First-line Treatment in Elderly Patients with Advanced Non-small Cell Lung Cancer

  

    
Study
    
Number of patients
    
Median Age, years (range)
    
Treatment
    
RR (%)
    
Median PFS
      
or TTP
    
p-value
    
Median OS
    
p-value
  
  

    
INTACT-1 [31]
    
365
    
61 (31–85)
    
G (500 mg)+CG
    
50.3
    
5.5 mo
    
0.7633
    
9.9 mo
    
0.456
  
  

    
365
    
59 (34–83)
    
G (250 mg)+CG
    
51.2
    
5.8 mo
    
9.9 mo
  
  

    
363
    
61 (33–81)
    
Placebo+CG
    
47.2
    
6.0 mo
    
10.9 mo
  
  

    
INTACT-2 [32]
    
347
    
62 (26–82)
    
G (500 mg)+CP
    
30.0
    
4.6 mo
    
0.0562
    
8.7 mo
    
0.6385
  
  

    
345
    
61 (27–86)
    
G (250 mg)+CP
    
30.4
    
5.3 mo
    
9.8 mo
  
  

    
345
    
63 (31–85)
    
Placebo+CP
    
28.7
    
5.0 mo
    
9.9 mo
  
  

    
TRIBUTE [33]
    
539
    
63 (24–84)
    
E+CP
    
21.5
    
5.1 mo
    
0.36
    
10.6 mo
    
HR = 0.995 (95% CI = 0.86–1.16)
      
0.95
  
  

    
540
    
63 (26-84)
    
Placebo+CP
    
19.3
    
4.9 mo
    
10.5 mo
  
  

    
TALENT
      
[34]
    
580
    
61 (26-82)
    
E+CG
    
31.5
    
23.7 wk
    
HR = 0.98 (95% CI = 0.86–1.11)
      
0.74
    
43 wk
    
HR = 1.06 (95% CI = 0.90–1.23)
      
0.49
  
  

    
579
    
60 (28-84)
    
Placebo+CG
    
29.9
    
24.6 wk
    
44.1 wk
  
  

    
FASTACT-2
      
[35]
    
226
    
59 (31-96)
    
E+CG/CAG
    
44
    
7.6 mo
    
HR = 0.57 (95% CI = 0.47–0.69)
      
<0.0001
    
18.3 mo
    
HR = 0.79 (95% CI = 0.64–0.99)
      
0.042
  
  

    
225
    
57 (37-88)
    
Placebo+CG/CAG
    
16
    
6.0 mo
    
15.2 m
  
  

    
Abbreviations: EGFR-TKIs: Epidermal    Growth Factor Receptor-tyrosine-kinase Inhibitors; NSCLC: Non-small Cell Lung    Cancer; RR: Response Rate; PFS: Progression-free Survival; TTP: Time to Progression;    OS: Overall Survival; G: Gefitinib; CG: Cisplatin plus Gemcitabine; CP: Carboplatin    plus Paclitaxel; E: Erlotinib; CAG: Carboplatin plus Gemcitabine 
      
 
  

Table 3:  Phase III trials of EGFR-TKIs combined with platinum-doublet chemotherapy as first-line treatments for unselected patients with advanced NSCLC.

Afatinib is a second-generation EGFR-TKI that irreversibly inhibits pan-human epidermal receptor (pan-HER) including EGFR, HER2, and HER4 by covalently binding to the kinase domain of these receptors. The LUX-Lung 3 [36] and 6 [37] studies were randomized phase III trials of front-line afatinib compared with standard platinum-doublet chemotherapy for chemotherapy-naïve patients with advanced NSCLC harboring EGFR mutations. Both trials uncovered significant survival and response advantages for afatinib, and the Food and Drug Administration approved the EGFR-TKI as a first-line treatment regimen for patients with advanced NSCLC and activating EGFR mutations. Subset analysis in these LUX-Lung trials revealed the similar efficacy of the drug between elderly patients aged 60 years or older and non-elderly patients. Meanwhile, severe treatment-related toxicities (grade 3–5) attributable to afatinib occurred more frequently in the elderly population. To the best of our knowledge, no results of prospective trials of afatinib for elderly patients with advanced EGFR-mutated NSCLC have been reported.

Crizotinib is an oral TKI targeting the EML4-ALK fusion gene. Crizotinib has been approved for the optimal treatment for ALKpositive NSCLC based on the results of previous studies [38-39]. A recent phase III trial demonstrated the superiority of front-line crizotinib regarding survival compared with standard platinumdoublet chemotherapy consisting of cisplatin plus pemetrexed in patients with advanced ALK-positive NSCLC [40]. A total of 343 patients were enrolled in this trial, and the median patient age was 52 years (range: 22–76) in the crizotinib arm and 54 years (range: 19–78) in the chemotherapy arm. PFS, which was the primary endpoint, was significantly longer in the crizotinib arm (median, 10.9 months vs. 7.0 months, HR = 0.45, 95% CI = 0.35–0.60, p < 0.001). The objective RR was significantly higher in the crizotinib arm than in the chemotherapy arm (74% [95% CI = 67–81%] vs. 45% [95% CI = 37–53%], p < 0.001). Based on the results of this trial, crizotinib was approved as a first-line treatment for advanced ALK-positive NSCLC. Among all patients enrolled in this study, 55 were elderly patients aged 65 years or older. The HR favored crizotinib in elderly patients (HR = 0.37, 95% CI = 0.17–0.77). Crizotinib is also recommended as a second-line treatment for ALK-positive NSCLC based on the results of an open-label phase III trial of crizotinib versus standard second-line chemotherapy with pemetrexed or docetaxel in previously treated patients with ALK-positive NSCLC [41]. A total of 347 patients were enrolled in this study, and the median patient age was 51 years (range: 22–81) in the crizotinib arm, 50 years (range: 26–85) in the pemetrexed arm, and 49 years (range: 24–71) in the docetaxel arm. This study met its primary endpoint, with significantly longer PFS recorded in patients treated with crizotinib than in those with chemotherapy (median, 7.7 months vs. 3.0 months, HR = 0.49, 95% CI = 0.37–0.64, p < 0.001). The RR was significantly higher in the crizotinib arm than in the chemotherapy arm (65% [95% CI: 58–72%] vs. 20% [95% CI = 14–26%], p < 0.001). The most common severe treatment-related toxicities were elevated aminotransferase levels (16%) and neutropenia (13%) in the crizotinib arm. On the contrary, severe neutropenia occurred in 19% of patients treated with chemotherapy. Among all patients included in the safety analysis, the number of elderly patients aged 65 years or older was 50 (27 in the crizotinib arm and 23 in the chemotherapy arm). No significant difference was observed in terms of PFS between the elderly and nonelderly groups (HR = 0.54, 95% CI = 0.27–1.08).

Bevacizumab is an anti-VEGF monoclonal antibody inhibitor that is approved as a first-line treatment in combination with standard chemotherapy in patients with advanced non-squamous cell NSCLC based on the Eastern Cooperative Oncology Group 4599 trial [42]. In this trial, 878 patients were randomized to treatment with chemotherapy plus bevacizumab or chemotherapy alone as a control. The experimental and control arms included 177 and 189 elderly patients aged 65 years or older, respectively. The median PFS was significantly longer in the experimental arm than in the control arm (12.3 months vs. 10.3 months, HR = 0.79 [95% CI = 0.67–0.92], p = 0.003). Additionally, chemotherapy plus bevacizumab significantly improved the RR versus chemotherapy (35% vs. 15%, p < 0.001). No significant advantage of chemotherapy plus bevacizumab was observed in terms of OS in elderly patients (HR = 0.89 [95% CI = 0.70–1.14]). Although a subset analysis of elderly patients aged 70 years or older (111 in the experimental arm and 113 in the control arm) uncovered a trend toward a higher RR and longer PFS in favor of chemotherapy plus bevacizumab (29% vs. 17%, p = 0.067; median PFS: 5.9 months vs. 4.9 months, p = 0.063), OS was similar (11.3 months vs. 12.1 months, p = 0.4). Meanwhile, severe toxicities including treatment-related death were more common in the experimental arm than in the control arm (87% vs. 61%, p < 0.001) [43]. The AVAiL study was a randomized phase III trial that evaluated the efficacy and safety of two different doses of bevacizumab (7.5 and 15 mg/kg) combined with platinum-doublet chemotherapy as a firstline treatment compared with placebo for patients with advanced non-squamous cell NSCLC [44]. Significant longer PFS was noted in the low- and high-dose groups (median, 6.7 and 6.5 months, respectively) than in the placebo group (6.1 months, p = 0.003 and 0.03, respectively). The objective RRs of the placebo, low-dose, and high-dose groups were 20.1, 34.1, and 30.4%, respectively. The incidence of severe treatment-related toxicities was similar across the arms. A retrospective subgroup analysis of the AVAiL trial was performed to assess the efficacy and safety of bevacizumab combined with chemotherapy in elderly patients aged 65 years or older [45]. Among 1043 patients enrolled in AVAiL, the outcomes of 304 elderly patients were reviewed. Significant longer PFS was noted among patients treated with bevacizumab plus chemotherapy than among those treated with chemotherapy (low-dose group vs. placebo group: HR = 0.71, p= 0.023; high-dose group vs. placebo group: HR = 0.84, p = 0.25). The objective RRs were 40, 29, and 30% in the low-dose, high-dose, and placebo groups, respectively. OS was similar between the experimental and control arms. No particular safety signals were noted in the elderly population. The MO19390 trial was an international open-label, single-arm study that assessed the safety and efficacy of bevacizumab combined with standard chemotherapy as a first-line treatment in patients with advanced or recurrent nonsquamous cell NSCLC [46]. In this study, a preplanned subgroup analysis was conducted to evaluate the outcomes of elderly patients aged 65 years or older. Among 2212 patients in the MO19390 study population, 623 elderly patients were evaluated. The median OS, time to progression (TTP), and RR were 14.6 months, 8.2 months, and 49.3%, respectively, in elderly patients and 14.6 months, 7.6 months, and 52.4%, respectively, in non-elderly patients. These results were similar for both groups. Severe treatment-related adverse events occurred in 45.3% of elderly patients and 34.7% of non-elderly patients. Similar results were noted in a post hoc comparison of elderly patients aged 70 years or older and non-elderly patients. TTP, OS, and RR were 8.6 months, 14.6 months, and 49%, respectively, in elderly patients and 7.7 months, 14.6 months, and 52%, respectively, in non-elderly patients. These results were similar for elderly patients aged 70 years or older and younger patients. The incidence of adverse events of special interest was comparable. The PointBreak study was a randomized phase III trial of different standard platinumdoublet chemotherapy regimens (carboplatin plus pemetrexed and carboplatin plus paclitaxel) plus bevacizumab followed by maintenance bevacizumab with or without chemotherapy [47]. Although significantly prolonged PFS was noted in patients treated with carboplatin plus pemetrexed combined with bevacizumab, no significant difference was observed in terms of OS between the groups. Among 939 patients enrolled in this study, 247 patients were elderly patients aged 70 or older. No significant differences in PFS and OS were noted (PFS: HR = 0.98; OS: HR= 0.90).

Although several retrospective and subgroup analyses of elderly patients were performed in previous phase III trials of targeted agents, to the best of our knowledge, no prospective randomized phase III trials comparing targeted agents alone with targeted agents combined with chemotherapy as first-line treatments for elderly patients with advanced NSCLC have been conducted.

Discussion

Previous clinical data indicated that although severe adverse events would be more frequently observed in patients treated with combination chemotherapy consisting of two different types of third-generation cytotoxic agents, combination regimens did not confer significant survival advantages compared with single-agent chemotherapy in elderly patients with NSCLC. Thus, single thirdgeneration cytotoxic agents including gemcitabine, docetaxel, vinorelbine, and paclitaxel should be considered appropriate first-line treatments in non-selected elderly patients with a PS of 0–2. Previous phase III studies of pemetrexed as a first- or second-line treatment demonstrated the non-inferiority efficacy of pemetrexed as well as its statistically better tolerability versus standard chemotherapy for advanced NSCLC [48,49]. Two retrospective studies on these trials of pemetrexed were conducted. One study revealed the favorable efficacy of pemetrexed for NSCLC in patients with non-squamous cell histology [50]. Another study uncovered a longer TTP, longer survival, and a more favorable toxicity profile of pemetrexed for elderly patients compared with docetaxel [51]. Thus, pemetrexed may be a reasonable first-line treatment option in elderly patients with non-squamous NSCLC. However, no prospective randomized studies have examined whether pemetrexed would be more useful than third-generation cytotoxic agents for elderly chemotherapynaïve patients with advanced non-squamous NSCLC.

Platinum-doublet chemotherapy combined with third-generation cytotoxic agents may be more promising as first-line treatments in elderly patients, especially in those with a better PS (0–1). However, considering the frequency of severe hematological adverse events and treatment-related death, first-line treatment regimens using standard platinum-doublet chemotherapy with the same schedule and dose as those used in non-elderly patients would not be warranted for elderly patients. Based on the two aforementioned clinical trials for advanced NSCLC in patients with a PS of 2, although platinum-doublet chemotherapy regimens significantly improved survival versus single-agent chemotherapy, higher rates of toxicities and treatmentrelated death were observed in the platinum-doublet chemotherapy arm. Whereas both trials confirmed the positive effect of platinum doublet chemotherapy for patients with a PS of 2, few patients have been treated with this regimen in practice. Indeed, chemotherapy tends to be avoided in patients with a poor PS and elderly patients because of apprehension regarding the higher incidence of severe treatment-related toxicities. However, elderly patients comprise a heterogeneous population with significant differences in the level of organ function, number of complications, and other variables. Thus, it is difficult to state that the results of the two aforementioned trials of patients with a PS of 2 are applicable to elderly patient populations.

Generally, physicians have concerns about treatment strategies using cytotoxic agents for older patients because of decreasing tolerability to treatment with age. Indeed, only a small percentage of elderly patients were eligible for inclusion in clinical trials of new agents and regimens [52-54]. Thus, elderly patients treated with protocol chemotherapy may not be representative of the entire elderly patient population. Indeed, inevitably decreases in organ function, especially bone marrow reserves, with age and increases in the number of complications such as cardiovascular disease and pulmonary disease are obstacles to treatment with cytotoxic chemotherapy. The definition of elderly patients was different in each of the aforementioned phase III trials and retrospective studies. An age of 70 years may be considered the threshold age of cell senescence after which the rate of age-related changes increases [55]. Although platinum-doublet chemotherapy regimen may be an optimal firstline treatment regimen in elderly patients with advanced NSCLC, further studies are needed to define the most appropriate regimen and confirm its tolerability. The JCOG1210/WJOG7813L study (UMIN000011460) of docetaxel versus carboplatin plus pemetrexed followed by pemetrexed as a first-line treatment in patients aged 75 years or older with advanced non-squamous NSCLC is ongoing. Physicians make treatment decisions for elderly patients with NSCLC in consideration of PS, physical and organ function, level of complication, activity, and mental state. Elderly patients comprise a heterogeneous population, and thus, some patients have a similar tolerability for standard first-line chemotherapy as non-elderly patients. Thus, a viable tool to assist physicians in assessing the tolerability of elderly patients for chemotherapy is needed. Some investigators developed valid and reliable geriatric assessment tools [56,57]. However, these tools are complicated and difficult to use in practically situations.

First-generation EGFR-TKIs including gefitinib and erlotinib have similar efficacy and tolerability in elderly patients with advanced NSCLC and activating EGFR mutations. These agents have been proven to palliate clinical symptoms immediately in elderly patients regardless of their PS. Afatinib may have similar activity as first-generation EGFR-TKIs, and it may be an optimal first-line regimen similarly as other first-generation EGFR-TKIs with careful management for skin toxicities and diarrhea in elderly patients with EGFR-mutated NSCLC. Although the LUX-Lung 7 study (NCT01466660), which is a phase IIb head-to-head trial comparing afatinib with gefitinib in chemotherapy-naïve patients harboring EGFR-mutated NSCLC, is ongoing, no prospective trials comparing these three EGFR-TKIs have been conducted for elderly patients with EGFR-mutated NSCLC.

Trials of EGFR-TKIs plus chemotherapy have rarely uncovered improvements in survival excluding the FASTACT-2 trial. Preclinical studies demonstrated that EGFR-TKIs cause G1 cycle arrest in wild-type EGFR cancer cell lines, inhibiting the cell cycle-dependent cytotoxic effects of chemotherapy and induction of apoptosis in cell lines with EGFR mutations [58,59]. Based on these preclinical data, researchers examined new treatment regimens consisting of intercalated erlotinib combined with chemotherapy in the FASTACT-2 study. However, intercalated erlotinib plus chemotherapy did not improve survival in patients with wild-type EGFR. Although significantly longer survival was noted in the experimental arm with this new treatment regimen, its positive result should be largely attributed to the longer survival time of erlotinib responders. Further investigations will be needed to assess whether intercalated combinations of EGFR-TKI and chemotherapy are superior to EGFR-TKI monotherapy and whether these new regimens would be suitable first-line treatments for elderly patients with EGFR-mutated NSCLC.

Whereas crizotinib is a promising first-line therapy for ALKpositive NSCLC, only a few patients experienced a benefit of the targeted agent. The ALK fusion gene appears to be present in approximately 3–6% of non-selected patients with NSCLC, and it is significantly more common in never-smokers than in smokers and in non-elderly patients than in elderly patients [60-66]. Although it is difficult to perform large-scale clinical trials of crizotinib as firstline treatment for elderly patients with ALK-positive NSCLC, further assessments are needed to evaluate the efficacy and tolerability of crizotinib as a first-line treatment in elderly patients with the ALK fusion gene.

Bevacizumab combined with platinum-doublet chemotherapy is approved as a first-line treatment in patients with advanced nonsquamous NSCLC. However, no subset analysis of elderly patients in previous phase III trials demonstrated an OS benefit despite a higher RR and longer PFS because of significantly higher incidences of severe treatment-related toxicity. Combination treatment with platinum-doublet chemotherapy plus bevacizumab may potentially confer a survival benefit according as a proper chemotherapy regimen for elderly patients with non-squamous NSCLC. Even if this devised combination regimen does not meaningfully prolong overall survival, improvements in PFS and response conferred by the therapy may improve QOL in elderly patients if the incidence of treatmentrelated adverse events is acceptable. In the future, prospective clinical trials should be conducted to assess the efficacy and tolerability of bevacizumab combined with platinum-doublet chemotherapy, single third-generation cytotoxic agent monotherapy, or pemetrexed.

Conclusion

Third-generation cytotoxic agents are recommended as first-line treatments for elderly patients with advanced NSCLC, and clinical data support the potentially equivalent efficacy and better tolerability of pemetrexed compared to those agents. Whereas first-generation EGFR-TKIs, especially gefitinib, are commonly administered as first-line therapies in elderly patients harboring activating EGFR mutations irrespective of their clinical condition, further assessment of the efficacy and tolerability of afatinib and crizotinib in select elderly patients with NSCLC is needed. Although platinum-doublet chemotherapy and combined treatment with targeted agents plus chemotherapy may be promising treatment regimens, further investigations are needed to define the treatment schedule and dose for elderly patients who are suitable for chemotherapy and validate its superiority to standard single-agent chemotherapy or monotherapy with targeted agents. To that end, the establishment of a suitable geriatric assessment tool for practical use is urgently needed because of the heterogeneity of elderly patient populations.

References

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014; 64: 9-29.
2. Davidoff AJ, Gardner JF, Seal B, Edelman MJ. Population-based estimates of survival benefit associated with combined modality therapy in elderly patients with locally advanced non-small cell lung cancer. J Thorac oncol. 2011; 6: 934-941.
3. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl Jo Med. 1999; 341: 2061-2067.
4. Kumar A, Soares HP, Balducci L, Djulbegovic B; National Cancer I. Treatment tolerance and efficacy in geriatric oncology: a systematic review of phase III randomized trials conducted by five National Cancer Institute-sponsored cooperative groups. J Clin Oncol. 2007; 25: 1272-1276.
5. [No authors listed]. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst. 1999; 91: 66-72.
6. Frasci G, Lorusso V, Panza N, Comella P, Nicolella G, Bianco A, et al. Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000; 18: 2529-2536.
7. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst. 2003; 95: 362-372.
8. Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006; 24: 3657-3663.
9. Comella P, Frasci G, Carnicelli P, Massidda B, Buzzi F, Filippelli G, et al. Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer. 2004; 91: 489-497.
10. Hainsworth JD, Spigel DR, Farley C, Shipley DL, Bearden JD, Gandhi J, et al. Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network. Cancer. 2007; 110: 2027-2034.
11. Russo A, Rizzo S, Fulfaro F, Adamo V, Santini D, Vincenzi B, et al. Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer: a Literature-based Meta-analysis. Cancer. 2009; 115: 1924-1931.
12. Quoix E, Zalcman G, Oster JP, Westeel V, Pichon E, Lavole A, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011; 378: 1079-1088.
13. Abe T, Takeda K, Ohe Y, Kudoh S, Ichinose Y, Okamoto H, et al. Randomized phase III trial comparing weekly docetaxel plus cisplatin versus docetaxel monotherapy every 3 weeks in elderly patients with advanced non-small-cell lung cancer: the intergroup trial JCOG0803/WJOG4307L. J Clin Oncol. 2015; 33: 575-581.
14. Biesma B, Wymenga AN, Vincent A, Dalesio O, Smit HJ, Stigt JA, et al. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011; 22: 1520-1527.
15. Zhu J, Sharma DB, Chen AB, Johnson BE, Weeks JC, Schrag D. Comparative effectiveness of three platinum-doublet chemotherapy regimens in elderly patients with advanced non-small cell lung cancer. Cancer. 2013; 119: 2048-2060.
16. Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, et al. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013; 81: 77-83.
17. Zukin M, Barrios CH, Pereira JR, Ribeiro Rde A, Beato CA, do Nascimento YN, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013; 31: 2849-2853.
18. Lilenbaum RC, Herndon JE, 2nd, List MA, Desch C, Watson DM, Miller AA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005; 23: 190-196.
19. Socinski MA, Okamoto I, Hon JK, Hirsh V, Dakhil SR, Page RD, et al. Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013; 24: 2390-2396.
20. Gridelli C, de Marinis F, Thomas M, Prabhash K, El Kouri C, Blackhall F, et al. Final efficacy and safety results of pemetrexed continuation maintenance therapy in the elderly from the PARAMOUNT phase III study. J Thorac Oncol. 2014; 9: 991-997.
21. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet oncol. 2010; 11: 121-128.
22. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362: 2380-2388.
23. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12: 735-742.
24. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246.
25. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009; 27: 1394-1400.
26. Asami K, Koizumi T, Hirai K, Ameshima S, Tsukadaira A, Morozumi N, et al. Gefitinib as first-line treatment in elderly epidermal growth factor receptor-mutated patients with advanced lung adenocarcinoma: results of a Nagano Lung Cancer Research Group study. Clin Lung Cancer. 2011; 12: 387-392.
27. Maemondo M, Minegishi Y, Inoue A, Kobayashi K, Harada M, Okinaga S, et al. First-line gefitinib in patients aged 75 or older with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations: NEJ 003 study. J Thorac Oncol. 2012; 7: 1417-1422.
28. Goto K, Nishio M, Yamamoto N, Chikamori K, Hida T, Maemondo M, et al. A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Lung Cancer. 2013; 82: 109-114.
29. Rosell R, Viteri S, Molina MA, Benlloch S, Taron M. Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer. Curr Opin Oncol. 2010; 22: 112-120.
30. Jackman DM, Yeap BY, Lindeman NI, Fidias P, Rabin MS, Temel J, et al. Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007; 25: 760-766.
31. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004; 22: 777-784.
32. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004; 22: 785-794.
33. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005; 23: 5892-5899.
34. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007; 25: 1545-1552.
35. Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013; 14: 777-786.
36. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31: 3327-3334.
37. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15: 213-222.
38. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363: 1693-1703.
39. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012; 13: 1011-1019.
40. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014; 371: 2167-2177.
41. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368: 2385-2394.
42. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355: 2542-2550.
43. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, et al. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008; 26: 60-65.
44. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009; 27: 1227-1234.
45. Leighl NB, Zatloukal P, Mezger J, Ramlau R, Moore N, Reck M, et al. Efficacy and safety of bevacizumab-based therapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer in the phase III BO17704 study (AVAiL). J Thorac Oncol. 2010; 5: 1970-1976.
46. Laskin J, Crino L, Felip E, Franke F, Gorbunova V, Groen H, et al. Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). J Thorac Oncol. 2012; 7: 203-211.
47. Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013; 31: 4349-4357.
48. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22: 1589-1597.
49. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008; 26: 3543-3551.
50. Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009; 14: 253-263.
51. Weiss GJ, Langer C, Rosell R, Hanna N, Shepherd F, Einhorn LH, et al. Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2006; 24: 4405-4411.
52. Morabito A, Gebbia V, Di Maio M, Cinieri S, Viganò MG, Bianco R, et al. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Lung Cancer. 2013; 81: 77-83.
53. Zukin M, Barrios CH, Pereira JR, Ribeiro Rde A, Beato CA, do Nascimento YN, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013; 31: 2849-2853.
54. Owonikoko TK, Ragin CC, Belani CP, Oton AB, Gooding WE, Taioli E, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol. 2007; 25: 5570-5577.
55. Balducci L. Geriatric oncology: challenges for the new century. Eur J Cancer. 2000; 36: 1741-1754.
56. Ramsey SD, Howlader N, Etzioni RD, Donato B. Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end results-Medicare. J Clin Oncol. 2004; 22: 4971-4978.
57. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol. 2011; 29: 1290-1296.
58. Nie X, Liu D, Li Q, Bai C. Predicting chemotherapy toxicity in older adults with lung cancer. J Geriatr Oncol. 2013; 4: 334-339.
59. Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Jänne PA, et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res. 2004; 64: 7241-7244.
60. Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out? J Clin Oncol. 2005; 23: 5856-5858.
61. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007; 448: 561-566.
62. Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008; 14: 6618-6624.
63. Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, Moss BJ, et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia. 2008; 10: 298-302.
64. Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009; 115: 1723-1733.
65. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009; 15: 5216-5223.
66. Koh Y, Kim DW, Kim TM, Lee SH, Jeon YK, Chung DH, et al. Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors. J Thorac Oncol. 2011; 6: 905-912.