Treating advanced non-small cell lung cancer in the elderly

Abstract

More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70 years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70–79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.

Introduction

Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in western countries [Parkin et al. 2005]. Non-small cell lung cancer (NSCLC) constitutes between 80% and 85% of all lung cancers; small cell lung cancer (SCLC) makes up the remaining 15–20%. Unfortunately, at the time of diagnosis, the majority of patients already have metastatic disease and a systemic, palliative treatment is the primary therapeutic option.

More than 50% of cases of advanced NSCLC are diagnosed in patients over the age of 65 years [Ries et al. 2003], and recent Surveillance, Epidemiology and End Results (SEER) Program data in the United States show that patients 70 years or older account for 47% of all lung cancers [Owonikoko et al. 2007]. Thus, lung cancer in the older individual is an increasingly common problem faced by the oncologist. Of special interest, from year 2000, the incidence and the mortality from lung cancer has decreased among women aged 50 and younger, but has increased among those aged 70 and older; in men, mortality has been falling in all age groups except among those aged 70–74, where it has plateaued [Wingo et al. 2003]. Elderly cancer patients often present with medical and physiological challenges that make the selection of their optimal treatment daunting [Repetto et al. 2003]. Ageing is inextricably associated with physiological changes in functional status, organ function, and drug pharmacokinetics. Ageing is associated with decreases in marrow reserve, drug clearance, and lean body mass. Furthermore, concomitant comorbidities that affect functional status, general health and tumor symptoms, are frequently present in this patient population. Unfortunately, as a result, these patients are often undertreated.

In current practice, the elderly are often excluded from participation in clinical trials and receive untested or inadequate treatment [Lewis et al. 2003]. In fact, although most phase II and III trials now do not have an upper age limit, only a minority of elderly patients are enrolled in these trials. An analysis of the North Central Cancer Treatment Group demonstrated that elderly-specific trials are needed to accrue more elderly cancer patients to trials and better define their optimal treatment [Jatoi et al. 2005]. This was a pooled analysis of elderly patients who participated in elderly-specific trials (required age ≥65 years) or age-unspecified trials (required age ≥18 years). Intriguing differences were observed. The median age of elderly patients in elderly-specific trials was higher as was the percentage older than 80 years. Moreover, elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events (grade ≥3 nonhematologic 81% versus 57%, p  <  0.001; grade ≥3 hematologic 68% versus 10%, p  <  0.001) without significant differences in survival. This analysis demonstrated that elderly-specific trials provide quality care in the elderly, particularly among the oldest of the old.

The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease [Pallis et al. 2010].

Chemotherapy

Single-agent chemotherapy was one of the first approaches to be evaluated in this setting, and third-generation monotherapy with vinorelbine, gemcitabine and taxanes (paclitaxel and docetaxel) is currently the approach supported by prospective, elderly-specific clinical data, by American Society of Clinical Oncology (ASCO) guidelines and International Experts panels in unselected patients [Gridelli et al. 2005; Pfister et al. 2004]. The landmark phase III trial in 191 patients (the Elderly Lung Cancer Vinorelbine Italian Study, or ELVIS study) showed that single-agent vinorelbine improved quality of life and survival compared with supportive care alone (median survival, 27 versus 21 weeks, p = 0.04) [Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) Group, 1999]. Several phase II trials showed the role of gemcitabine in this setting with an overall response rate of 18–38%, a median survival of 6.8–9 months, and a predictable and acceptable toxicity profile [Gridelli et al. 2001].

Also, paclitaxel and docetaxel have demonstrated both activity and tolerability in the treatment of advanced NSCLC. In an effort to reduce toxicity, weekly regimens of single-agent paclitaxel have been investigated in three phase II studies with response rates ranging from 3% to 23%, median survival of 6.8–10.3 months, and tolerable toxicity profiles [Fidia et al. 2001].

Regarding docetaxel, a randomized phase III trial (with 182 patients enrolled) showed that docetaxel, administered at 60 mg/m² every 21 days, was at least as good as vinorelbine in terms of median survival in the treatment of elderly advanced NSCLC patients (14.3 months versus 9.9 months with docetaxel and vinorelbine, respectively; hazard ratio [HR], 0.780; 95% confidence interval [CI], 0.561–1.085; p  = 0.138) [Kudoh et al. 2006]. Docetaxel improved progression-free survival (PFS) (5.5 months versus 3.1 months; p < 0.001) and response rate (22.7% versus 9.9%; p = 0.019) versus vinorelbine, but was associated with more grade 3–4 neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; p = 0.031). Thus, docetaxel can be considered a reasonable option in this clinical setting.

To improve upon the results obtained with single-agent chemotherapy, nonplatinum-based combinations have been developed. The most studied regimen is gemcitabine plus vinorelbine. The largest randomized phase III trial, named MILES (Multicenter Italian Lung Cancer in the Elderly Study), accrued about 700 elderly patients and showed that the combination of vinorelbine plus gemcitabine was no more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC [Gridelli et al. 2003]. Median survival was 36, 28 and 30 weeks, and the probability of being alive after 1 year was 38%, 28% and 30%, for vinorelbine, gemcitabine and the combination, respectively. Although quality of life was similar across the three treatment arms, the combination treatment was slightly more toxic than the two drugs given singly (Table 1).

Table 1.

Main phase III randomized trials dedicated to elderly patients with advanced non-small cell lung cancer.

Trial	Study arm	Number of patients	Response rate (%)	Median overall survival	Quality-of-life comparison
ELVIS  [ELVIS Group, 1999]	BSC	78	n.a.	21 weeks	Functional scales and  several cancer-related symptoms better for vinorelbine
Vinorelbine	76	20	28 weeks*  (p = 0.03)
WJTOG 9904  [Kudoh et al. 2006]	Vinorelbine	91	10	14.3 months	Docetaxel improved  overall disease-related symptoms over vinorelbine
Docetaxel	91	23	9.9 months
MILES  [Gridelli et al. 2003]	Vinorelbine	233	18	36 weeks	Quality of life similar  among the three treatment arms
	Gemcitabine	233	16	28 weeks
Vinorelbine  + gemcitabine	232	21	30 weeks

ELVIS, Elderly Lung Cancer Vinorelbine Italian Group Study; WJTOG, West Japan Thoracic Oncology Group trial; MILES, Multicenter Italian Lung Cancer in the Elderly; BSC, Best Supportive Care; n.a., not applicable; *statistically significant difference.

Cisplatin-based chemotherapy is currently recommended as the standard approach for patients with advanced NSCLC. However, to date, no prospective phase III study has explored the reproducibility of this benefit in elderly patients. Cisplatin administration is associated mainly with significant renal, neurological and gastrointestinal toxicity, and the evaluation of the risk versus benefit ratio should be particularly rigorous in elderly patients. In fact, in this patient population, reduction of creatinine clearance and cisplatin renal excretion is expected to increase the potential for toxicity. Furthermore, required hydration, presence of comorbidities and compromised performance status may preclude the safe administration of cisplatin to a significant proportion of patients. Compared with cisplatin, carboplatin causes lower rates of emesis, nephrotoxicity and neurotoxicity, and it represents an appealing alternative for cisplatin-based chemotherapy. However, the evaluation of cisplatin-based chemotherapy in elderly patients, in our opinion should be a priority over carboplatin evaluation because a recent meta-analysis showed superior results in favor of cisplatin- versus carboplatin-based chemotherapy in the first-line treatment of advanced NSCLC [Ardizzoni et al. 2007]. In fact, in this meta-analysis, the authors showed a benefit in favor of cisplatin in terms of response rate over carboplatin, but in a subgroup analysis restricted to platin-based chemotherapy with third-generation agents, a survival benefit in favor of cisplatin was reported. Moreover, although carboplatin causes lower rates of emesis, nephrotoxicity and neurotoxicity, it is associated with higher hematological toxicity than cisplatin, particularly when combined with other myelotoxic drugs as gemcitabine. Thus, in elderly patients, safety remains a problem also with carboplatin-based chemotherapy. The issue of cisplatin- and carboplatin-based therapy for elderly patients with advanced NSCLC has been addressed in retrospective analyses of large randomized trials [Lilenbaum et al. 2005; Belani and Fossella, 2003; Hensing et al. 2003; Langer et al. 2003; Kelly et al. 2001]. Treatment outcomes of patients younger and older than 70 years enrolled on these trials were compared. Overall, these analyses found no differences in survival between elderly and younger patients with a small but significant increase in toxicity in the elderly. Also, in the adjuvant setting, a recent pooled analysis found no effect of age on the outcomes of cisplatin-based adjuvant chemotherapy [Fruh et al. 2008]. This is a further finding that suggests that cisplatin-based chemotherapy should not be withheld from elderly patients with NSCLC purely on the basis of age.

However, it must be noted that the aforementioned analyses may suffer from selection bias. In fact, elderly patients enrolled in these sorts of trials are likely not representative of the whole elderly population, but rather of a small subgroup thought by investigators to be eligible for aggressive treatment [Perrone et al. 2002]. Thus, prospective clinical trials of platin-based chemotherapy with inclusion criteria limited to the elderly population are needed. A main issue is the exploration of innovative schedules and attenuated doses of cisplatin that would be more suitable in the elderly. Interesting results have been obtained with combinations of cisplatin plus either gemcitabine, vinorelbine or docetaxel [Ohe et al. 2004; Feliu et al. 2003]. Very recently, we performed two phase I/II trials to evaluate the feasibility of cisplatin at attenuated doses combined with gemcitabine or vinorelbine in elderly patients with advanced NSCLC [Gridelli et al. 2007]. Cisplatin was feasible and active at 60 mg/m² with gemcitabine and at 40 mg/m² with vinorelbine. The most interesting results were observed with the gemcitabine combination: 50 out of 60 (83.3%) patients were treated without unacceptable toxicity; objective responses were reported in 26 of 60 patients (43.5%; 95% CI, 30.6–56.8); median PFS and overall survival (OS) were 25.3 and 43.6 weeks, respectively. The authors concluded that cisplatin plus gemcitabine deserves comparison versus single-agent chemotherapy in this setting of patients. Our group is launching a phase III randomized trial of cisplatin at 60 mg/m² plus gemcitabine versus gemcitabine in elderly patients with advanced NSCLC.

About carboplatin, the CALGB 9730 phase III randomized trial, that compared paclitaxel with carboplatin plus paclitaxel in advanced NSCLC and showing improved response rate and failure-free survival with the combination, showed similar efficacy results in the elderly subset of patients compared with the younger counterpart [Lilenbaum et al. 2005]. In addition, several recently published phase II studies of combination chemotherapy based on modified schedules of carboplatin (low-dose or weekly administration) have shown reasonable levels of activity and tolerability [Maestu et al. 2003; Choi et al. 2003]. In particular, Maestu and colleagues treated 88 elderly patients in a phase II trial with gemcitabine 1250 mg/m² days 1 and 8 plus carboplatin (area under curve (AUC) 4) on day 1, every 21 days [Maestu et al. 2003]. The combination of carboplatin and gemcitabine at these doses in this population was well tolerated and active, with a response rate of 37% and median survival of 9 months. Choi and colleagues treated 35 NSCLC patients of either age ≥65 years or ECOG PS 2 (Eastern Cooperative Oncology Group Performance Status Scale) with a modified regimen of attenuated doses of paclitaxel (135 mg/m²) and carboplatin (AUC 5) on day 1 every 21 days. The objective response rate was 40% and the median time to progression was 22 weeks. Moreover, the modified regimen of paclitaxel plus carboplatin was well tolerated in this special population [Choi et al. 2003].

In general, few data exist regarding the outcome of chemotherapy in NSCLC patients aged ≥80 years, a rapidly expanding, potentially vulnerable population cohort [Pallis et al. 2010]. A retrospective chart review of 111 octogenarians diagnosed with any stage of NSCLC shows that the vast majority of them received therapy, but only one-third were treated with stage-specific guideline-recommended therapy [Oxnard et al. 2007; Hesketh et al. 2007; Langer et al. 2003]. Patients ≥80 years of age fared worse than patients aged 70–79 years in terms of OS, although it should be noted that only a very small number of patients aged ≥80 years were enrolled (nine patients in the ECOG trial [Langer et al. 2003] and 26 and 23 in the Southwest Oncology Group 0027 and LUN 6 trials [Hesketh et al. 2007], respectively). The lack of data on octogenarians remains troublesome. Based on retrospective analyses, clinicians should exercise caution when applying the existing data for patients aged 70–79 years to those aged >80 years [Lichtman et al. 2007]. Clearly, more data are needed on appropriate therapy recommendations for this patient population and more studies need to be conducted.

With regard to the role of second-line chemotherapy in elderly patients [Pallis et al. 2010], a recent publication reported the results of an age-specific subgroup analysis of a randomized phase III trial comparing pemetrexed with docetaxel in pretreated patients with NSCLC [Weiss et al. 2006]. The original trial randomized 571 previously treated NSCLC patients. Eighty-six of those (15%) were ≥70 years old. Objective response rates, median PFS and median OS were not significantly different between younger and elderly patients, irrespective of the treatment arm. Elderly patients had a median OS of 9.5 and 7.7 months in the pemetrexed and docetaxel arms, respectively, while for younger patients, the corresponding OS was 7.8 and 8.0 months for pemetrexed and docetaxel arms, respectively. Furthermore, no significant difference between younger and elderly patients was reported regarding toxicity. The authors concluded that second-line cytotoxic treatment is feasible for elderly patients, with pemetrexed producing a more tolerable toxicity profile compared with docetaxel. Nevertheless, as this is a retrospective analysis, it is likely to suffer from selection bias.

Targeted therapies

Targeted therapies are a potential treatment option for elderly advanced NSCLC patients. Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has demonstrated a survival advantage compared with best supportive care in a phase III trial for patients with advanced NSCLC after first- and second-line failure. Jackman and colleagues have investigated erlotinib in a phase II study in 80 patients over 70 years of age with previously untreated advanced NSCLC [Jackman et al. 2007]. Erlotinib was well tolerated with an encouraging response rate of 10% and disease stabilization of 41%. There was a significant improvement of key symptoms (dyspnea, cough, fatigue, pain) and an interesting median survival of 10.9 months. At the last ASCO meeting, Chen and colleagues presented a phase II randomized trial of erlotinib versus oral vinorelbine in elderly patients with untreated advanced NSCLC [Chen et al. 2009]. In 77 of 116 enrolled Taiwanese patients available for efficacy and safety analyses, objective response rates were 21.6% with erlotinib and 12.8% with vinorelbine. Disease control rate was 70.3% with erlotinib and 56.4% with vinorelbine. Median time to disease progression was 4.4 months with erlotinib compared with 3.9 months with vinorelbine (p = 0.6). The most common treatment-related toxicities were skin rash and diarrhea with erlotinib, and diarrhea and nausea with vinorelbine. Crinò and colleagues performed a randomized phase II trial comparing gefitinib (another EGFR tyrosine kinase inhibitor) to vinorelbine in 196 chemotherapy-naive elderly patients with advanced NSCLC [Crinò et al. 2008]. HRs (gefitinib versus vinorelbine) were 1.19 for PFS and 0.98 for OS. Overall response rate and disease control rates were 3.1% and 43.3% for gefitinib, and 5.1% and 53.5% for vinorelbine, respectively. Overall quality-of-life improvement and pulmonary symptom improvement rates were 24.3% and 36.6% for gefitinib and 10.9% and 31% for vinorelbine, respectively. Moreover, there were fewer treatment-related grade 3–5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%) (Table 2). A retrospective analysis of the BR.21 trial (a double-blind phase III trial that randomly assigned 731 advanced NSCLC patients to erlotinib or placebo) studied the influence of age on erlotinib outcomes [Wheatley-Price et al. 2008]. In the study population, there were 163 elderly patients and 568 young patients. There was no significant difference between age groups randomly assigned to erlotinib or placebo in PFS and in OS (elderly: 7.6 versus 5.0 months; HR = 0.92; p = 0.67; young: 6.4 versus 4.7 months; HR = 0.73; p = 0.0014; interaction, p = 0.31). Response rates were similar between age groups. Compared with young patients, elderly patients had significantly more overall and severe (grade 3 and 4) toxicity (35% versus 18%; p < 0.001), were more likely to discontinue treatment as a result of treatment-related toxicity (12% versus 3%; p < 0.0001), and had lower relative dose intensity (64% versus 82% received >90% planned dose; p  < 0.001). The authors concluded that elderly patients treated with erlotinib gain similar survival and quality-of-life benefits as younger patients but experience greater toxicity.

Table 2.

Main phase II trials on epidermal growth factor receptor tyrosine kinase inhibitors in elderly patients with advanced non-small cell lung cancer.

Author	Study arm	Number of patients	Response rate (%)	Median overall survival	Toxicity
Jackman  et al. [2007]	Erlotinib	80	10	10.9 months	Well tolerated. Rash and  diarrhea were the most common toxicities
Chen  et al. [2009]	Erlotinib Vinorelbine  (oral)	116	21.6	Not available	The most common  toxicities were skin rash and diarrhea with erlotinib, and diarrhea and nausea with vinorelbine
12.8
Crinò  et al. [2008]	Gefitinib	99	3.1	5.9 months	Fewer treatment-related  grade 3–5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%)
Vinorelbine	97	5.1	8.0 months

Activating mutations in the EGFR gene confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced NSCLC. Very recently, Rosell and colleagues evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment [Rosell et al. 2009]. Lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (p < 0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median PFS and OS for 217 patients who received erlotinib were surprising: 14 and 27 months, respectively. Moreover, following the results of a phase III randomized trial of gefitinib against chemotherapy in the first-line treatment of lung adenocarcinoma of never/former light smokers [Mok et al. 2009], the United States Food and Drug Administration (FDA) has recently approved gefitinib for first-line treatment of patients whose tumors are positive for the EGFR gene mutations. Thus, screening of patients with lung cancer for EGFR gene mutations will have an important role in decisions about treatment, also in elderly patients.

Very recently, we performed a randomized phase II trial to select the optimal way of adding cetuximab (an anti-EGFR monoclonal antibody) to chemotherapy with gemcitabine in the first-line treatment of elderly patients with advanced NSCLC. Cetuximab was administered concurrently with gemcitabine from the beginning of treatment or after gemcitabine as maintenance or second-line treatment. No striking differences in efficacy were observed between the two arms (1-year survival rate of 41.4% and 31%, respectively). We concluded that a sequential strategy cannot be proposed for future trials because of low compliance (with this approach 34% of patients were never able to start cetuximab as maintenance or second-line treatment). In our opinion, inconsistency of survival outcomes makes also concomitant treatment not a candidate for further testing in unselected elderly patients [Gridelli et al. 2010].

Sorafenib, is a multitarget tyrosine kinase inhibitor with main antiangiogenetic properties against the vascular endothelial growth factor (VEGF) receptor (VEGFR). Recently, in the GEST (Gemcitabine Erlotinib Sorafenib Trial) phase II study, we randomized advanced elderly NSCLC patients to sorafenib plus gemcitabine or sorafenib plus erlotinib, recently concluding the accrual with pending results.

Vandetanib is an oral tyrosine kinase inhibitor with a double mechanism of action (anti-EGFR and anti-VEGFR) that showed to improve docetaxel efficacy in second-line treatment of advanced NSCLC [Herbst et al. 2009]. Vandetanib is the first oral targeted therapy in phase III trials to show significant evidence of clinical benefit when added to standard chemotherapy in NSCLC. Currently, we are running in a first-line setting the ZELIG (Zactima in NSCLC ELderly patients In combination with or versus Gemcitabine) phase II randomized trial of gemcitabine or gemcitabine plus vandetanib in untreated elderly NSCLC patients.

Among angiogenesis inhibitors, the anti-VEGF monoclonal antibody, bevacizumab, represents the most successful targeted agent in cancer therapy. In chemotherapy-naive advanced NSCLC patients with nonsquamous histology, the combination of bevacizumab with chemotherapy has demonstrated to produce better efficacy outcomes than chemotherapy alone. Recently, a retrospective analysis of a randomized trial (ECOG 4599) has shown that in elderly NSCLC patients (≥70 years), the combination of carboplatin plus paclitaxel chemotherapy and bevacizumab is associated with a higher degree of toxicity and no survival improvement compared with chemotherapy alone [Ramalingam et al. 2008]. In fact, among elderly patients (n = 224; 26% of the entire study population), there was a trend towards higher response rate (29% versus 17%; p = 0.067) and PFS (5.9 versus 4.9 months; p = 0.063) with chemotherapy plus bevacizumab compared with chemotherapy alone, although OS (11.3 versus 12.1 months; p = 0.4) was similar. Grade 3–5 toxicities occurred in 87% of elderly patients with chemotherapy plus bevacizumab versus 61% with chemotherapy alone (p < 0.001), with seven treatment-related deaths in the bevacizumab arm compared with two in the chemotherapy alone arm. Elderly patients had higher incidence of grade 3–5 neutropenia, bleeding, and proteinuria with chemotherapy plus bevacizumab compared with younger patients. Conversely, a retrospective analysis of the AVAiL phase III randomized trial, has compared efficacy and safety of first-line bevacizumab plus cisplatin and gemcitabine in elderly patients (≥65 years) with those of young population (<65 years), and has reported similar PFS benefit from bevacizumab-based treatment in the elderly subpopulation with acceptable tolerability of bevacizumab in elderly patients [Leighl et al. 2009]. Efficacy data were available for 304 patients ≥65 years and 739 patients <65 years. Also bevacizumab-treated patients (at 7.5 mg/kg) aged ≥65 years derived an improvement in PFS (HR = 0.71; p = 0.023) and response rate (40% versus 30%) compared with the placebo group. Survival was similar in all treatment arms regardless of age. Safety data were available for 284 patients ≥65 years and 702 patients <65 years. There were no safety signals of concern in older patients. The incidence of hypertension and febrile neutropenia and the rate of treatment-related deaths were similar in patients ≥65 and <65 years treated with bevacizumab. Also a retrospective analysis of a large single-arm trial (SAIL study) of first-line bevacizumab combined to standard chemotherapy, reported no unexpected safety signals in the elderly population [Jager et al. 2008]. In fact, in this analysis patients older than 65 years did not appear to be more likely to experience adverse events, including thromboembolic events, compared with patients ≤65 years. In the SAIL trial, the great majority of the patients were treated with carboplatin- or cisplatin-based chemotherapy, and 4% of the patients were treated with single-agent chemotherapy. The divergence of the results of these three retrospective analyses may be due to the different cut-off age used for the definition of elderly patients (Table 3). In fact, the ECOG analysis focused on patients above the age of 70 years and noted higher degree of toxicity with bevacizumab-based treatment, while the AVAiL and SAIL analyses used a cut-off age of 65 years and did not report any unexpected safety signals. This observation suggests that bevacizumab may be safe in the 65–70 age group as in younger patients, but not as much in the population aged 70 years and older. However, these controversial retrospective data on the safety of bevacizumab in elderly patients, justify prospective evaluation in this special population of bevacizumab. To date, we are running in Italy a phase II randomized trial (Elderly Avastin Gemcitabine Lung in the Elderly Study [EAGLES]) of bevacizumab at a dose of 7.5 mg/kg combined with single-agent gemcitabine or cisplatin plus gemcitabine at reduced doses of drugs [Gridelli, 2008].

Table 3.

Retrospective analyses on efficacy and safety of bevacizumab combined with chemotherapy in elderly patients with advanced non-small cell lung cancer.

Trial	Treatment	Cut-off age	Efficacy	Safety
ECOG 4599  [Ramalingam et al. 2008]	Carboplatin and  paclitaxel plus bevacizumab versus chemotherapy alone	≥70 years	Bevacizumab is  associated with no survival improvement compared with chemotherapy alone in the elderly	Bevacizumab is  associated with a higher degree of toxicity compared with chemotherapy alone in the elderly
AVAiL [Leighl  et al. 2009]	Cisplatin and gemci  tabine plus bevacizumab versus chemotherapy alone	≥65 years	Similar progression-  free survival benefit from bevacizumab-based treatment in the elderly subpopulation	Acceptable tolerability  of bevacizumab-based treatment in elderly patients
SAIL [Jager  et al. 2008]	Platin-based poly  chemotherapy plus bevacizumab	≥65 years	Similar efficacy  results to younger counterparts	No unexpected safety signals in the elderly population

Conclusions

Clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with NSCLC. Elderly patients have more comorbidities and tend to tolerate toxic medical treatments less well than their younger counterparts. This patient population is at risk of both empirical undertreatment resulting in poor survival or excessive toxicity from standard therapy. Some of the data available today is based on retrospective studies of trials which included patients with good performance status and of all ages. However, retrospective analyses of ordinary trials without age-specific entry criteria are potentially biased by intrinsic selection that govern enrollment. Relevant prospective data are available for advanced NSCLC. In this clinical setting, single-agent chemotherapy with third-generation agents is to be considered the routine standard of care for unselected patients. Platinum-based chemotherapy with platinum at attenuated doses is an active and feasible option. Among targeted therapies, the use of EGFR inhibitors, erlotinib and gefitinib, in the elderly is sustained by relevant phase II data showing a good tolerability. The anti-VEGF monoclonal antibody, bevacizumab, should be studied in phase II trials specifically designed for elderly patients, combined to chemotherapy more suitable to elderly patients. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.

Conflict of interest statement

The authors have no conflicts of interest in writing this article.