Initial systemic therapy for elderly patients with advanced non-small cell lung cancer
INTRODUCTION — Development of a therapeutic plan for a patient with lung cancer depends upon the cell type (non-small cell versus small cell), tumor stage, molecular characteristics, and an assessment of the patient's overall medical condition.
Patients with stage I, II, or III non-small cell lung cancer (NSCLC) are generally treated with curative intent using surgery, chemotherapy, radiation therapy (RT), or a combined modality approach (table 1 and table 2). In contrast, palliative systemic therapy is appropriate for patients with advanced (stage IV) NSCLC, which includes those who present with disseminated metastases and those with a malignant pleural or pericardial effusion. Palliative systemic therapy is also used for patients who have relapsed with advanced disease following prior definitive treatment.
The majority of the data on the optimal approach to systemic therapy for patients with advanced NSCLC is derived from trials in nonelderly patients with a good performance status. However, the median age of patients with newly diagnosed NSCLC in developed countries is approximately 68 years, and up to 40 percent are older than 70 years at diagnosis [1].
The efficacy and tolerability of chemotherapy are common concerns in older patients with NSCLC, particularly for cisplatin-containing regimens [2,3]. However, a 1995 meta-analysis of 52 trials of chemotherapy versus best supportive care (BSC) did not give any indication that cytotoxic chemotherapy for advanced NSCLC is associated with a significantly worse outcome in older compared to younger patients [4].
Clinical trials conducted exclusively in elderly populations have established the feasibility and potential benefits of cytotoxic chemotherapy in carefully selected elderly individuals. These results and the approach to this patient population are reviewed here.
Research has led to the development of agents that target specific pathways in the development or progression of NSCLC. Small molecules targeting the epidermal growth factor receptor (EGFR) tyrosine kinase (gefitinib, erlotinib) have become the preferred initial treatment for patients whose tumors contain a mutation in EGFR. Similarly, crizotinib is preferred for patients whose tumors contain the ALK fusion oncogene. (See "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer".)
Other topics presented separately include:
CHEMOTHERAPY VERSUS TARGETED THERAPY — Whenever possible, therapy of metastatic NSCLC should be individualized based upon molecular and histologic features of the tumor.
If feasible, patients should have tumor tissue assessed for the presence of a somatic mutation in the epidermal growth factor receptor (EGFR), which confers sensitivity to EGFR tyrosine kinase inhibitors, and for the anaplastic lymphoma kinase (ALK) fusion oncogene, which confers sensitivity to crizotinib. (See "Small molecule epidermal growth factor receptor inhibitors for advanced non-small cell lung cancer", section on 'Molecular markers' and "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Molecular pathogenesis'.)
Patient management can then be dictated by the results of these molecular studies:
NO EGFR MUTATION OR ALK FUSION ONCOGENE — Cytotoxic chemotherapy, either alone or in combination with bevacizumab or cetuximab, is preferred for elderly patients whose tumors do not contain a characteristic molecular abnormality conveying sensitivity to a targeted agent. (See "Initial systemic therapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene", section on 'Combination chemotherapy'.)
The toxicity and safety of cytotoxic chemotherapy may pose special concerns in the elderly. However, randomized phase III trials limited to elderly patients have demonstrated that chemotherapy can provide substantial clinical benefits, including improved overall survival, for appropriately selected patients.
Single agent chemotherapy versus BSC — The ability of chemotherapy to prolong survival without impairing quality of life (QOL) in elderly patients with advanced NSCLC was initially demonstrated in a phase III trial by the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) group [5]. In the ELVIS trial, patients over the age of 70 years were randomly assigned to vinorelbine (30 mg/m2 on days 1 and 8 of every 21 day cycle for up to six cycles) plus best supportive care (BSC) or BSC alone. The trial was terminated prematurely because of poor accrual but included 161 evaluable patients.
Patients treated with vinorelbine had a significantly better median survival than those managed with BSC alone (28 versus 21 weeks). Toxicity-related symptoms associated with chemotherapy were counterbalanced by significantly fewer lung cancer-related symptoms. As a result, the chemotherapy group had higher scores on QOL scales.
Docetaxel — The only single agent that has been directly compared to vinorelbine in a randomized phase III trial is docetaxel. In a trial conducted by the West Japan Thoracic Oncology Group Trial (WJTOG 9904), 182 patients aged 70 years or older were randomly assigned to docetaxel (60 mg/m2 day 1) or vinorelbine (25 mg/m2 days 1 and 8) [6]. Both regimens were repeated every 21 days for four cycles.
Key results included the following:
- Docetaxel was associated with a significantly higher response rate and a longer progression-free survival compared to vinorelbine (23 versus 10 percent and 5.5 versus 3.1 months, respectively).
- The difference in overall survival was not statistically significant (median 14.3 versus 9.9 months, hazard ratio [HR] 0.78, 95% CI 0.56-1.09).
- Treatment with docetaxel resulted in greater improvement in appetite and fatigue.
- Severe neutropenia was significantly more common with docetaxel (83 versus 69 percent).
Weekly administration of docetaxel may be less toxic than vinorelbine without sacrificing efficacy and may represent a useful alternative in patients treated with a single agent. (See "Second-line therapy for patients with previously treated advanced non-small cell lung cancer", section on 'Docetaxel'.)
Other single agents — A number of other contemporary agents have significant single agent activity in previously untreated patients with advanced NSCLC. Although the efficacy of these agents in the elderly has not been demonstrated in randomized trials, such agents may be useful in appropriately selected patients. (See "Initial systemic therapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene", section on 'Active single agents'.)
Combination versus single agent chemotherapy — In younger patients, combination therapy is generally preferred over single agent chemotherapy in the treatment of advanced NSCLC, based upon improved survival, with only a moderate increase in toxicity. (See "Initial systemic therapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene", section on 'Combination chemotherapy'.)
Combination chemotherapy using a contemporary platinum-based doublet may be preferable in elderly patients as well, based upon the results of the French Intergroup trial. However, data from the MILES study does not support the use of a non-platinum doublet regimen in this population, and a preliminary report of a Japanese study suggests that single agent docetaxel is an effective alternative [7].
French Intergroup trial — A French Intergroup study (IFCT-0501) randomly assigned 451 patients to a combination of carboplatin (AUC 6, day 1) plus paclitaxel (90 mg/m2, days 1, 8, and 15) repeated every four weeks for four cycles or to single agent chemotherapy [8]. Single agent chemotherapy consisted of either gemcitabine (1150 mg/m2) or vinorelbine (30 mg/m2), and was given on days 1 and 8 of a three-week cycle for five cycles with the choice predetermined based upon institution. Patients from both arms were treated with erlotinib after failure on their initial regimen. Patients were aged 70 to 89 years, performance status (PS) 0-2, and had previously untreated stage III or IV disease. Approximately 70 percent of patients were PS 0 or 1.
Recruitment to the trial was stopped after the second planned interim analysis, based upon the recommendation of the data safety monitoring committee. At a median follow-up of 30 months, the following results were observed:
- Overall survival, the primary objective of the study, was significantly prolonged with combination chemotherapy compared to single agent chemotherapy (median 10.3 versus 6.2 months, HR 0.64, 95% CI 0.52-0.78, and one-year survival 45 versus 25 percent). Progression-free survival was also significantly prolonged (6.0 versus 2.8 months, HR 0.51, with one-year progression-free survival 13 versus 2 percent). There were no significant differences in efficacy between the two single agent chemotherapy arms.
- Treatment was generally well tolerated with both combination and single agent chemotherapy. Grade 3 or 4 neutropenia was more common with the combination compared with monotherapy (48 versus 12 percent). Febrile neutropenia was also more common with the combination regimen (9 versus 3 percent).
- Ten deaths (4.4 percent) in the combination arm were attributed to treatment, compared with three (1.3 percent) in the monotherapy group. Despite this, early deaths from all causes (less than three months after starting treatment) were significantly less frequent with the combination compared to single agent therapy (16 versus 27 percent, p=0.04).
MILES trial — In the Multicenter Italian Lung Cancer in the Elderly Study (MILES), 698 patients ≥70 years old were randomly assigned to gemcitabine alone (1200 mg/m2 days 1 and 8, every three weeks), vinorelbine alone (30 mg/m2 on days 1 and 8, every three weeks), or gemcitabine (1000 mg/m2) plus vinorelbine (25 mg/m2), both administered on days 1 and 8, every three weeks [9]. The combination regimen did not significantly improve the objective response rate or median survival compared to vinorelbine or gemcitabine (21 versus 18 and 16 percent and 30 versus 36 and 28 weeks, respectively). Quality of life was similar in all three arms, although combination treatment was more toxic.
JCOG0803/WJOG4307L trial — In a Japanese multicenter trial, 276 patients aged 70 years or more were randomly assigned to docetaxel (20 mg/m2) plus cisplatin (25 mg/m2) given on days 1, 8, and 15 every 28 days or single agent docetaxel (60 mg/m2 every three weeks) [7]. The trial was designed to demonstrate the superiority of the combination regimen.
Preliminary results were presented at the 2011 American Society of Clinical Oncology (ASCO) meeting. At a planned interim analysis, the combination did not improve overall survival compared with single agent docetaxel (median 13.8 versus 14.8 months, HR 1.18), and was the reason for early termination of the trial. More mature data are required. It is uncertain if the low dose weekly schedule of the doublet chemotherapy may have contributed to the difference in results compared with the French trial [8].
Chemotherapy plus bevacizumab — For good performance status patients with nonsquamous NSCLC, the addition of bevacizumab to a platinum-based doublet improves progression-free survival and may prolong overall survival compared with chemotherapy alone. (See "Initial systemic therapy for advanced non-small cell lung cancer without an epidermal growth factor receptor mutation or the ALK fusion oncogene", section on 'Chemotherapy plus bevacizumab'.)
However, there are concerns that excess toxicity in elderly adults due to bevacizumab may counterbalance any increase in antitumor activity. Unplanned retrospective analyses have been conducted on both the Eastern Cooperative Oncology Group phase III (E4599) and AVAiL trials:
The retrospective nature of these unplanned subset analyses precludes definitive conclusions, but caution is advised when using bevacizumab in elderly patients with advanced NSCLC.
Summary — For appropriately selected elderly patients with a good performance status, combination chemotherapy with a platinum-based regimen may prolong survival without compromising quality of life. Single agent therapy may be useful in patients whose overall condition does not permit this approach.
SECOND LINE THERAPY — Second line therapy for elderly patients is discussed separately. (See "Second-line therapy for patients with previously treated advanced non-small cell lung cancer".)
EGFR MUTATION POSITIVE DISEASE — For patients whose tumors contain a characteristic mutation in the EGFR, an EGFR tyrosine kinase inhibitor is preferred for initial therapy, based upon results in patients selected for the presence of this mutation. (See "Initial systemic therapy for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor".)
The evaluation of these agents specifically in elderly patients was conducted in unselected populations where the oral administration and toxicity profile of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors may offer some advantages from a safety and convenience perspective.
- In the phase II INVITE trial, in which 196 chemotherapy-naive patients ≥70 years of age were randomly assigned to treatment with either gefitinib or vinorelbine [12]. There were no statistically significant differences in progression-free or overall survival (2.7 versus 2.9 months and 5.9 versus 8.0 months for gefitinib and vinorelbine, respectively). However, the trial was not initially designed as a non-inferiority trial, and a clinically significant inferiority with gefitinib cannot be excluded [13]. Similar results were seen in a nonrandomized phase II trial using erlotinib in chemotherapy-naive patients aged ≥70 years [14].
- The phase III TROPICAL trial in the United Kingdom compared erlotinib with placebo in chemotherapy-naive, poor performance status patients who were not candidates for first-line chemotherapy [15]. The median patient age in that trial was 77 years. There was no benefit in overall survival for patients assigned to erlotinib. The results of the TROPICAL trial are discussed separately. (See "Systemic therapy for poor performance status patients with advanced non-small cell lung cancer", section on 'EGFR mutation positive patients'.)
ALK FUSION ONCOGENE POSITIVE — The presence of the ALK fusion oncogene conferred sensitivity to crizotinib, a specific inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase, in phase II studies. Although these studies contained only a limited number of elderly patients, this approach is preferred for these patients. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer".)
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SUMMARY AND RECOMMENDATIONS — Elderly patients with advanced non-small cell lung cancer (NSCLC) need to be managed on an individual basis, and appropriately selected patients may benefit from systemic therapy. Factors that may be useful in selecting patients for chemotherapy include performance status, extent of metastatic disease, and baseline quality of life.
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