Lung cancer is the second most common malignancy and the leading cause of cancer-related death in the United States.1 The median age of diagnosis of non–small cell lung cancer (NSCLC) is 70 years, and therefore it represents a major disease burden in the elderly.2 However, most evidence used in the treatment of older patients with NSCLC is extrapolated from data on younger patients because of the lack of good quality evidence specific to the older population.3,4 Studies also suggest that older patients are not prescribed standard therapy, despite evidence suggesting that older patients with minimal comorbid conditions tolerate and respond to chemotherapy just as well as young patients.5,6 This article discusses the evaluation of older patients with NSCLC and presents the current evidence to direct their management.
Assessment of Older Patients With NSCLC
Older patients have unique issues that must be considered when determining a management plan, including chronologic age, functional status, comorbid conditions, concurrent medications, nutritional status, and cognitive abilities. Multiple screening tools have been designed to assess patient fitness based on these parameters. The more commonly used scales include Katz’s basic activities of daily living (ADL)7 and Lawton’s instrumental activities of daily living (IADL).8 Although increasing age and comorbidities are associated with increasing toxicity with standard therapy, fit older patients may derive the same benefit from aggressive treatment as younger patients. A retrospective analysis of a prospective clinical trial of advanced lung cancer in older adults undergoing chemotherapy found that although pretreatment quality-of-life and IDAL scores predicted for survival, ADL and comorbidity burden (based on the Charlson Index) did not.9 Unfortunately, no universally accepted and validated parameters are available to identify the “fit” older patient with lung cancer.
A comprehensive geriatric assessment (CGA) is a multidisciplinary approach aimed at assessing the life expectancy and morbidity associated with the individual’s malignancy. Recent studies show that a CGA can predict morbidity and mortality in older patients with cancer.10 The feasibility of incorporating a CGA into the oncology setting was evaluated in recent trials.11,12 The preoperative assessment of cancer in the elderly that incorporates the American Society of Anesthesiologists grade, performance status, CGA, and the Brief Fatigue Inventory has helped evaluate the fitness of older patients for cancer surgery.13–15
Clinical trials are ongoing to establish more simplified, time-efficient, and validated instruments to quantify fitness for various forms of therapy. Recent reports suggest that the Short Physical Performance Battery,16 G8,17 Vulnerable Elders Survey,16,17 and simplified geriatric assessment18 seem to be valid screening tools to decide which patients would benefit from more frequent monitoring before starting chemotherapy. Another area of investigation is the development of predictive models for chemotherapy toxicity in older adults with cancer, although these tools are not lung cancer–specific.19,20 Validation of these instruments in patients with NSCLC will provide better guidance in selecting patients for cytotoxic chemotherapy.
Surgery for Older Patients With Early-Stage Non–Small Cell Lung Cancer
Early-Stage NSCLC
Role of Surgery
Most of the evidence for the role of surgery in older patients comes from retrospective single-institution analyses and is somewhat variable. Most of this evidence, however, suggests that although older patients may have an increased risk for complications, perioperative mortality and survival seem to be similar to those of younger individuals, with the possible exception of a pneumonectomy, which seems to be associated with a higher mortality in older patients21 (Table 1).
When interpreting these data, it is important to recognize that these outcomes are from large centers with expertise in dealing with complicated cases, and may not be reproducible in smaller, low-volume centers. Therefore, these patients may be best served by referral to a center with appropriate expertise.22 Furthermore, single-institution retrospective trials magnify the risk of selection bias, making these results difficult for clinicians to apply to a given elderly patient.
Role of Adjuvant Chemotherapy
Adjuvant chemotherapy after resection is the standard of care for patients with stages II and IIIA and selected patients with stage I (large tumor size) NSCLC.22 The data supporting the use of adjuvant chemotherapy in older patients are mainly from 2 retrospective analyses. A large meta-analysis of 14 randomized studies23 using older agents that are no longer routinely used showed no evidence suggesting that the benefit of adjuvant chemotherapy was impacted by the patient’s age. A retrospective subset analysis of the JBR10 study (adjuvant cisplatin plus vinorelbine after resection of stage IB and II NSCLC) found that older patients received lower cumulative doses of the agents secondary to issues with tolerability.24 Despite this, however, the benefit seen with adjuvant therapy in older patients was similar to that seen in younger patients. A recent SEER-Medicare database analysis seems to confirm these findings.25 In this analysis of 3759 patients older than 65 years, the authors found that patients who received adjuvant chemotherapy had a significantly better overall survival (hazard ratio, 0.80; 95% CI, 0.72–0.89). Similarly, patients who received adjuvant chemotherapy had better 5-year adjusted survival rates compared with those who did not receive adjuvant therapy (35%; 95% CI, 32%–39% vs. 27%; 95% CI, 25%–29%, respectively). Although these data do not support the use of adjuvant chemotherapy in patients older than 80 years, the authors admit that their study was not sufficiently powered to detect a difference in this subset of patients.
In summary, a few prospective studies have evaluated the feasibility of lung cancer surgery in older patients. The available retrospective evidence suggests that although older patients tolerate surgery well, a pneumonectomy should be recommended with caution and only performed by thoracic surgeons with expertise in this population. Among patients enrolled in randomized clinical trials, the benefits of adjuvant chemotherapy seem to be maintained with age and should be recommended after resection if indicated based on the disease stage and functional status of the patient.
Locally Advanced NSCLC
Patients with locally advanced NSCLC are a heterogeneous group, and therefore treatment can be challenging. The optimal treatment of patients with locally advanced NSCLC has not been clearly defined, even though most patients are treated with concurrent chemotherapy and radiation. Many trials of combined modality therapy included patients with stages I through III disease, and therefore subset analyses are hampered by the lack of statistical power, making treatment decisions in older patients even more challenging (Table 2).
Although initial studies suggested that older patients (age ≥ 70 years) did not derive any benefit from the addition of chemotherapy to radiation26,27 and experienced increased toxicity, more recent analyses have challenged this finding. Langer et al.28 retrospectively analyzed data from RTOG 94-10, a randomized phase III trial comparing sequential versus concurrent chemotherapy and radiation. They found that although acute toxicities (esophagitis and neutropenia) were higher in older patients, no differences were seen in long-term toxicity or overall survival based on age. In a similar analysis, Schild et al.29 compared outcomes based on age of patients who had been randomized to chemotherapy with either once- or twice-daily radiation. They also found that although older patients had greater hematologic and pulmonary toxicity, their survival rates were similar to those of younger patients. Similar results were seen in CALGB 9130, which evaluated the role of concurrent carboplatin along with radiation after induction cisplatin and vinorelbine.30 In this study, although older patients experienced more myelosuppression and renal toxicity during induction therapy, no effect of age was seen on response rates and overall survival.
In another analysis, Schild et al.31 examined the role of chemotherapy in patients aged 65 years or older with stage III NSCLC who were enrolled on 2 North Central Cancer Treatment Group (NCCTG) trials of radiation alone or a combination of radiation and chemotherapy with cisplatin and etoposide. Although expectedly they found that patients who received combined modality therapy had increased hematologic and nonhematologic toxicity, the distant failure rates were lower and the median and 5-year survivals were significantly higher in the combined modality group. Therefore, although the efficacy of combined modality therapy is maintained in older patients, they are more likely to experience acute adverse effects, such as esophagitis, pneumonitis, and myelosuppression, especially if their Karnofsky performance status is less than 90.
Advanced/Metastatic NSCLC
Although several studies have evaluated the efficacy and toxicity of various chemotherapy agents in older patients with advanced NSCLC, their objective analysis requires a detailed look at the study population in each study. The major reason for this is that older patients often have been grouped with patients having a poor performance status, implying that age is analogous to poor performance.32,33 Multiple analyses of these 2 subgroups have conclusively shown that advanced age does not automatically equal poor performance status.34 Older patients with a good performance status (0–1) tolerate chemotherapy as well as younger patients with similar benefits,35 as opposed to patients with poor performance status who do not tolerate cytotoxic chemotherapy as well and have inferior outcomes, no matter their age.36,37
Combined Modality Therapy in Older Patients With Locally Advanced Non–Small Cell Lung Cancer
Data on the treatment of advanced NSCLC in elderly patients come from 2 main sources: retrospective analyses of clinical trials that did not discriminate based on age, and prospective trials specific for older patients. The next section reviews these separately.
Retrospective Analysis of Non–Age-Specific Trials
Platinum-based doublet therapy is the standard of care in the treatment of advanced NSCLC; however, prospective data in older patients are sparse.38 Therefore, most of the evidence supporting the use of platinum doublets in older patients is derived from retrospective analyses of trials that included patients of all ages (Table 3). The results consistently show that older patients had outcomes similar to those of younger patients, but, as shown by the combined modality studies described earlier, these were associated with an increased incidence of side effects. These findings suggest that, although standard therapy may be appropriate in some older patients, it cannot be routinely recommended to everyone given the increased toxicity.
Advanced Disease: Subset Analyses of Non–Age-Specific Trials
Elderly-Specific Trials
Single-Agent: The Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS) study, which was among the first randomized studies designed specifically for older patients, compared chemotherapy using single-agent vinorelbine with best supportive care in patients aged 70 years and older (Table 4).39 This study found that vinorelbine improved median survival compared with best supportive care (28 vs. 21 weeks). The West Japan Thoracic Oncology Group (WJTOG) compared docetaxel with vinorelbine and found an improvement in progression-free survival, response rates, and symptom control, and a nonsignificant improvement in survival (14.3 vs. 9.9 months) for docetaxel compared with vinorelbine, but at the expense of more severe neutropenia.40
Advanced Non–Small Cell Lung Cancer: Randomized Phase III Trials in Older Patients
Combination Versus Single-Agent: The Southern Italy Cooperative Oncology Group (SICOG) compared a combination of gemcitabine and vinorelbine versus vinorelbine alone in patients aged 70 years or older and found that combination therapy improved survival (Table 4).41 However, the larger Multicenter Italian Lung Cancer in the Elderly Study (MILES) using the same agents, albeit at different doses, found that either single agent was as effective as the combination,42 but with lesser toxicity. The Intergroupe Francophone de Cancérologie Thoracique (IFCT)-0501 trial compared a combination of carboplatin and paclitaxel with single-agent chemotherapy (either gemcitabine or vinorelbine) in patients between ages 70 and 89 years.43 In this study, median overall survival was better in the doublet arm, with a 4-month improvement in overall survival (6.2 vs. 10.3 months; P = .0001). In contrast, however, the WJOG4307L trial, which compared weekly cisplatin and docetaxel versus docetaxel administered every 3 weeks, did not show a survival benefit with doublet therapy.44 One explanation for this could be the schedule of the platinum agent used. Although the IFCT-0501 trial used carboplatin at standard doses every 3 weeks, the Japanese study (WJOG4307L) used weekly attenuated doses of cisplatin, which may have accounted for the disparate results.
Despite the relative safety of the chemotherapy agents mentioned earlier, toxicity remains a major issue for the treatment of older adults. Of the 71 patients assessed for toxicity in the ELVIS trial, 5 had to stop treatment; 4 because of constipation and 1 because of cardiac toxicity.39 In the SICOG trial, 38% of patients in the combination group and 28% in the vinorelbine arm developed grade 3/4 neutropenia.45 In the MILES trial, the combination arm had higher rates of both hematologic and nonhematologic toxicities.42 The combination was associated with more thrombocytopenia and hepatic toxicity than vinorelbine. Compared with gemcitabine, the combination increased rates of neutropenia, vomiting, fatigue, cardiac toxicity, and constipation. In the IFCT-0501 study, increased grade 3/4 hematologic toxicity (54.1% vs. 17.9%) and more toxic deaths were seen in the combination arm (23.7% vs. 16.6%).43
One of the major difficulties in evaluating chemotherapy options for older patients has been the realization that fit elderly patients seem to benefit from the therapies used to treat younger patients, but that a clear definition of what constitutes “fit” is lacking. Performance status has been used empirically, but almost all studies have precluded patients with a performance status greater than ECOG 1. The CGA has been shown to identify older adults at risk for morbidity and mortality9; however, additional research is needed to identify time-efficient ways of incorporating this assessment into oncology practice. Shortened geriatric assessment tools are being evaluated. Recent studies have also sought to develop predictive instruments (including geriatric assessment questions) that are likely to identify older patients who are more likely to experience increased toxicity from chemotherapy.20
Based on the current evidence,39 chemotherapy is associated with an improved quality of life even in the older population. Emerging data suggest that doublet therapy may confer a survival advantage over single-agent therapy, but toxicity, especially myelosuppression, may prevent routine use of doublet therapy in this cohort of patients.
Targeted Therapies
Recent advances in understanding of the molecular pathogenesis of cancer have led to the development of targeted therapies that affect specific molecules or pathways that are critical in tumor growth and progression.46–48 Because these agents affect cancer-specific pathways, it is widely believed that they have a broader therapeutic index and are potentially less toxic.49 Two of these agents, erlotinib and bevacizumab, are currently approved by the FDA for the treatment of NSCLC.
Erlotinib, a small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was shown to improve survival in patients with advanced NSCLC for whom prior chemotherapy failed compared with placebo in a randomized phase III trial conducted by the National Cancer Institute of Canada Clinical Trials Group (BR.21).50 A subgroup analysis of the older patients (≥ 70 years) enrolled in the BR.21 trial51 found no significant differences in survival or quality of life among the older and young patients who received erlotinib. However, the older cohort developed more toxicities of grade 3 or greater (35% vs. 18%), especially rash, fatigue, stomatitis, and dehydration, and were more likely to discontinue the drug because of toxicity (12% vs. 3%; P = .003).
Bevacizumab conferred a small but statistically significant survival advantage for patients with metastatic nonsquamous NSCLC in combination with carboplatin and paclitaxel in a randomized phase III trial (ECOG 4599).52 However, a post hoc subgroup analysis of this study examining the outcomes in patients aged 70 years or older showed higher toxicity (neutropenic fever, hemorrhage, nausea, anorexia, and hypertension) in the elderly patients who received bevacizumab.53 Moreover, the addition of bevacizumab did not confer a survival advantage over chemotherapy alone in this population (11.3 vs. 12.1 months; P = .4). Thus, the role of bevacizumab in the older patient should be reexamined given the lack of a significant survival advantage and the increased incidence of adverse events.
Conclusions
The treatment of older patients with NSCLC is challenging. Although the available evidence suggests that outcomes after aggressive therapy are similar to those seen in younger patients, the increased incidence of adverse events is a significant concern in this population (Table 5). This phenomenon seems to be true even with targeted agents. Unfortunately, few good predictors of either efficacy or toxicity outcomes are known that could guide therapy. The lack of randomized trials specifically for the elderly, the selection bias inherent in retrospective reviews, and the current difficulty in defining “fit” older adults makes it difficult for practicing physicians to select therapy based on high-level evidence. Until better predictive markers are available to guide therapy, available tools, including a CGA, should be used to individualize therapy to older patients with NSCLC. Currently, older patients who have been evaluated and deemed fit by their physicians and who desire therapy can be treated according to the guidelines appropriate for younger individuals.
Take Home Messages
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