherapy plus thoracic RT with close attention to treatment-related toxicity. Elderly patients with extensive-stage SCLC and good performance status should be considered for treatment with carboplatin-based chemotherapy, while those with poor performance status may still benefit from palliative chemotherapy or RT, particularly if their debility is due to SCLC.

 

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