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Elderly Patients Benefit From Second-Line 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

Glen J. Weiss, Corey Langer, Rafael Rosell, Nasser Hanna, Frances Shepherd, Lawrence H. Einhorn, Binh Nguyen, Sofia Paul, Patrick McAndrews, Paul A. Bunn, Jr, Karen Kelly

From the University of Colorado Health Sciences Center, Division of Medical Oncology Center, Aurora, CO; Fox Chase Cancer Center, Philadelphia, PA; Catalan Institute of Oncology, Barcelona, Spain; Indiana University Medical Center; Eli Lilly and Co, Indianapolis, IN; and the Princess Margaret Hospital, Toronto, Ontario, Canada

Address reprint requests to Karen Kelly, MD, University of Colorado Health Sciences Center, Division of Medical Oncology Center, Aurora, CO 80010; e-mail: Karen.Kelly{at}uchsc.edu

	ABSTRACT

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PURPOSE: Numerous prospective and retrospective studies have concluded that elderly patients ( 70 years old) achieve a similar survival benefit, with acceptable toxicity, from first-line cytotoxic chemotherapy for the treatment of advanced non–small-cell lung cancer (NSCLC) compared with their younger counterparts. However, few published data exist on the efficacy and tolerability of second-line cytotoxic therapy in this population.

PATIENTS AND METHODS: Retrospective analysis of a large second-line trial was performed. Data from 571 patients randomly assigned to docetaxel 75 mg/m² or pemetrexed 500 mg/m² every 3 weeks were analyzed for efficacy and toxicity comparisons between age groups and treatment arms.

RESULTS: Eighty-six of 571 patients (15%) were 70 years old, similar to rates of elderly observed in the first-line setting. Elderly patients receiving pemetrexed (n = 47) or docetaxel (n = 39) had a median survival of 9.5 and 7.7 months compared with 7.8 and 8.0 months for younger patients receiving pemetrexed (n = 236) or docetaxel (n = 249), respectively. Elderly patients treated with pemetrexed had a longer time to progression and a longer survival than their counterpart patients treated with docetaxel (not statistically significant). Febrile neutropenia was less frequent in elderly patients treated with pemetrexed (2.5%) compared with docetaxel (19%; P = .025), with only one death as a result of toxicity (docetaxel arm).

CONCLUSION: Elderly patient participation was similar to rates observed in the first-line setting. There was no significant difference in outcome or toxicity between elderly and younger patients. For elderly patients with advanced NSCLC and good performance status, second-line cytotoxic therapy is appropriate. In this subset, pemetrexed produced a more favorable toxicity profile.

	INTRODUCTION

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Elderly patients, defined as those 70 years old or older, constitute at least half of the patients diagnosed with lung cancer in the United States, and most of these patients will have advanced disease.¹ Some physicians may be reluctant to administer cytotoxic chemotherapy to elderly patients because of the belief that chemotherapy is palliative at best in this setting, and produces significant and life-threatening toxicities without prolonging survival. However, numerous retrospective and prospective studies have concluded that elderly patients with good performance status tolerate chemotherapy sufficiently well with the same degree of palliation and survival benefit.^2-10 Thus, chemotherapy is the standard of care for the first-line treatment of advanced lung cancer for elderly patients with good performance status. Current American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines recommend a single-agent regimen; however, nonplatinum- and platinum-based doublets may also be considered.^11,12

Second-line chemotherapy has prolonged survival in patients with advanced lung cancer. Two chemotherapy agents, docetaxel and pemetrexed, are approved by the US Food and Drug Administration in this setting. In an international study of 204 patients, Shepherd et al¹³ compared docetaxel 75 to 100 mg/m² to best supportive care. Patients in the docetaxel 75 mg/m² arm had a median survival of 7.5 v 4.6 months in the control arm, which translated into a superior 1-year survival rate of 37% v 12% (P = .003), respectively. Fossella et al¹⁴ compared docetaxel 75 or 100 mg/m² to the control group of either vinorelbine or ifosfamide in 373 patients. Patients treated with docetaxel had significantly longer time to progression compared with the control group (P = .046). Overall survival did not differ between the arms, but the 1-year survival was 32% for docetaxel 75 mg/m² versus 19% for vinorelbine or ifosfamide (P = .025). In a large second-line trial of cytotoxic chemotherapy (571 patients), Hanna et al¹⁵ demonstrated the noninferiority of pemetrexed to docetaxel, with median survival time of 8.3 and 7.9 months, respectively (hazard ratio [HR], 0.99; 95% CI, 0.82 to 1.2). Both agents differ in their toxicity profile, but were found to be well tolerated in all studies.^13-15

Although elderly patients benefit from first-line chemotherapy, few published data exist on their ability to derive similar benefit from second-line chemotherapy. To address this issue, we conducted a retrospective analysis of the phase III, randomized trial comparing elderly patients and younger patients treated with chemotherapy, and comparing treatment arms in the elderly and younger study groups.¹⁵

	PATIENTS AND METHODS

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All patients had histologic or cytologic confirmation of non–small-cell lung cancer (NSCLC) with stage III or IV disease. Patients must have received one prior chemotherapy regimen for the treatment of advanced disease, and those who received prior neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy were also eligible. Patients were required to be 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 2. Measurable or assessable disease and adequate bone marrow, hepatic, and renal function were required. Exclusion criteria included prior docetaxel or pemetrexed treatment, grade 3 peripheral neuropathy, significant weight loss ( 10% body weight during the previous 6 weeks), uncontrolled pleural effusions, symptomatic or uncontrolled brain metastases, or an inability to interrupt nonsteroidal anti-inflammatory drugs. The protocol was approved by each institution's ethical review board, and all patients provided written informed consent before treatment.

Treatment Plan
Patients were randomly assigned to receive either docetaxel 75 mg/m² or pemetrexed 500 mg/m². Patients in the pemetrexed group were instructed to take folic acid daily and received intramuscular injections of vitamin B₁₂ every 9 weeks. Cycles were repeated every 3 weeks until disease progression, unacceptable toxicity, or the patient/investigator requested therapy discontinuation. For both arms, premedication with dexamethasone was required. The antiemetic regimen was determined by the treating physician. A maximum of two dose reductions was allowed based on nadir counts or clinically significant nonhematologic toxicities. Dose delays up to 42 days from day 1 of the current cycle were permitted for recovery from adverse events. Granulocyte colony-stimulating factor support was allowed.

Baseline assessment included a history and physical examination, CBC, comprehensive blood chemistry, vitamin metabolite panel, calculated creatinine clearance, computed tomography scan of the chest and upper abdomen, and chest x-ray. If clinically indicated, bone scans and brain imaging were performed. Evaluation of toxicity was based on the National Cancer Institute Common Toxicity Criteria, version 2.¹⁶ Hematologic measurements were completed weekly, whereas chemistry values were evaluated after days 1 and 8 of each cycle. After every two cycles, tumor measurements were assessed.

Statistical Analysis
The retrospective statistical analysis compared efficacy and safety for elderly ( 70 years) and younger (< 70 years) study groups. Comparison of treatment arms (docetaxel or pemetrexed) was also performed within the study groups. Unless otherwise stated, all tests of hypotheses were conducted at the = .05 level, with a 95% CI.

The Cox proportional hazards model was used for the comparison of survival and time to progression between the two treatment arms in the elderly and younger study groups. Kaplan-Meier estimates were used to assess medians and percentiles. Comparison of the tumor response rates between the two treatment arms was made using the Fisher's exact test with 95% CI calculated using the method of Leemis and Trivedi,¹⁷ whereas age and homocysteine level comparisons were made using two-factor analysis of variance without replication. The incidence of Common Toxicity Criteria toxicities was analyzed using Fisher's exact test.

	RESULTS

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From March 2001 through February 2002, 571 patients were randomly assigned to receive either docetaxel (n = 288) or pemetrexed (n = 283). Eighty-six of the 571 patients (15%) were 70 years old. In the docetaxel group, the median age of the elderly patients was 73 (n = 39; range, 70 to 87 years), whereas the younger patients had a median age of 56 (n = 249; range, 28 to 69 years). In the pemetrexed group, the median age of the elderly patients was 74 (n = 47; range, 70 to 81 years), whereas the younger patients had a median age of 57 (n = 236; range, 22 to 69 years). Baseline characteristics for the two age groups are listed in Table 1. There were no significant differences in clinical features between the two groups, except for stage at diagnosis, with a higher percentage of stage III disease in elderly patients.

View larger version (14K): [in this window] [in a new window]   Fig 1. Median time to progression (A) for patients younger than 70 years of age: pemetrexed, 3.0 months v docetaxel, 3.9 months (hazard ratio [HR], 1.03; 95% CI, 0.83 to 1.26); (B) for patients 70 years of age: pemetrexed, 4.6 months v docetaxel, 2.9 months (HR, 0.72; 95% CI, 0.43 to 1.21).

View larger version (13K): [in this window] [in a new window]   Fig 2. Median overall survival time (A) for patients younger than 70 years of age: pemetrexed, 7.8 months v docetaxel, 8.0 months (hazard ratio [HR], 1.02; 95% CI, 0.82 to 1.26); (B) for patients 70 years of age: pemetrexed, 9.5 months v docetaxel, 7.7 months (HR, 0.86; 95% CI, 0.53 to 1.42).

Toxicity
Five hundred forty-one patients were assessable for toxicity. Grade 3/4 toxicities by age group are summarized in Table 3. Grade 3/4 hematologic toxicity included the following: neutropenia, febrile neutropenia, infection with grade 3/4 neutropenia, anemia, and thrombocytopenia. Overall, elderly patients tolerated second-line chemotherapy as well as their younger counterparts; however, incidence of febrile neutropenia was slightly higher for elderly patients (10.4% v 6.9%; P = .343). Within the elderly population, patients administered docetaxel had more hematologic toxicity compared with patients administered pemetrexed, including neutropenia (29.7% v 12.5%; P = not significant), febrile neutropenia (18.9% v 2.5%; P = .025), and anemia (2.7% v 0%; P = not significant). Muscle weakness was more frequent in the pemetrexed arm (5.0%; two patients) versus the docetaxel arm (0%), but the difference was not statistically significant. Overall, there were four treatment-related deaths, but only one occurred in an elderly patient. This elderly patient was in the docetaxel arm.

	DISCUSSION

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This analysis shows that elderly patients can have as much benefit from second-line cytotoxic chemotherapy as younger patients, and this can be achieved with acceptable toxicity rates. Moreover, therapy with pemetrexed produced longer survival and lower febrile neutropenia than docetaxel in elderly patients, although these differences failed to reach statistical significance. There was no significant difference in outcome (response, TTP, median OS), toxicity, or drug delivery between elderly and younger patients. Baseline demographics between the two age groups were similar, except for a higher percentage of stage III patients at diagnosis in the elderly population. This baseline characteristic was no longer significant, with analysis within the age groups by treatment arm. Although the size of the elderly population in this retrospective study limits the statistical power of this analysis, it suggests that age alone should not deter the pursuit of cytotoxic therapy.

Pemetrexed had a more tolerable toxicity profile than docetaxel in both younger and elderly patients. The differences in the rates of febrile neutropenia (2.5% v 18.9%, respectively) were clinically relevant. Elderly patients randomly assigned to pemetrexed withdrew from therapy less frequently. They had less febrile neutropenia despite the fact that treatment was less frequently withdrawn. We do not have data on additional treatments patients may have received after removal from the trial. We speculate that lower toxicity encountered with pemetrexed allowed for more therapy compared with the docetaxel-treated group.

A prospective evaluation of pharmacokinetics and toxicity of docetaxel 75 mg/m² in 25 cancer patients age 65 and 26 younger cancer patients revealed that docetaxel plasma pharmacokinetics were unaltered in the elderly patients.¹⁸ The percentage of older patients developing grade 4 neutropenia and febrile neutropenia was higher (61% and 16%, respectively), compared with values for the younger cohort (30% and 0%, respectively), but this was not statistically significant. In our study, only a slight increase in febrile neutropenia was observed in the elderly patients compared with the younger patients treated with docetaxel. A pharmacokinetic analysis of 36 patients age 70 receiving pemetrexed showed no difference in drug metabolism or toxicity when compared with younger patients.¹⁹

To our knowledge, no subset analysis of elderly patients has been performed on other randomized trials evaluating second-line cytotoxic chemotherapy. Two randomized trials that established docetaxel as second-line chemotherapy for NSCLC allowed adult patients of any age to participate. Comparing docetaxel to best supportive care, Shepherd et al¹³ reported a median age of 61 (range, 28 to 77 years) among the 204 patients enrolled. One patient who received docetaxel 75 mg/m² developed febrile neutropenia. Fossella et al¹⁴ reported a median age of 60 years in their large trial of 373 patients randomly assigned to docetaxel, ifosfamide, or vinorelbine. Febrile neutropenia occurred in 8% of patients treated with docetaxel 75 mg/m². No deaths as a result of toxicity were reported with docetaxel 75 mg/m² in either study.

If rates of febrile neutropenia and deaths as a result of toxicity are used as surrogates for unacceptable toxicity, data suggest that toxicity should not be a barrier for effective treatment in any age group. However, for patients age 80 years, extra caution is required because no data are available on the risk/benefit ratio of chemotherapy in this small subset of patients. In our study, only two patients were 80 years. In the first-line setting, Hesketh et al²⁰ conducted a retrospective analysis of two chemotherapy trials comparing outcomes in patients 80 years to patients 70 to 79 years. Both trials required patients to be 70 years with a performance status of 0 to 2. Southwest Oncology Group trial 0027 administered sequential vinorelbine followed by docetaxel, and LUN6 trial administered docetaxel either weekly or every 3 weeks. Forty-nine of the 228 patients (21.5%) were 80 years. There was no difference in grade 3 to 5 toxicity among the age groups. When stratified by good performance status, survival was 7 months for the octogenarians and 11 months for patients 70 to 79 years old (P = .20). The authors concluded that selected patients 80 years might benefit from first-line, single-agent therapy.

In addition to age and performance status, other factors need to be considered in determining if a patient is an appropriate chemotherapy candidate. Elderly patients typically have other comorbidities that may influence treatment decisions. Furthermore, performance status alone may not reflect their true functional ability. Investigators of the Multicenter Italian Lung Cancer in the Elderly Study evaluated prospectively the prognostic significance of pretreatment quality of life (QoL), comorbidities, and functional status.²¹ This randomized, phase III trial compared single-agent gemcitabine or vinorelbine to the combination of gemcitabine and vinorelbine in 556 untreated patients with advanced NSCLC. The study showed no advantage of the doublet over either single agent. In the prognostic analysis, better baseline scores for QoL and the instrumental activities of daily living were significantly associated with a favorable prognosis. The more commonly used activities of daily living scale and the Charlson comorbidity scale were not predictive of outcome. Performance status of 2 and a higher number of metastatic sites were unfavorable prognostic factors. Although this study was conducted in the first-line setting, determining QoL and instrumental activities of daily living status could be valuable in customizing salvage therapy and should be explored further.

Cytotoxic chemotherapy is not the only treatment option for previously treated elderly patients. Erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has similar efficacy to pemetrexed and docetaxel but does not produce life-threatening hematologic toxicity; however, it can produce significant cutaneous toxicity and diarrhea. In the randomized, phase III trial (BR.21) comparing erlotinib to placebo in previously treated patients with lung cancer, the investigators reported 57% of patients in the erlotinib arm and 49% of patients in the placebo arm were 60 years.²² The age range for all assessable patients was 32 to 89 years. Overall survival for the erlotinib arm was 6.7 months, treatment effect did not vary by age, and significant toxicities were infrequent. A randomized phase III study comparing an epidermal growth factor receptor tyrosine kinase inhibitor versus cytotoxic therapy has completed accrual, but results have not yet been reported.

It is encouraging that elderly patients, including those 80 years, are participating in clinical trials. In our study, elderly patients accounted for 15% of the participants, which is similar to the 12% to 29% of elderly patients participating in first-line studies. However, this percentage is unacceptably low given that 50% of patients with lung cancer are age 70 years. More clinical trials for the elderly are being conducted, but there is debate about the appropriate clinical design for this population. Should elderly patients be enrolled in age-independent trials? Or should we design trials specifically for this population? Both strategies are needed to determine the optimal treatment for this heterogeneous population that ranges from the fit to the fragile.

In conclusion, elderly patients with good performance status who have experienced failure after first-line treatment benefit from salvage therapy. Several treatment options are available. Toxicity profiles may be as important as therapeutic effect. Selection of the most appropriate agent should be discussed with the treating physician. Meanwhile, continued research into the efficacy, tolerability, and QoL of new therapies is critical for this growing population of lung cancer patients.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Corey Langer Eli Lilly & Co (B) Eli Lilly & Co (B) Nasser Hanna Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (B); Sanofi-Aventis (A) Eli Lilly & Co (C) Frances Shepherd Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (A) Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (N/R) Binh Nguyen Eli Lilly & Co (N/R) Eli Lilly (B) Sofia Paul Eli Lilly & Co (N/R) Eli Lilly (B) Patrick McAndrews Eli Lilly & Co (N/R) Eli Lilly (A) Paul A. Bunn Jr Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (C) Karen Kelly Eli Lilly & Co (A); Sanofi-Aventis (A) Eli Lilly & Co (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Karen Kelly Administrative support: Glen J. Weiss, Patrick McAndrews Provision of study materials or patients: Corey Langer, Rafael Rosell, Nasser Hanna, Frances Shepherd, Lawrence H. Einhorn, Sofia Paul, Paul A. Bunn Jr, Karen Kelly Collection and assembly of data: Patrick McAndrews Data analysis and interpretation: Sofia Paul Manuscript writing: Glen J. Weiss, Paul A. Bunn Jr, Karen Kelly Final approval of manuscript: Glen J. Weiss, Corey Langer, Rafael Rosell, Nasser Hanna, Frances Shepherd, Lawrence H. Einhorn, Binh Nguyen, Paul A. Bunn Jr, Karen Kelly

 

	ACKNOWLEDGMENTS

 
We thank Peter Fairfield, Eli Lilly & Co, for editorial support.

	NOTES

 
Supported by a grant from Eli Lilly and Co, Indianapolis, IN.

Presented in part at the 11th World Conference on Lung Cancer, Barcelona, Spain, July 3-6, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted March 28, 2006; accepted July 13, 2006.

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