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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 13-15 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1820
Treatment of Advanced Non–Small-Cell Lung Cancer in the Elderly: From Best Supportive Care to the Combination of Platin-Based Chemotherapy and Targeted TherapiesDivision of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy Lung cancer in elderly patients is an increasingly common problem for the oncology practitioner. Because most patients with non–small-cell lung cancer (NSCLC) have advanced disease at diagnosis, chemotherapy is the mainstay of management. Elderly patients often present with medical and physiological characteristics that make the selection of their optimal treatment more challenging. Unfortunately, as a result, these patients are at risk of being undertreated and being included in clinical trials only rarely. Moreover, many of these patients have preexisting comorbid conditions that, independently of cancer-related symptoms, may adversely affect organ function and influence functional status. Furthermore, comorbidities often require treatment with multiple drugs, which may interfere with cancer treatment or its toxicity profile. In this issue of the Journal of Clinical Oncology, Asmis et al evaluated age and comorbidities as independent prognostic factors in the treatment of NSCLC through a retrospective analysis of two studies carried out by the National Cancer Institute of Canada Trials Group.1 The authors analyzed elderly patients older than 65 years and enrolled onto a randomized phase II/III study (BR.18) that compared the combination of carboplatin, paclitaxel, and an oral metalloproteinase inhibitor to carboplatin plus paclitaxel alone in advanced NSCLC, and onto a phase III study (BR.10) that addressed the role of adjuvant cisplatin plus vinorelbine chemotherapy in stage I to II NSCLC. They found that although age did not influence survival, the presence of comorbid conditions was associated with poor survival. These results should be interpreted with caution for the following reasons: the study pooled two patient populations affected by different stages of disease, early and advanced; the cutoff age of 65 years of age in defining elderly patients; the risk of selection bias occurring with this kind of retrospective analyses. In fact, usually only a low percentage of elderly patients is enrolled onto studies without an upper age limit. Therefore, the elderly patients enrolled onto these trials may be not representative of the whole elderly population, but rather of a small subgroup which the investigators considered eligible for aggressive treatments.2 The selection of elderly patients enrolled into the adjuvant BR.10 trial should be taken in particular consideration because these patients underwent major surgery and were considered suitable for aggressive, cisplatin-based adjuvant chemotherapy. We should consider that it is very difficult to establish a cutoff age in defining an elderly cancer patient. Within the epidemiologic literature, age 65 years is usually considered as a cut point to select elderly population. On the contrary, in clinical trials, the age of 70 is frequently used as the lower limit for patient selection, whereas a cutoff age of 75 years is less common. For these reasons, indirect comparison of trials including or not including patients age 65 to 70 years may be biased. In clinical practice, biologic instead of chronological age should be considered. Unfortunately, to date, laboratory tests and geriatric evaluation are inadequate to define aging. A comprehensive geriatric assessment (CGA), which has proven to provide more indications compared with the performance status assessment alone, ought to be carried out. The CGA should include evaluation of comorbidities, socioeconomic issues, nutritional status, polypharmacy, functional dependence, emotional and cognitive conditions, an estimate of life expectancy, and recognition of frailty. Nevertheless, a CGA may be too lengthy in busy clinical practice. Therefore, validated and shorter screening instruments are needed. Of these, the evaluation proposed by the Cardiovascular Health Study, which allows for the classification of elderly patients into three groups (fit, prefrail, frail) according to five items (unintentional weight loss, self-reported exhaustion, weakness, walking speed, and level of physical activity),3 has gained particular prominence because it is well correlated with mortality and risk of functional dependence. This classification has been proposed as a standard language for the classification of older individuals. However, at present, chronological age should be used as a frame of reference for clinical trials, and a cutoff of 70 years of age seems to be the most appropriate. In fact, 70 years of age may be considered as the lower boundary of senescence, because the incidence of age-related changes starts to increase after this age.4 Eight years ago, we showed that single-agent vinorelbine improves survival and quality of life compared with best supportive care in elderly advanced NSCLC patients.5 Two large randomized phase III trials showed that non–platin-based doublets including gemcitabine plus vinorelbine and gemcitabine plus docetaxel failed to improve survival, and with increasing toxicity, compared single-agent chemotherapy.6,7 With the currently available evidence, single-agent chemotherapy with a third-generation agent (gemcitabine, vinorelbine, taxanes) could be considered a reasonable treatment option for elderly advanced NSCLC patients.8,9 However, which single agent? Several factors should be considered by the clinician when choosing the drug to be administered. This choice should take into account the expected toxicity profile of the agent, pharmacokinetics, organ function, and comorbidities. Cisplatin-based chemotherapy may represent a valid option for fit elderly patients with adequate organ function. Data for cisplatin- and carboplatin-based therapy for elderly patients with advanced NSCLC come from retrospective analyses of large randomized trials without an upper age limit. These suggest that the efficacy of platin-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. However, it must be noted, as already discussed herein, that the aforementioned analyses have a risk of selection bias, and that there is the need for randomized phase III trials with adequate power comparing platin-based chemotherapy to single-agent chemotherapy. Few data exist regarding the outcome of chemotherapy in NSCLC patients 80 years of age or older, a rapidly expanding, potentially vulnerable population cohort. The second article dedicated to the elderly lung cancer patients in this issue of the Journal of Clinical Oncology is by Ramalingam et al,10 who carried out an unplanned retrospective analysis of Eastern Cooperative Oncology Group (ECOG) trial 4599 comparing the combination of bevacizumab, carboplatin, and paclitaxel against carboplatin plus paclitaxel in advanced NSCLC, and presented the outcome for elderly patients.9 The authors reported no survival benefit for the elderly when adding bevacizumab to cisplatin-based chemotherapy, in contrast to the survival advantage observed in the general patient population. This can be explained mainly by the higher toxicity of bevacizumab plus chemotherapy compared with chemotherapy alone reported in the elderly group. In fact, grade 3 to 5 toxicities were noted in 87% of elderly patients treated with bevacizumab, paclitaxel, and carboplatin compared with 61% with paclitaxel plus carboplatin (P < .001). Treatment-related death rates with chemotherapy plus bevacizumab versus chemotherapy alone were 6.3% versus 1.8% for the elderly. Febrile neutropenia (6% v 0.9%), proteinuria (8% v 0), and hypertension (6% v 0.9%) were more common with chemotherapy plus bevacizumab than chemotherapy alone among the elderly. To date, no prospective data of bevacizumab in elderly advanced NSCLC patients are available; however, the drug does not appear particularly suitable for the elderly population, often affected by cardiovascular comorbid conditions and with a more frequent squamous histology.6 Merza et al have retrospectively studied 106 male elderly patients diagnosed with advanced NSCLC in the past 3 years in their center, and have identified the factors that would have excluded patients from participating in clinical trials with bevacizumab.11 The authors used the exclusion criteria as per ECOG 4599, and an open industry-sponsored trial (erlotinib ± bevacizumab for second-line treatment of NSCLC). Patients with squamous predominant histology (n = 26) were excluded. Of the remaining 80 patients evaluated for use of bevacizumab, 72 (90%) met one or more exclusion criteria. The majority of the factors, which would have contraindicated the use of bevacizumab in this patient population, were cardiovascular comorbidities, which are reported with high incidence in elderly NSCLC patients. This retrospective analysis, although performed in a small population, suggests that there may be further limits to treatment in elderly NSCLC patients, with overall approximately only 10% of patients suitable for bevacizumab. However, even considering the risk of bias of this kind of retrospective analysis, further evaluation of bevacizumab in elderly advanced NSCLC patients should be made with caution and careful patient selection. Future fields of investigation may be the use of a lower dose of bevacizumab (7.5 v 15 mg/kg); the combination of bevacizumab with platin-based chemotherapy using attenuated doses of cisplatin or carboplatin; the combination of bevacizumab with single-agent chemotherapy; and the combination of bevacizumab with other active targeted therapies such as erlotinib or gefitinib. In conclusion, we need to better define the elderly to select the optimal treatment for elderly patients with advanced NSCLC. Single-agent chemotherapy? Platin-based chemotherapy at standard doses or at attenuated doses or with modified schedule? Targeted therapies? Large prospective randomized trials specifically dedicated to the elderly, including validation of objective measures of biologic age, are warranted. The role of bevacizumab in the elderly should be better defined with caution; however, the angiogenesis target needs to be independently developed considering the promising activity and toxicity profile of other drugs such as ZD6474. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Cesare Gridelli, Eli Lilly (C), Roche (C) Stock Ownership: None Honoraria: Cesare Gridelli, Eli Lilly, Roche Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES 1. Asmis T, Ding K, Seymour L, et al: Age and comorbidities as independent prognostic factors in the treatment of non-small cell lung cancer: A review of the National Cancer Institute of Canada Trials Group Trials. J Clin Oncol 26:53-58, 2008 2. Perrone F, Gallo C, Gridelli C: 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 94:1029-1030, 2002 3. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: Evidence for a phenotype. J Gerontol A 56:M146-M156, 2001[CrossRef] 4. Balducci L: Geriatric oncology: Challenges for the new century. Eur J Cancer 36:1741-1754, 2000[CrossRef][Medline] 5. The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non small cell lung cancer. J Natl Cancer Inst 91:66-72, 1999 6. 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 95:362-372, 2003 7. Greco FA, Spigel DR, Burris HA, et al: Weekly docetaxel versus docetaxel/gemcitabine in elderly/poor performance status (PS) patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC): Randomised phase III trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 25:393s, 2007 (suppl; abstr 7534) 8. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004 9. Gridelli C, Aapro M, Ardizzoni A, et al: Treatment of advanced non-small-cell lung cancer in the elderly: Results of an international expert panel. J Clin Oncol 23:3125-3137, 2005 10. Ramalingam SS, Dalhberg SE, Langer C, et al: Outcome for elderly advanced non-small cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: Analysis of the ECOG 4599 study. J Clin Oncol 26:60-65, 2008 11. Merza T, Howard LM, Junagadhwalla M: Exclusions to use of bevacizumab in elderly veterans with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 25:687s, 2007 (suppl; abstr 18046)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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