Lung Cancer in the Elderly: What’s Age Got to Do With It?

The review by Dr. Chiappori and colleagues in this issue of ONCOLOGY addresses an important challenge relating to the optimal management of elderly patients with lung cancer. The authors provide an excellent overview of the data in patients with various stages of non-small cell lung cancer (NSCLC). They also highlight the limitations of the existing data in the management of elderly NSCLC patients.

Although there is no clear consensus on the appropriate definition of the elderly, 65 or 70 years has been used most frequently by investigators. Irrespective of the definition, age-induced decline in physical performance and organ function begin around the age of 40, with approximately 20% decline in physical function estimated to occur between the fourth and sixth decade of life.[1,2] However, the elderly patient population is a very heterogeneous group in terms of physical, biological, emotional and cognitive function. More importantly, the body of evidence from human and animal research showed that while aging and senescence may be related, increasing longevity has also resulted in the postponement in functional limitations and debility expected at the end of life.[3,4] The fact that chronological age has become an acceptable surrogate for the determination of patient’s ability to tolerate toxic therapeutic interventions is therefore a very disconcerting reality in oncology practice. This issue has now acquired greater clinical and research significance because of the increasing gentrification of the population in industrialized Western societies.[5]

The challenge with cancer management in elderly patients relates to the physiologic decline in organ function with age, and the higher prevalence of age-associated co-morbid illnesses. This complex interplay of host factors results in altered pharmacokinetic behavior of established anti-cancer agents, most of which were developed in relatively younger, fit patient populations.[6] Also, alteration in pharmacodynamic effects due to age-related physiologic change may alter the risk-benefit balance even in the absence of any significant difference in the overall toxicity in the elderly patient population.[6] A less well-articulated but quite important factor here is the potential biological differences in lung cancer diagnosed in the elderly compared to that diagnosed in the younger patient population.

The last decade witnessed major advancements in our understanding of lung cancer biology, especially in NSCLC. Minimally invasive surgical approaches have made surgical management of early stage NSCLC more tolerable to elderly patients. It is now well-established that surgical intervention by experienced hands is beneficial in carefully selected elderly patients.[7,8] The benefit of adjuvant chemotherapy has also been demonstrated in pooled analyses of randomized trials with cisplatin-based chemotherapy.[9,10] However, robust data is lacking on patients older than 75 years with adjuvant chemotherapy because the majority of patients enrolled in the trials that established the efficacy of this therapeutic strategy were younger than 75 years.[10]

The emergence of novel systemic therapies for advanced-stage disease has also improved lung cancer outcomes in patients of all age groups.[11-14] Notwithstanding, contemporaneous epidemiologic studies and population database reviews have demonstrated a consistent pattern of inferior survival outcome for elderly patients. Our analysis of the national SEER database and work by other groups also confirmed the previous observations that survival outcomes are inferior in the elderly patients reported from regional cancer registries.[15,16] It is likely that sub-optimal treatment or the withholding of active therapies due to concern for toxicity contributed significantly to the poor outcomes of the elderly patients.[17,18] Platinum-based cytotoxic chemotherapy doublet remains the cornerstone of therapy for advanced NSCLC. The incorporation of anti-angiogenesis agents in non-squamous NSCLC led to further survival improvement.[19] More recently, maintenance therapy using both conventional cytotoxic and biologic agents demonstrated incremental benefit over frontline therapy alone.[20,21] Subset analyses of some of these studies indicate that chronologic age does not limit therapeutic benefit, but may impact the adverse event profile.[22] Recently reported prospective elderly-specific studies provided further supportive evidence and demonstrated the tolerability and clinical benefit of multi-agent chemotherapy, especially in carefully selected elderly patients.[23]

As the use of multi-agent chemotherapy for advanced disease in elderly patients finds widespread acceptance, the optimal use of biologically targeted agents in elderly patients has assumed greater importance. Molecular and histologic characterization of NSCLC led to the identification of two previously unrecognized tumor subtypes with key genetic aberrations that drive tumor growth: EGFR mutated and EML4-ALK translocated tumors.[24-26] These tumor subtypes constitute roughly 15% of all NSCLC cases in the Western population and up to 50% in Asian patients.[25-29] One key clinical characteristic of these tumor types is the predominant affliction of young patients who have had negligible tobacco exposure. However, the identification of molecular subsets of NSCLC in this predominantly younger patient population should not be construed to mean that clinically important molecular subsets of lung cancer are restricted to younger patients. In fact, this finding may simply be an artifact, due to the low rate of participation of elderly patients in the clinical trials from which tumor samples are obtained for translational studies. It is conceivable that focused screening in elderly patients may result in the discovery of other novel driver molecular alterations that are unique to the elderly lung cancer population.

As we enter the era of personalized therapy, we contend that the increasing prevalence of elderly lung cancer patients calls for a reversal of the long-standing paradigm of developing therapeutic agents in younger patients for the treatment of a largely elderly patient population. Such an approach would ensure that elderly patients were offered timely treatments that best impacted the biology of their disease. Because poor performance status and advanced age are not necessarily interchangeable factors, it is our expectation that the investigational approach in which elderly patients are considered comparable to poor performance status patients would be an exception rather than the rule.[30-32]

In conclusion, the treatment of lung cancer in patients with advanced age is an important clinical challenge. The appropriate management of this special patient population will assume greater importance in the ensuing era of personalized anticancer therapies. The succinct review by Dr. Chiappori and his colleagues is therefore timely and useful for those interested in and responsible for the care of this important patient populations.

Financial Disclosure:All authors are supported by unrestricted research funding grant from the Georgia Cancer Coalition as Distinguished Cancer Scholar, and supported by NCI P01 grant CA116676.

References:

References:

1. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Experimental Gerontology 1986;21:379-406.

2. Kenny GP, Yardley JE, Martineau L, et al. J Physical work capacity in older adults: Implications for the aging worker. Am J Ind Med 2008;51:610-625.

3. Vaupel JW. Biodemography of human ageing. Nature;464:536-542.

4. Christensen K, Doblhammer G, Rau R. Ageing populations: The challenges ahead. Lancet 2009;374:1196-1208.

5. Wan He MS, Victoria A Velkoff, Kimberly A DeBaross, 65+ in the united states: 2005: Current Population Reports. Washington D.C., U. S. Government Printing Office, 2005, pp 23-209.

6. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004;56:163-184.

7. McVay CL, Pickens A, Fuller C, et al. Vats anatomic pulmonary resection in octogenarians. Am Surg 2005;71:791-793.

8. Palma DA, Tyldesley S, Sheehan F, et al.: Stage i non-small cell lung cancer (nsclc) in patients aged 75 years and older: Does age determine survival after radical treatment? J Thorac Oncol;5:818-824.

9. Douillard JY, Tribodet H, Aubert D, et al. Adjuvant cisplatin and vinorelbine for completely resected non-small cell lung cancer: Subgroup analysis of the lung adjuvant cisplatin evaluation. J Thorac Oncol;5:220-228.

10. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: A pooled analysis by the lace collaborative group. J Clin Oncol 2008;26:3552-3559.

11. Hanna N, Shepherd FA, Fossella FV, 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.

12. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-2103.

13. Shepherd FA, Rodrigues Pereira J, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-132.

14. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98.

15. Owonikoko TK, Ragin CC, Belani CP, et al.: Lung cancer in elderly patients: An analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25:5570-5577.

16. Davidoff AJ, Tang M, Seal B, et al. Chemotherapy and survival benefit in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol;28:2191-2197.

17. Taylor KM, Feldstein ML, Skeel RT, et al.: Fundamental dilemmas of the randomized clinical trial process: Results of a survey of the 1,737 eastern cooperative oncology group investigators. J Clin Oncol 1994;12:1796-1805.

18. Sawada S, Komori E, Nogami N, et al. Advanced age is not correlated with either short-term or long-term postoperative results in lung cancer patients in good clinical condition. Chest 2005;128:1557-1563.

19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-2550.

20. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 2009;374:1432-1440.

21. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol;11:521-529.

22. Ramalingam SS, Dahlberg SE, Langer CJ, 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.

23. Quoix EAO, J; Westeel, V; Pichon, E; et al. Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: Ifct-0501 randomized phase iii study in advanced non-small cell lung cancer (nsclc). J Clin Oncol 2010;28

24. Wong DW, Leung EL, So KK, 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.

25. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming eml4-alk fusion gene in non-small-cell lung cancer. Nature 2007;448:561-566.

26. Paez JG, Janne PA, Lee JC, et al. Egfr mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.

27. Johnson BE, Janne PA: Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. Cancer Res 2005;65:7525-7529.

28. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor eml4-alk. J Clin Oncol 2009;27:4247-4253.

29. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize alk-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009;15:5216-5223.

30. 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;25:760-766.

31. Goss G, Ferry D, Wierzbicki R, et al. Randomized phase ii study of gefitinib compared with placebo in chemotherapy-naive patients with advanced non-small-cell lung cancer and poor performance status. J Clin Oncol 2009;27:2253-2260.

32. Inoue A, Kobayashi K, Usui K, 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.