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The Oncologist, Vol. 8, No. 3, 270–277, June 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Lung Cancer

Chemotherapy Options for the Elderly Patient with Advanced Non-Small Cell Lung Cancer

B.T. Hennessya, E.O. Hanrahanb, O.S. Breathnacha,c

a Department of Medical Oncology, Cork University Hospital, Cork, Ireland; b Department of Medical Oncology, Mater Misericordiae Hospital, Dublin, Ireland; c Mercy University Hospital, Cork, Ireland

Correspondence: Bryan Hennessy, M.D., Department of Medical Oncology, Cork University Hospital, Wilton, Cork, Ireland. Telephone: 353-85-722-7666; Fax: 353-21-492-1346; e-mail: bryanhen{at}gofree.indigo.ie


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Advanced NSCLC Treatment
 Elderly Patients
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Describe the available clinical trial data of chemotherapy for advanced non-small cell lung cancer in elderly patients.
  2. Compare older chemotherapy combinations with newer single agents in the treatment of advanced non-small cell lung cancer.
  3. Identify reasons why elderly patients with lung cancer have been excluded from clinical trials.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Advanced NSCLC Treatment
 Elderly Patients
 Conclusion
 References
 
Combination chemotherapy has been shown to improve overall survival compared with best supportive care in patients with advanced non-small cell lung cancer (NSCLC). The survival advantage is modest and was initially demonstrated with cisplatin-containing regimens in a large meta-analysis of randomized trials reported in 1995. Newer chemotherapy combinations have been shown to be better tolerated than older cisplatin-based combinations, and some trials have also shown greater efficacy and survival benefits with these newer combinations. Combination chemotherapy is, therefore, the currently accepted standard of care for patients with good performance statuses aged less than 70 years with advanced NSCLC. However, there are limited data from clinical trials to support the use of combination chemotherapy in elderly patients over 70 years of age with advanced NSCLC. Subgroup analyses of large randomized phase III trials suggest that elderly patients with good performance statuses do as well as younger patients treated with combination chemotherapy. There are few randomized trials reported that evaluate chemotherapy in patients aged greater than 70 years only. Based on data from trials performed by an Italian group, single-agent vinorelbine has been shown to have significant activity in elderly patients with advanced NSCLC and to be well tolerated by those patients with Eastern Cooperative Oncology Group performance statuses of two or less, with associated improvements in measures of global health.

Key Words. Non-small cell lung cancer • Chemotherapy • Vinorelbine • Gemcitabine • Elderly


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Advanced NSCLC Treatment
 Elderly Patients
 Conclusion
 References
 
Combination chemotherapy became the standard treatment for patients, aged less than 70 years with good performance statuses with advanced non-small cell lung cancer (NSCLC) based on the results of a large meta-analysis of clinical trials prior to 1991, which demonstrated a survival advantage with cisplatin-containing regimens [1, 2]. The preliminary results of the Big Lung Trial (BLT), which were reported recently, confirm this finding [3]. In fear of potential toxicity, however, chemotherapy is often withheld from elderly patients and patients with poorer performance statuses [4]. Newer chemotherapy combinations have recently been shown to be better tolerated than older cisplatin-based combinations, and some trials have also shown greater efficacy and survival benefits with these newer combinations [5–10]. Thus, for example, the reference regimen of the Eastern Cooperative Oncology Group (ECOG) is now paclitaxel and carboplatin.

However, there are less data to support the use of chemotherapy in older patients (>70 years) or in individuals with poorer performance statuses and, therefore, there is more uncertainty. Whether these patients are best served by single-agent chemotherapy or by nonchemotherapeutic palliative care alone continues to be a matter of debate in certain countries. The purpose of this review is to describe the available literature pertaining to the use of chemotherapy for advanced NSCLC in elderly patients aged 70 years and over.


   ADVANCED NSCLC TREATMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Advanced NSCLC Treatment
Elderly Patients
 Conclusion
 References
 
Chemotherapy in patients with advanced NSCLC has been shown to improve overall survival in comparison with best supportive care. The survival advantage is, however, modest and was initially demonstrated with cisplatin-containing regimens in a large meta-analysis of randomized trials [1]. Cisplatin-based combination chemotherapy was shown to produce a 26% reduction in the hazard rate of death. Subsequently, in 1996, the American Society of Clinical Oncology published guidelines on the treatment of patients with advanced NSCLC [2]. According to these guidelines, treatment with a cisplatin-based combination should be offered to patients with stage IV NSCLC if they have good performance statuses (ECOG 0 or 1). The superiority of cisplatin-based chemotherapy over best supportive care alone was reconfirmed in the recently reported BLT [3]. However, because of the potential toxicities of combined cisplatin-based chemotherapy regimens and the modest survival benefits, this treatment is not offered to many elderly patients or patients with poorer performance statuses [4].

In more recent trials, newer platinum-based cytotoxic combination regimens generally have been shown to have advantages over older two-drug cisplatin-based regimens (Table 1Go). These trials point to benefits in efficacy, toxicity, and quality of life with the newer regimens [5–10] and have led to the general acceptance of the newer combinations as standard treatment for stage IV NSCLC. These newer combinations probably all have equivalent efficacy [11], with carboplatin-containing regimens being generally as effective as cisplatin-containing regimens and easier to administer. New chemotherapy doublets have also been shown to be superior to single agents (both cisplatin and newer agents) in randomized trials, with higher response rates, longer median survival times, and 1-year survival advantages of 4%–15% [12–16]. In addition, nonplatinum-based regimens have demonstrated statistically equivalent efficacy to the new platinum-based regimens in randomized trials [17–20], although the trend toward inferior survival in the nonplatinum arm of one trial [17] has led to some controversy. Nonplatinum-based regimens are somewhat less toxic and more convenient than cisplatin-containing combinations.


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  		Table 1. Results of some randomized trials comparing old cisplatin (CDDP)-based chemotherapy combinations with second-generation chemotherapy combinations in patients with advanced NSCLC
 
There had been much excitement related to the early data on ZD1839 (Iressa) as a minimally toxic therapy with clinically significant activity that might herald a change in the management of patients with advanced NSCLC. However, the Iressa NSCLC Trial Assessing Combination Treatment 1 (INTACT 1) and INTACT 2 trials have shown no benefit in advanced NSCLC from the addition of the tyrosine kinase inhibitor Iressa (ZD1839) to combination chemotherapy [21]. The optimal usage of this novel agent and other targeted therapies has yet to be defined in patients with NSCLC.


   ELDERLY PATIENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Advanced NSCLC Treatment
 Elderly Patients
Conclusion
 References
 
Elderly patients and patients with poorer performance statuses are often excluded from clinical trials. This applies not only to studies evaluating cytotoxic chemotherapy in advanced NSCLC, where it was generally considered that these patients experienced higher toxicity rates with marginal survival advantages, especially with older cisplatin-based combinations, but also to clinical trials of chemotherapy and other treatments in other types of cancer. While the enrollment rates for women and African Americans in Southwest Oncology Group (SWOG) trials of cancer treatment were similar to the proportions of women and African Americans in the U.S. population of patients with cancer, the enrollment rate for patients 65 years of age and older was unexpectedly low. Potential reasons for this underrepresentation of patients aged 65 years and older in cancer-treatment trials include misconceptions about the benefits of enrollment in clinical trials for older patients on the part of the patients themselves, their family members, or their physicians, stringent eligibility criteria, coexisting medical conditions, logistic and financial barriers, and perceived increased toxicity with advancing age [22, 23]. In a survey of U.S. oncologists, 80% of those who responded agreed that patients in clinical trials had better outcomes, but 50% would deem a patient unsuitable for enrollment in a clinical trial based on age alone [24]. Elderly patients often have comorbid conditions and reduced functional reserve. Oshita et al. [25] found only 29% of patients with advanced NSCLC over 75 years of age satisfied their eligibility criteria for treatment with cisplatin-based chemotherapy. They regarded the remainder as ineligible because of comorbidities, most commonly ischemic heart disease, and poor performance statuses. Of the patients with advanced NSCLC treated with chemotherapy, the majority experienced severe myelosuppression and infections. They concluded that chemotherapy should be given to elderly patients only after careful consideration, even if they appear to have normal organ function. As a result of the low numbers of elderly patients enrolled in cancer clinical trials, there are little data on the toxicity and efficacy of chemotherapy in older people, and thus it is not surprising that oncologists are often reluctant to treat these patients with potentially toxic therapy.

Changes occur in drug metabolic and excretory pathways with aging. Hepatic drug-metabolizing enzyme activity, particularly of the P450 microsomal system, is approximately 30% lower in healthy elderly people than in their younger counterparts, and glomerular filtration rate falls by approximately 1 ml/minute for every year over the age of 40 [26]. Thus, the toxicities of drugs removed by those pathways can be expected to be greater in elderly patients. Chemotherapy drugs that must be used carefully in elderly people, with consideration given to dose reduction, include methotrexate, topotecan, some oral fluoropyrimidines, etoposide, doxorubicin, and cisplatin [26]. Many recently approved drugs, however, have an improved therapeutic index and a broad range of activity in the elderly. These include gemcitabine, docetaxel, paclitaxel, vinorelbine, some oral fluoropyrimidines, irinotecan, and liposomal drug formulations [27]. This list includes many of the newer drugs shown to have activity in NSCLC. With carboplatin, dose calculation using a targeted area under the concentration time curve and taking renal function changes with age into account allows for safe delivery. More studies are needed, however, regarding chemotherapy toxicities, metabolism, and effects in the elderly population.

In a pilot study addressing tolerance to chemotherapy in an unselected group of older cancer patients treated in a tertiary referral center, Extermann et al. found that the ability to deliver chemotherapy was excellent [28]. Thirteen percent of the patients stopped treatment due to toxicity. Many patients experienced significant side effects, but support structures, such as a tertiary care center and a specialized geriatric oncology program, allowed toxicity management and treatment continuation. The study identified some baseline factors associated with the occurrence of the toxicity-MAX2 index (a score based on published toxicities of various chemotherapy regimens), bone marrow invasion, diastolic blood pressure, and pretreatment lactate dehydrogenase level. Factors associated with lower delivered dose intensity (a surrogate for tolerance) were lower body mass index, previous treatment with another chemotherapy, polypharmacy, and lower baseline red blood cell and platelet counts. Performance status and comorbidity were surprisingly absent from the significant variables in this study. Age alone was not associated with tolerance to chemotherapy.

Though available randomized controlled trial data on the efficacy and tolerability of chemotherapy in elderly patients with cancer are lacking, retrospective subgroup statistical analysis using clinical trial data [29–32] and examination of the Surveillance, Epidemiology, and End Results Medicare database using multivariate analysis and propensity score methodology [33, 34] both provide evidence that chemotherapy for elderly patients seems to have an effectiveness that approaches the benefits seen in randomized trials with mostly younger, highly selected patients, without excessive toxicity. Such retrospective analyses have addressed many forms of cancer, including colorectal, breast, and lung.

Inclusion of elderly patients in randomized clinical trials of chemotherapy is essential to allow generalization of the results to the entire population. After all, more than half of all new cancers in the U.S. occur in patients 65 years of age and older [35], and the incidence of cancer in this age group is 11 times that in the population under 65. The prognosis of the general population cannot be inferred from a selected group of patients in a trial. Elderly-specific trials of chemotherapy are also essential to allow us to apply evidence-based medicine to the treatment of cancer in older patients, the burden of which can only increase as the population longevity increases.

Treatment of Advanced NSCLC in the Elderly
More than 50% of lung cancers arise in patients aged over 65 years, and the median age of patients with advanced lung cancer is 68 years [36]. Yet the optimal treatment for many patients with stage IV NSCLC has not been defined because of the frequent exclusion of elderly patients from clinical trials. Elderly patients differ in fundamental pharmacokinetic characteristics, such as drug metabolism and excretion, volume of distribution, and drug absorption. For these reasons, it is not valid to infer that they derive the same benefit from chemotherapy as younger, highly selected patients treated in clinical trials. Elderly-specific trials of chemotherapy for advanced lung cancer are needed to properly address the question of how best to treat older patients—a population of more than 60,000 people in the U.S. aged over 65 years diagnosed annually with lung cancer, many of whom will have metastatic disease [37].

Many of the newer chemotherapeutic agents are better tolerated than older cisplatin-based combinations, with favorable therapeutic indices in the elderly. These newer agents alone (e.g., vinorelbine and gemcitabine) have proven to have equivalent efficacy to the older cisplatin-based combinations in clinical trials (Table 2Go). Three randomized phase II and III trials [38–40] have shown single-agent gemcitabine to be as effective in terms of response rate and survival as cisplatin/etoposide or cisplatin/vindesine, but less toxic and more convenient. Other trials have produced similar findings for single-agent vinorelbine and irinotecan (CPT-11) [6, 41].


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  		Table 2. Results of randomized trials of chemotherapy for advanced NSCLC showing no significant difference in outcomes between single-agent therapy with newer drugs and treatment with older cisplatin (CDDP)-based combinations
 
It may, therefore, be reasonable to treat some elderly patients with advanced NSCLC with single agents such as vinorelbine or gemcitabine (Table 3Go). Because of the success of weekly vinorelbine in phase II study [42], a phase III trial, the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) was performed, comparing best supportive care with best supportive care plus weekly vinorelbine in patients over the age of 70 years with advanced NSCLC [43]. The objective response rate in the vinorelbine group was 19.7%. Median survival was significantly longer in the chemotherapy arm (28 versus 21 weeks, p = 0.03), and 1-year survival was significantly higher in the vinorelbine arm also (32% versus 14%). These differences are similar to those described in younger patients. Single-agent vinorelbine was well tolerated and had a positive impact on quality of life compared with best supportive care. Of note, vinorelbine was administered on days 1 and 8 every 3 weeks in the ELVIS trial as opposed to weekly as it was in the phase II trial. As a result, the rate of grade 3–4 leukopenia was lower in the ELVIS study at 7% of patients compared with 33% of patients in the phase II trial.


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  		Table 3. Results of trials of chemotherapy for advanced NSCLC in elderly patients over the age of 70 years
 
Two trials have directly compared a two-drug combination with single-agent therapy in elderly patients with advanced NSCLC. Frasci et al. [44] demonstrated that gemcitabine and vinorelbine combination therapy was associated with significantly better survival in patients with advanced NSCLC over the age of 70 years than vinorelbine alone. In the combination and single-agent arms, respectively, median survival times were 29 weeks and 18 weeks, 1-year survival rates were 30% and 13%, and response rates were 22% and 15%. Combination therapy was also associated with a clear delay in symptom progression and deterioration in quality of life. However, the outcome of the vinorelbine-treated group in this trial was worse than the outcome of the groups treated with this agent in the trials of Gridelli et al. [42, 43] despite the fact that a greater proportion of patients in the ELVIS trial had stage IV versus IIIB disease and over 80% of patients in the ELVIS trial had ECOG performance statuses of 1 or 2. The reasons for this difference are not clear. In the Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of Gridelli et al. [45], patients over the age of 70 with stage IIIB or IV NSCLC were randomized to treatment with gemcitabine, vinorelbine, or a combination of the two agents. There were no significant differences in survival among the arms. Median survival was longest in the vinorelbine alone group (37 weeks) and shortest in the gemcitabine alone group (28 weeks). The 1-year survival rates were also highest in the former arm (42%) and lowest in the latter arm (28%). The combination group fell between the single-agent arms. Toxicity was regarded as tolerable in all three arms. Again, patients treated with vinorelbine alone had better results than in the trial of Frasci et al. [44].

Table 4Go summarizes the results of subgroup analyses performed on some large phase III trials of chemotherapy for advanced NSCLC to investigate whether patients over 70 years of age did as well as younger patients. Langer et al. [46] performed a retrospective analysis of ECOG 5592, a phase III randomized trial of cisplatin plus either etoposide or paclitaxel for advanced NSCLC, and compared outcomes in enrollees 70 years of age and older (15% of total) with those of younger patients. Leukopenia and neuropsychiatric toxicity were significantly more common in elderly than in younger men, and elderly women lost significantly more weight than younger women. Other toxic effects were similar between older and younger patients. The objective response rates (21.5% versus 23.3%, p = 0.66), median times to progression (4.37 versus 4.3 months, p = 0.29), median survival times (9.05 versus 8.53 months, p = 0.29), and 1-year survival rates (38% versus 29%, p = 0.29) were similar in younger and older groups (respectively). The researchers concluded, therefore, that advanced age alone should not preclude appropriate NSCLC treatment. Single-agent paclitaxel was compared with the combination of paclitaxel and carboplatin by the Cancer and Leukemia Group B (CALGB) trialists [12]. The combination proved to be significantly superior in terms of response rate (30% versus 16%), median survival time (36.8 versus 28.2 weeks), and 1-year survival rate (37% versus 33%). In a subset analysis of those patients aged 70 years and older, the drug combination was associated with a 2 month longer median survival time (8 versus 5.8 months) and a higher 1-year survival rate (35% versus 31%). These differences were not significant in this subset analysis (small numbers). However, there was not a major difference between the outcomes for the elderly group and those for the entire study group.


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  		Table 4. Results of subgroup analyses performed on some large phase III trials to investigate how elderly patients over the age of 70 years did with combination chemotherapy for advanced NSCLC in comparison with younger patients
 
Kelly et al. [47] performed an analysis to determine the effect of age older than 70 years on survival, toxicity, and drug delivery in patients with good performance statuses receiving combination chemotherapy for advanced NSCLC on SWOG protocol 9509, a randomized trial comparing carboplatin and paclitaxel with vinorelbine and cisplatin, and SWOG 9308, a randomized phase III trial comparing cisplatin and vinorelbine with cisplatin alone. They found that only 19% of patients in the combination arms of both trials were aged over 70 years. Grade 3–5 toxicities on the drug combination arms of these two trials, both hematological and nonhematological, were similar between the two age groups, that is, those older and those younger than 70 years, although there was a trend toward more toxicity in the older group. There was also a trend toward shorter median survival in the older group (8.6 versus 6.9 months, p = 0.06) and the 1-year survival rate was somewhat higher in the younger group (40% versus 30%). These differences are probably a reflection of advanced age and more frequent comorbidities in the older group. Fewer patients of any age were able to complete vinorelbine/cisplatin treatment compared with paclitaxel/carboplatin treatment, and significantly more older patients discontinued vinorelbine/cisplatin due to toxicity. These results suggest that elderly patients with good performance statuses do almost as well as younger patients with combination chemotherapy for advanced NSCLC, although they may experience somewhat more toxicities, particularly when the platinum used is cisplatin.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Advanced NSCLC Treatment
 Elderly Patients
 Conclusion
References
 
Chemotherapy is an appropriate intervention for elderly patients with advanced NSCLC with good performance statuses (ECOG 0–2). The trials described above, which were designed specifically to evaluate chemotherapeutic agents in elderly patients with advanced NSCLC, suggest single-agent chemotherapy with vinorelbine is a good approach to treatment, is well tolerated, and is as effective as the combinations with which it has been compared. Single-agent gemcitabine is a reasonable alternative or second-line approach; taxanes have not received the same evaluation in phase III trials in the elderly. The subset analyses of large randomized trials using combination therapy suggest that combination chemotherapy with newer combinations is almost as well tolerated in older as in younger patients, particularly when carboplatin is used, and the newer combinations are associated with improved response rates. It is, however, likely that patients 70 years or older will be treated with single-agent chemotherapy regimens. The role of novel agents in elderly patients with NSCLC has yet to be established.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Advanced NSCLC Treatment
 Elderly Patients
 Conclusion
 References
 

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Received January 2, 2003; accepted for publication February 28, 2003.




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