Adelaide Cancer Centre, Ashford, South Australia.
Elderly patients represent a significant and rising proportion of patients with Non-Small Cell Lung Cancer and historically they have been under-treated and under-represented in clinical trials. Increasing elderly specific research into the management of this disease has been performed in the last decade and has demonstrated both quality of life and survival benefits for patients with advanced non-small cell lung cancer managed with modern chemotherapy. This paper will discuss the evidence for systemic therapy (chemotherapy and targeted therapy) in advanced non small cell lung cancer and adjuvant therapy.
Lung cancer is the most lethal of the common solid malignancies. The median survival for advanced disease, despite modern oncological techniques, remains less than 12 months. Long-term cure is largely limited to early stage disease and unfortunately this remains the exception rather than the norm. The most common sub-type is Non-Small Cell Lung Cancer (NSCLC), now representing three quarters of lung cancer presentations in the western world.1 Histological patterns in NSCLC are also changing with time, with the frequency of adenocarcinoma presentation now much more frequent. This is believed to reflect both the rising incidence of NSCLC in non-smokers and the change in cigarette composition.2 The median age at presentation of lung cancer is 68 years, with one third of patients aged over 75 years. Patterns of care studies from both Europe and the US have demonstrated that elderly patients receive non-standard treatment and often receive no active treatment at all.3-5 Patients aged over 65 years have largely, until the last decade, been excluded from clinical trials based predominantly on the premise of age rather than inadequate organ function.6
Ageing is associated with reductions in physiological reserve and also the increasing prevalence of comorbidity, all having distinct implications for the delivery of chemotherapy and the ability to withstand its toxicity. Arbitrary definitions for ‘elderly’ have often been used largely based on the availability of population and census data eg. 65 years. However, 70 years of age is a more appropriate physiological definition for when changes in organ reserve are more common.4,7 More recent studies concentrate on patients aged 75 years or older. This age group has a much higher likelihood of frailty, implying limited minimal physiological reserve. Prospective data on this group, with regards to outcome or toxicity with treatment, is sadly lacking.
Comprehensive geriatric assessment has been a concept widely encouraged in geriatric oncology, although it has largely been limited to the research setting due to its multidisciplinary nature. Its benefit is that it formally assesses multiple areas which may influence an older patient’s ability to tolerate therapy. These include functional status, nutrition, psychological state and social support, in addition to the more routinely assessed co-morbidity and medication.8 Importantly, these additional parameters can also provide prognostic information separate to what is gained from performance status assessment, which is by far the most common tool employed by oncologists to stratify treatment paradigms based on fitness for therapy.
Functional state has been shown to be a more useful prognostic indicator than performance status in many studies of elderly patients receiving cancer therapy, including one specific for NSCLC. In this study, impairment of instrumental activities of daily living (IADL) was a stronger predictor of prognosis than impaired activities of daily living (ADL) regarding survival.9 Functional status is also often impaired despite preservation of a good performance status. In one study of elderly patients, 20% of patients were assessed as ECOG 2 or greater, however over half had impairment of IADLs.10 Application of co-morbidity indices such as a Charlson score, can also provide prognostic information independent of performance status. A French group has employed both the Charlson score and performance status to stratify patients to treatment and demonstrate that good performance status patients with a low Charlson score tolerate combination chemotherapy with similar results to those aged <65 years.11
The current standard of care for advanced NSCLC is a platinum-based doublet using a third generation agent such as gemcitabine, vinorelbine or a taxane.12 It is also generally accepted that a modern non-platinum doublet is also as effective as a platinum-based doublet, but significantly more expensive.13 Currently there are four published elderly-specific phase III studies, the largest performed by Gridelli and colleagues. The landmark study was the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS), which demonstrated that vinorelbine provided both a survival advantage and quality of life improvement for patients aged over 70 in comparison to best supportive care. Median survival, as expected for a single agent, was 6.4 months in comparison to 4.8 months for best supportive care.14 Surprisingly then, their second phase III trial, the Multicenter Italian Lung Cancer in the Elderly Study, found that a vinorelbinegemcitabine doublet did not demonstrate any significant advantage over either vinorelbine or gemcitabine as single agents. This is the largest of the elderly-specific studies with over 700 patients enrolled. Median survival for vinorelbine in this study was nine months and for the doublet 7.5 months.15
The most recently published study was by a Japanese group which compared docetaxel at 60mg/m2 three weekly, lower than the more standard 75mg/m2 used in Western populations, to vinorelbine at 25mg/m2 d1, 8 q21 and found that there was no significant survival difference between the groups, however there was an improvement in progression free survival. Median survival was 14.3 months for the docetaxel group and 9.9 months for the vinorelbine group. The negative conclusion could be attributed to several reasons. Firstly, the study was powered for 60% improvement in median survival for the docetaxel group, with the control arm presumed to have a median survival of six months. Secondly, 37% of the docetaxel patients received gefitinib as a second-line treatment compared to 20.9% of the vinorelbine group. The prevalence of the EGFR mutation, which is associated with improved activity and survival with gefitinib, is higher in Japanese populations. Interestingly, there was also a significant difference in the severe neutropenia rates between the Japanese vinorelbine group and the Italian vinorelbine group, with rates of 67% and 25% respectively.16 This may reflect pharmacogenomic differences, which are increasingly being recognised as an explanation for discordance in international study outcomes.
Subset analyses of large phase III studies are the other main source of information regarding chemotherapy management of elderly patients. Langer et al performed a subset analysis of the ECOG 5594, which used cisplatin-based chemotherapy and demonstrated that full dose platinum-based doublets are possible to administer in elderly patients with outcomes consistent with their younger counterparts. However, these were associated with higher rates of neuropsychological toxicity and leucopenia.17 Subset analysis of ECOG 1594 demonstrated no difference in outcome for fit, elderly patients.18 There are concerns however, regarding selection bias of fitter elderly patients into these studies. The role of combination chemotherapy in consensus statements is that it should be a consideration, but single agent chemotherapy based on phase III evidence remains the recommendation.19
Many elderly-specific NSCLC studies, for the purpose of more rapid recruitment, have also allowed entry of ECOG 2 patients of any age into the study, believing them to be similar in terms of capacity to tolerate therapy and outcome. ECOG 2 patients are by definition bedbound <50% of the day, but unable to perform general activities. Median survival for this group however, is only two months untreated, reflecting how much more frail they are in comparison to a fit elderly patient with advanced NSCLC.20 The median survival in the ELVIS study for the best supportive care arm was 21 weeks.14 Gridelli’s phase II study of fit elderly patients ECOG 0-1 with cisplatin-based doublets and their outcomes were typical of that found in non-age specific first line NSCLC study. This study is important in that cisplatin has been felt to be toxic for elderly patients given its renal clearance, with subsequent for high volume fluid loading pre and post administration and cumulative neuro and oto-toxicity, in addition to its high emetogenicity.21 It is the platinum of choice though for efficacy in the management of NSCLC, although substantial debate exists within the Oncological community regarding its positions on platinum of choice when quality of life considerations are taken into account in the advanced setting.22
Data for second line chemotherapy again is limited to subset analysis. Weiss et al demonstrated in their analysis of the pemetrexed versus docetaxel study that elderly patients (aged >70 years) had no significant difference in outcome and toxicity was similar to their younger counterparts. However, elderly patients only represented 15% of patients enrolled. Pemetrexed was associated with a significant reduction in the rate of febrile neutropenia in comparison to docetaxel (2.5% vs 18.9%). Pharmacokinetic substudy studies were also performed in this study, which did not demonstrate any difference for pemetrexed or docetaxel between patients aged >65 years or younger. There were however, higher rates of severe neutropenia and febrile neutropenia in the docetaxel arm for older patients (61% and 16% respectively compared to 30% and 0%), but this did not reach statistical significance.23 Again the choice of second line agent will be largely influenced by co-morbidity, particularly the presence of neuropathy.
Evidence-based management for patients aged over 80 is particularly sparse. They represented <1% of patients enrolled in ECOG 1594, the landmark study demonstrating relative equivalence for platinum-based doublets in advanced NSCLC.12 A French group performed a retrospective analysis over 10 years in their department and only found 79 patients aged over 80 with biopsy proven NSCLC. One quarter was early stage, while only 40% were stage IV. Co-morbidity was common, with nearly half having a Charlson Comorbidity Index of six or more – this appeared to trend with poorer outcome.24
More recently, targeted agents have been incorporated into the management of NSCLC. The oral EGFR tyrosine kinase inhibitors have now been demonstrated to have efficacy in the second and third line setting, and erlotinib has also shown both a survival advantage and quality of life advantage in comparison to placebo.25 They have attracted great interest in the management of the elderly patient with lung cancer given their lesser toxicity in comparison to the chemotherapy. They are not associated with any haematological toxicity and in general are well tolerated with the main toxicity being that of rash, diarrhoea, ocular irritation and in a small subset, interstitial fibrosis. Response appears related to particular EGFR mutations, which appear to be particularly prevalent in Asian, female non-smoking populations, whereby response rates of 50% or more can be achieved in this cohort.24 First line studies of these agents in chemo-naïve patients aged over 70, not selected for EGFR mutations, revealed the expected 10% objective response rate and a median survival of 10.9 months, with over 40% of patients receiving chemotherapy on progression. Those patients who did have the mutation had a median survival of >15 months.26 Phase III studies are awaited against chemotherapy. Their use in combination with first line chemotherapy did not demonstrate any significant advantage.27-30
Bevacizumab is a monoclonal antibody directed against VEGF and its administration with carboplatin and paclitaxel has demonstrated a survival advantage over chemotherapy alone. The magnitude is similar to that achieved with chemotherapy over best supportive care. Its use has been limited to non-squamous varieties due to the increased risk of catastrophic pulmonary haemorrhage with this agent in the squamous sub-type. Enrolment was limited to patients with good performance status ECOG 0-1. Forty four per cent of patients enrolled in this study were aged over 65 years.31 Formal subgroup analysis has not been published as yet. These findings have been confirmed in a second study presented in abstract form only in 2007.32
The application of adjuvant chemotherapy in resected NSCLC is now considered a standard of care for fit patients, however its routine use in elderly patients on current evidence is not. Evidence only exists for cisplatin-based treatment, which in elderly patients may have considerable long-term consequences regarding peripheral neuropathy and its impact on mobility and independence. Ototoxicity also has significant functional costs for elderly patients, with high-pitched hearing loss the main consequence.
Pepe et al performed a retrospective subset analysis of the Canadian study BR10.33 This study was restricted to patients with completely resected stage 1B or 2 disease. It compared four cycles of cisplatin and vinorelbine to observation post surgery and demonstrated a 31% reduction in death for the chemotherapy arm.34 Patients aged over 65 represented a significant proportion of patients enrolled in this study (n=155, 32%). Less than half of these patients were aged over 70 years and only 23 patients were aged 75 or older. They found that this sub-group did significantly worse in comparison to those aged between 65 and 74 years. Their survival was found to be half that of those aged 65-74 years, albeit with substantially smaller numbers of patients recruited. There was no difference between the sub-groups for disease free survival.
This suggests that the excess of deaths in the 75 or older age group was due to co-morbid conditions. They also noted a difference in histological subtype for patients aged over 65 in comparison to their younger counterparts with a predilection for squamous carcinoma (49% vs 32%). The survival benefit for adjuvant chemotherapy though remained significant in the elderly as a whole HR 0.61 p=0.04. Interestingly this was achieved with lower dose intensity than in their younger counterparts.33 This is the most likely explanation for why the severe toxicity profiles were not different in contrast to most subset analyses which in general, demonstrates higher levels of haematological and neuro-psychiatric toxicity for similar doses of drugs to their younger cohorts. Adjuvant chemotherapy should only be recommended with caution to patients aged over 75 years.
Outcomes for patients with NSCLC have significantly improved over the past decade largely due to the availability of effective systemic therapy, with improved patient toxicity profiles. Treatments have demonstrated improvement in both survival and quality of life. Application of chemotherapy to elderly patients has often been low due to perceived difficulties with tolerability and benefit. However, a substantial evidence base now exists demonstrating the benefits. Careful evaluation of the patient with regard to co-morbidity and functional status can minimise potential toxicity and allow the safe administration of treatment. Consideration of therapy remains critical to the optimal management of elderly patients with NSCLC, enabling them with therapeutic options rather than therapeutic nihilism.
3. de Rijke JM, Schouten LJ, ten Velde GP et al. Influence of age, comorbidity and performance status on the choice of treatment for patients with non-small cell lung cancer; results of a population-based study. Lung Cancer. 2004 Nov; 46(2):233-45.
9. Maione P, Perrone F, Gallo C, et al. Pre-treatment quality of life and functional status assessment significantly predict survival of elderly patients with advanced non-small-cell lung cancer receiving chemotherapy: a prognostic analysis of the multicenter Italian lung cancer in the elderly study. J Clin Oncol. 2005 Oct 1;23(28):6865-72.
10. Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol. 2002 Jan 15;20(2):494-502.
11. LeCaer H, Fournel P, Jullian H, et al. An open multicenter phase II trial of docetaxel-gemcitabine in Charlson score and performance status (PS) selected elderly patients with stage IIIB pleura/IV non-small-cell lung cancer (NSCLC): the GFPC 02-02a study. Crit Rev Oncol Hematol. 2007 Oct;64(1):73-81.
13. Ardizzoni A, Boni L, Tiseo M, et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 2007 Jun 6;99(11):847-57.
14. 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 Jan 6; 91(1): p.66-72.
15. Gridelli C, Perrone F, Gallo C, 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 Mar 5;95(5):362-72.
16. Kudoh S, Takeda K, Nakagawa K, et al. Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-smallcell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol. 2006 Aug 1; 24(22):3657-63.
17. Langer CJ, Manola J, Bernardo P, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst. 2002 Feb 6; 94(3):173-81.
20. Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer—a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer. 2000 Aug;83(4):447-53.
21. Gridelli C, Maione P, Illiano A, et al. Cisplatin plus gemcitabine or vinorelbine for elderly patients with advanced non small-cell lung cancer: the MILES-2P studies. J Clin Oncol. 2007 Oct 10;25(29):4663-9.
22. Rajeswaran A, Trojan A, Burnand B, et al. Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: A systematic review of randomized controlled trials. Lung Cancer. 2007 Aug 27.
23. Weiss GJ, Langer C, Rosell R, et al. Elderly patients benefit from secondline 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 Sep 20;24(27): 4405-11.
24. Breen D, Barlesi F, Zemerli M, et al. Results and impact of routine assessment of comorbidity in elderly patients with non-small-cell lung cancer aged >80 years. Clin Lung Cancer. 2007 Mar; 8(5):331-4.
26. Jackman DM, Yeap BY, Lindeman NI, 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 Mar 1; 25(7):760-6
27. Herbst RS, Giaccone G, Schiller JH, 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 Mar 1; 22(5):785-94.
28. Giaccone G, Herbst RS, Manegold C, 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 Mar 1; 22(5):777-84.
29. Herbst RS, Prager D, Hermann R, 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 Sep 1; 23(25):5892-9.
30. Gatzemeier U, Pluzanska A, Szczesna A, 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 Apr 20; 25(12):1545-52.
32. Manegold C, Von Pawel J, Zatloukal P, et al. Randomized, double blind, multicentre phase 3 study of bevacizumab in combination with cisplatin and gemcitabine in chemo-naive patients with advanced or recurrent non-squamous non-small cell lung cancer: BO17704. Proc Am Soc Clin Oncol. 2007. Chicago.
33. Pepe C, Hasan B, Winton TL, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol. 2007 Apr 20; 25(12):1553-61.