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Benefit of Active Treatment in Non–Small-Cell Lung Cancer in Elderly Patients and Patients with Poor Performance Status
research in brief
rnb Benefit of Active Treatment in Non–Small-Cell Lung Cancer in Elderly Patients and Patients with Poor Performance Status Rationale ________________________ • The optimal management of non–smallcell lung cancer (NSCLC) in elderly patients and those with poor performance status (PS) has long been debated, and the needs of this population are just beginning to be addressed. More than half of patients with NSCLC are aged > 65 years, and approximately 30% are aged > 70 years.1 Furthermore, because the over-65 age group is growing faster than other age groups and the overall risk for cancer increases with age,2 elderly patients will likely make up an increasingly large percentage of patients with NSCLC. Despite this, patients aged ≥ 65 years make up only approximately 39% of the patients enrolled in lung cancer clinical trials.3 • One controversial issue in the debate over whether elderly patients respond as well to chemotherapy as younger patients is the widespread assumption that elderly patients are more likely to have comorbidities or decreased organ and hematopoietic function, which would increase their likelihood of experiencing toxicities and reduce the likelihood of a response. However, there might be a subset of elderly but fit patients who will experience treatment outcomes with chemotherapy similar to those of younger patients. A retrospective study by Earle and colleagues demonstrated that nontrial chemotherapy benefited elderly patients with NSCLC to an extent similar to that of younger patients enrolled in clinical trials.4 • At the 10th World Conference on Lung Cancer held in Vancouver, British Columbia, Canada, a series of presentations was given regarding the treatment of NSCLC in elderly patients and those with poor PS.5-10 Prepared by: David Lee, PhD Reviewed by: Chandra P. Belani, MD, Ravi Salgia, MD
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Active Treatment Versus Best Supportive Care Maguire and colleagues presented an analysis of survival data from elderly patients with NSCLC who were allowed to choose the treatment of their disease.5 Between 1997 and 2002, 397 patients aged ≥ 70 years with a PS of 0-2 were offered active treatment for NSCLC. Most patients had stage III (44%) or stage IV (30%) disease. Active treatment consisted of radical radiation therapy with or without chemotherapy for patients with stage I/II disease, 3-4 cycles of chemotherapy with radical external-beam radiation for patients with stage III disease, and 3-4 cycles of chemotherapy and radiation therapy for patients with stage IV disease. Patients who received active treatment experienced a statistically significant survival benefit compared with patients who chose best supportive care. Median survival with active treatment was 63 weeks, versus 34 weeks with best supportive care (P < 0.0001). The 1-year survival rate (59% vs. 28%; P < 0.0001) and 2-year survival rate (34% vs. 9%; P < 0.0001) also reflected the benefit conferred by active treatment. Treatment-related deaths
were independent of PS, occurring in 2%-3% of patients with a PS of 0/1 and patients with a PS of 2.
Concurrent Chemoradiotherapy The North Central Cancer Treatment Group (NCCTG) 94-24-52 study was a trial of chemotherapy in which radiation therapy was administered concurrently once daily or twice daily.11 Patients received etoposide 100 mg/m2 and cisplatin 30 mg/m2 on days 1-3 and 28-30 concurrently with radiation therapy. Patients were randomized to receive the radiation therapy with either the standard regimen of 60 Gy in 30 daily fractions or the twice-daily regimen (30 Gy in 20 1.5-Gy fractions twice daily followed by 2 weeks rest and an additional 30 Gy twice daily). Schild and colleagues performed an analysis of the subset of elderly patients in the NCCTG trial.6 Because no differences in outcome were observed between the 2 treatment regimens, the age-specific analysis combined data from both groups. Sixty-three of the 244 evaluable patients (26%) were aged ≥ 70 years. Both age groups were balanced in terms of PS, dis-
Table 1: Efficacy and Toxicity in NCCTG 94-24-526 Aged < 70 Years (n = 181)
Aged ≥ 70 Years (n = 63)
P Value
1.25 Years
1.13 Years
0.43
1-Year overall survival
58%
59%
NR
5-Year overall survival
17%
13%
NR
All grade 4 toxicities
62%
81%
0.007
Grade 4 leukopenia
31%
56%
0.0005
Efficacy Median survival
Toxicity
Abbreviations: NCCTG = North Central Cancer Treatment Group; NR = not reported
Aged < 70 Years (n = 912)
Aged ≥ 70 Years (n = 227)
P Value
Completion of 6 Cycles
34%
30%
0.36
Grade ≥ 4 Toxicity
66%
71%
0.04
22.1%
24.5%
0.76
1-Year
6.5%
9%
0.37
2-Year
0.5%
2%
0.04
8.15 Months
8.25 Months
1-Year Overall Survival
32.8%
35.2%
0.53
2-Year Overall Survival
11%
14%
0.24
Overall Response Rate Progression-Free Survival
Median Survival
Abbreviation: ECOG = Eastern Cooperative Oncology Group
ease stage, weight loss, tumor histology, and ability to complete radiation therapy. Patients were followed up for a median of 4.5 years. Survival rates were similar between the age groups (Table 1). The 1-year and 5year survival rates were 59% and 13%, respectively, in patients ≥ 70 years of age, compared to 58% and 17%, respectively, in patients < 70 years of age. Median survival was 1.13 years and 1.25 years, respectively (P = 0.43). The 2 age groups also had similar progression-free survival and local and distant failure rates. There was increased toxicity seen with the elderly patients (Table 1). Grade 4 toxicities were observed in 81% of elderly patients compared with 62% of younger patients (P = 0.007). Grade 4 leukopenia occurred more frequently in elderly patients (56% vs. 31%; P = 0.0005).
Single-Agent Chemotherapy Leong and colleagues carried out a randomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in NSCLC in elderly patients and those with poor PS.7 The study enrolled chemotherapy-naive patients with stage III/IV NSCLC disease who were ≥ 70 years of age or had an Eastern Cooperative Oncology Group (ECOG) PS of 2/3. Patients
were stratified by age (< 70 years vs. ≥ 70 years) and PS (0/1 vs. 2/3) and randomized to receive gemcitabine 800 mg/m2, vinorelbine 25 mg/m2, or docetaxel 30 mg/m2. Chemotherapy was administered on days 1, 8, and 15. A total of 84 patients were eligible for randomization, of whom 55 patients (65%) were aged ≥ 70 years. Sixty patients (71%) had stage IV disease. The majority of patients were considered frail, with 48% of patients having a PS of 3 and 20% having a PS of 2. Although 27 patients (32%) required dose omissions or reductions, 21 patients (25%) received all 6 cycles of therapy. The response rate was 18%, consisting of 15 partial responses. Patients with a PS of 1 had a response rate of 22% and patients with a PS of 2/3 had a response rate of 16%. Twenty-four patients (29%) had stabilization of disease. Treatment was well tolerated, with the most severe hematologic toxicity being grade 3/4 neutropenia in 17% of patients. The most frequent grade 3/4 nonhematologic adverse events were fatigue in 25% of patients and dyspnea in 20% of patients. Analysis of quality of life showed a trend toward improvement in global health, physical function, and emotional function during the course of treatment.
An age-specific analysis of the ECOG 1594 trial was carried out by Langer and colleagues.9 The study enrolled 1207 patients, 227 of whom (19%) were ≥ 70 years of age. The baseline demographics were similar for patients < 70 and ≥ 70 years of age. There were no statistically significant differences in response rates or survival between patients < 70 years of age and patients ≥ 70 years of age (Table 2). The overall response rates were 22.1% and 24.5%, respectively (P = 0.76). The median survival times for younger and elderly patients were 8.15 months and 8.25 months, and the 1-year survival rates were 32.8% and 35.2%, respectively (P = 0.53). There was a marginally statistically significant increase in grade 4 toxicities, occurring in 66% of young patients and 71% of elderly patients (P = 0.04). A total of 9 patients were ≥ 80 years of age. This group of patients experienced poor outcomes, with no responses to therapy. Median and progression-free survival times were approximately half those seen in patients aged 70-79 years.
research in brief
ECOG 1594 Trial
Table 2: Outcomes of ECOG 1594 by Age Group9
ECOG 1599 Trial Although progress has been made in prolonging survival of patients with advanced NSCLC, patients with a PS ≥ 2 have not benefited to the same extent as patients with a PS of 0/1. The assumption that patients with poor PS would experience increased toxicity from treatment has often led to the exclusion of this subset of patients from clinical trials. A subset analysis of patients with a PS of 2 in the ECOG 1594 trial, however, showed that the overall rate of toxicity in patients with a PS of 2 was not significantly higher than that in patients with a PS of 0/1.12 Median survival was only 4.1 months for patients with a PS of 2,12 however, underscoring the need to explore alternative approaches to treatment for this group of patients. Therefore, Langer and colleagues carried out a PS 2–specific study of dose-attenuated chemotherapy in NSCLC.8 Patients with advanced, chemotherapynaive NSCLC and a PS of 2 were eligible
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for the study. Treatment consisted of either carboplatin to an area under the curve of 6 plus paclitaxel 200 mg/m2 every 3 weeks or gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 every 3 weeks. The paclitaxel/carboplatin combination was chosen because of its low toxicity in the ECOG 1594 trial, and the gemcitabine/cisplatin doublet was selected because it yielded a median survival of 7.9 months in patients with a PS of 2 in the ECOG 1594 trial.8,12 Patient characteristics were similar for both arms. The median age was approximately 66 years. Forty-six percent of patients had weight loss of ≥ 5%, and 88% of patients had stage IV or recurrent disease. Twenty-one percent of patients on the gemcitabine/cisplatin arm responded, including 1 complete response, and the response rate was 10% in the carboplatin/paclitaxel group (Table 3). The disease control rate (response plus stable disease) was approximately 50% in both groups. Median time to progression was similar between the 2 regimens (4.8 months and 4.2 months, respectively), as was the median overall survival time (6.8 months and 6.1 months, respectively). The 2 regimens had different patterns of grade 3/4 adverse events (Table 3). There was a trend toward increased neutropenia with carboplatin/paclitaxel compared with gemcitabine/cisplatin (77% vs. 44%). Sensory neuropathy occurred in 8% of patients and no patients, respectively. Other toxicities included thrombocytopenia (12% vs. 38%), nausea/vomiting (6% vs. 23%), and fatigue (12% vs. 22%).
TAX 326 To further evaluate the efficacy of docetaxel/cisplatin and docetaxel/carboplatin in advanced NSCLC, the TAX 326 trial compared docetaxel/cisplatin and docetaxel/carboplatin to the reference regimen of vinorelbine/cisplatin as first-line treatment for NSCLC.13 Belani led an elderly patient–specific analysis of survival and toxicity data from the TAX 326 study to determine the benefit of platinum-based chemotherapy for elderly patients with NSCLC.10
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Patients were enrolled from 28 coun- (Table 4). The 1- and 2-year survival rates tries and 140 institutions between July for docetaxel/cisplatin were 52% and 1998 and January 2000. Eligible patients 24%, respectively. Patients on the docewere ≥ 18 years of age and had histolog- taxel/carboplatin and vinorelbine/cisplatin ically or cytologically confirmed stage arms experienced similar survival rates at 1 IIIB or IV NSCLC and a Karnofsky PS year (38% and 41%, respectively) and at 2 of ≥ 70%. No previous chemotherapy was years (19% and 17%, respectively). A comparison of survival data from eldallowed. This analysis stratified patients into 2 age groups: elderly (≥ 65 years of erly versus young patients treated with docetaxel/cisplatin showed that elderly paage) and young (< 65 years of age). Patients were randomized to receive 1 of tients actually had a longer median survival 3 regimens: docetaxel 75 mg/m2 intra- time (12.6 months) than did young pavenously (I.V.) over 1 hour followed by cis- tients (11.0 months; Table 4). One- and 2platin 75 mg/m2 I.V. every 3 weeks, doce- year survival rates were also higher in eldertaxel 75 mg/m2 I.V. over 1 hour followed ly versus young patients. There was little by carboplatin to an area under the curve difference in survival between age groups of 6 I.V. over 1 hour every 3 weeks, or vi- who received docetaxel/carboplatin or vinorelbine 25 mg/m2 I.V. on days 1, 8, 15, norelbine/cisplatin. There was a moderate trend toward inand 22 followed by cisplatin 100 mg/m2 creased grade 3/4 adverse events in elderly I.V. on day 1 every 4 weeks. Of the 1218 patients enrolled in the patients, even though elderly patients toltrial, 401 were aged ≥ 65 years. Baseline erated the 3 regimens well (Table 4). patient characteristics were well balanced Grade 3/4 asthenia, infection, and pain among the 3 treatment arms and, with the were more frequent in elderly patients in exception of age, were similar to those of all 3 regimens. Grade 3/4 nausea/vomitthe overall patient population. The medi- ing was less frequent on the docetaxel/ an ages were 69 years in the docetaxel/ platinum arms and occurred less frequentplatinum arms and 68 years in the vinorelbine/ Table 3: Efficacy and Safety Results cisplatin arm. Most pain ECOG 15998 tients had a Karnofsky PS ≥ 80%; only 2%-3% of Carboplatin/ Gemcitabine/ Paclitaxel Cisplatin patients had a Karnofsky PS of 70%. Approximately Efficacy two thirds of the patients 21%* 10% ORR had stage IV disease. The mean combined relative 50% 52.5% Disease control† dose intensity of treatment 4.8 Months 4.2 Months Time to progression was 0.93 for docetaxel/cisplatin and docetaxel/car6.8 Months 6.1 Months Median survival boplatin and 0.76 for vin = 47 n = 51 Grade 3/4 Toxicity norelbine/cisplatin, similar to those in the overall Neutropenia 44% 77% study population. Thrombocytopenia 38% 12% Docetaxel/cisplatin was the most efficacious regiNausea/vomiting 23% 6% men in patients aged ≥ 65 Neuropathy 0 8% years, with a median survival time of 12.6 months, Fatigue 22% 12% compared with 9.0 *Includes 1 complete response. months for docetaxel/car†Disease control was defined as overall response plus stable disease. boplatin and 9.9 months Abbreviation: ECOG = Eastern Cooperative Oncology Group for vinorelbine/cisplatin
Docetaxel/Cisplatin
Docetaxel/Carboplatin
Vinorelbine/Cisplatin
Aged ≥ 65 Years
Aged < 65 Years
Aged ≥ 65 Years
Aged < 65 Years
Aged ≥ 65 Years
Aged < 65 Years
n = 149
n = 259
n = 118
n = 288
n = 134
n = 270
Median survival, months
12.6
11.0
9.0
9.7
9.9
10.1
1-Year survival
52%
44%
38%
37%
41%
41%
2-Year survival
24%
19%
19%
17%
17%
13%
n = 148
n = 258
n = 114
n = 287
n = 128
n = 268
Nausea/vomiting
12%
13%
3%
9%
26%
18%
Asthenia
14%
11%
13%
10%
17%
13%
Infection
12%
7%
18%
8%
10%
7%
Pain
10%
7%
11%
8%
12%
7%
Efficacy
Grade 3/4 Toxicities
ly in elderly patients than in young patients. Overall, the rate of grade 3/4 toxicities was lower with the docetaxel/platinum regimens than with vinorelbine/cisplatin. There were also fewer discontinuations of treatment by elderly patients on the docetaxel/cisplatin (20%) and docetaxel/carboplatin arms (15%) than on the vinorelbine/cisplatin arm (32%).
Conclusion Data from several clinical trials indicate that elderly patients and those with poor PS with NSCLC indeed benefit from active treatment, with response and survival rates similar to those in young patients. Despite the pessimism surrounding chemotherapy and radiation therapy in this subgroup of patients, the data indicate that even these modalities can be used safely. This report indicates that age alone should not be the basis for denying elderly patients the potential benefits of active
treatment. Additionally, with appropriate dose attenuation, patients with a PS of 2 should be given the option of receiving such treatment in addition to supportive care. However, more data are needed regarding patients > 80 years of age.
References _______________________ 1. Gridelli C, Maione P, Barletta E. Individualized chemotherapy for elderly patients with nonsmall-cell lung cancer. Curr Opin Oncol 2002; 14:199-203. 2. Balducci L. The geriatric cancer patient: equal benefit from equal treatment. Cancer Control 2001; 8:1-25. 3. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancertreatment trials. N Engl J Med 1999; 341:2061-2067. 4. Earle CC, Tsai JS, Gelber RD, et al. Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 2001; 19:1064-1070. 5. Maguire J, Kelly V, Smith N, et al. Chemotherapy and radical radiotherapy for patients with inoperable NSCLC aged 70 or over - results of a treatment policy based on performance status and stage at presentation. Lung Cancer 2003; 41(suppl 2):S19 (Abstract #O-54). 6. Schild SE, Stella PJ, Geyer SM, et al. The outcome of combined modality therapy for non-small-cell lung cancer (NSCLC) in the elderly. Lung Cancer 2003; 41(suppl 2):S19 (Abstract #O-55). 7. Leong SS, Foo KF, Tay MH, et al. A randomized phase II trial of gemcitabine, vinorelbine or docetaxel in the
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12.
13.
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Table 4. Efficacy and Safety in TAX 326 Study by Age Group10
treatment of elderly and/or poor performance state patients with non-small-cell lung cancer (NSCLC). Lung Cancer 2003; 41(suppl 2):S18-S19 (Abstract #O-53). Langer CJ, Stephenson P, Schiller J, et al. ECOG 1599: randomized phase II study of paclitaxel/carboplatin vs cisplatin/gemcitabine in performance status (PS) 2 patients with treatment-naive advanced NSCLC. Lung Cancer 2003; 41(suppl 2):S18 (Abstract #O-52). Langer CJ, Vangel M, Schiller J, et al. Age-specific subanalysis of ECOG 1594: Fit elderly patients (70-80 yrs.) with NSCLC do as well as younger patients (<70). Lung Cancer 2003; 41(suppl 2):S17 (Abstract #O-49). Belani CP, Fossella FV, on behalf of the TAX 326 Study Group. Phase III study (TAX 326) of docetaxelcisplatin (DC) and docetaxel-carboplatin (DCB) versus vinorelbine-cisplatin (VC) for the first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC): analyses in elderly patients. Lung Cancer 2003; 41(suppl 2):S18 (Abstract #O-51). Schild SE, Stella PJ, Geyer SM, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 54:370-378. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic non-small-cell lung carcinoma. Cancer 2001; 92:2639-2647. Fossella FV, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus cisplatin for advanced non–small-cell lung cancer: the TAX 326 Study Group. J Clin Oncol 2003; 21:3016-3024.
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rnb Benefit of Active Treatment in Non–Small-Cell Lung Cancer in Elderly Patients and Patients with Poor Performance Status Rationale ________________________ • The optimal management of non–smallcell lung cancer (NSCLC) in elderly patients and those with poor performance status (PS) has long been debated, and the needs of this population are just beginning to be addressed. More than half of patients with NSCLC are aged > 65 years, and approximately 30% are aged > 70 years.1 Furthermore, because the over-65 age group is growing faster than other age groups and the overall risk for cancer increases with age,2 elderly patients will likely make up an increasingly large percentage of patients with NSCLC. Despite this, patients aged ≥ 65 years make up only approximately 39% of the patients enrolled in lung cancer clinical trials.3 • One controversial issue in the debate over whether elderly patients respond as well to chemotherapy as younger patients is the widespread assumption that elderly patients are more likely to have comorbidities or decreased organ and hematopoietic function, which would increase their likelihood of experiencing toxicities and reduce the likelihood of a response. However, there might be a subset of elderly but fit patients who will experience treatment outcomes with chemotherapy similar to those of younger patients. A retrospective study by Earle and colleagues demonstrated that nontrial chemotherapy benefited elderly patients with NSCLC to an extent similar to that of younger patients enrolled in clinical trials.4 • At the 10th World Conference on Lung Cancer held in Vancouver, British Columbia, Canada, a series of presentations was given regarding the treatment of NSCLC in elderly patients and those with poor PS.5-10 Prepared by: David Lee, PhD Reviewed by: Chandra P. Belani, MD, Ravi Salgia, MD
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Clinical Lung Cancer September 2003
Active Treatment Versus Best Supportive Care Maguire and colleagues presented an analysis of survival data from elderly patients with NSCLC who were allowed to choose the treatment of their disease.5 Between 1997 and 2002, 397 patients aged ≥ 70 years with a PS of 0-2 were offered active treatment for NSCLC. Most patients had stage III (44%) or stage IV (30%) disease. Active treatment consisted of radical radiation therapy with or without chemotherapy for patients with stage I/II disease, 3-4 cycles of chemotherapy with radical external-beam radiation for patients with stage III disease, and 3-4 cycles of chemotherapy and radiation therapy for patients with stage IV disease. Patients who received active treatment experienced a statistically significant survival benefit compared with patients who chose best supportive care. Median survival with active treatment was 63 weeks, versus 34 weeks with best supportive care (P < 0.0001). The 1-year survival rate (59% vs. 28%; P < 0.0001) and 2-year survival rate (34% vs. 9%; P < 0.0001) also reflected the benefit conferred by active treatment. Treatment-related deaths
were independent of PS, occurring in 2%-3% of patients with a PS of 0/1 and patients with a PS of 2.
Concurrent Chemoradiotherapy The North Central Cancer Treatment Group (NCCTG) 94-24-52 study was a trial of chemotherapy in which radiation therapy was administered concurrently once daily or twice daily.11 Patients received etoposide 100 mg/m2 and cisplatin 30 mg/m2 on days 1-3 and 28-30 concurrently with radiation therapy. Patients were randomized to receive the radiation therapy with either the standard regimen of 60 Gy in 30 daily fractions or the twice-daily regimen (30 Gy in 20 1.5-Gy fractions twice daily followed by 2 weeks rest and an additional 30 Gy twice daily). Schild and colleagues performed an analysis of the subset of elderly patients in the NCCTG trial.6 Because no differences in outcome were observed between the 2 treatment regimens, the age-specific analysis combined data from both groups. Sixty-three of the 244 evaluable patients (26%) were aged ≥ 70 years. Both age groups were balanced in terms of PS, dis-
Table 1: Efficacy and Toxicity in NCCTG 94-24-526 Aged < 70 Years (n = 181)
Aged ≥ 70 Years (n = 63)
P Value
1.25 Years
1.13 Years
0.43
1-Year overall survival
58%
59%
NR
5-Year overall survival
17%
13%
NR
All grade 4 toxicities
62%
81%
0.007
Grade 4 leukopenia
31%
56%
0.0005
Efficacy Median survival
Toxicity
Abbreviations: NCCTG = North Central Cancer Treatment Group; NR = not reported
Aged < 70 Years (n = 912)
Aged ≥ 70 Years (n = 227)
P Value
Completion of 6 Cycles
34%
30%
0.36
Grade ≥ 4 Toxicity
66%
71%
0.04
22.1%
24.5%
0.76
1-Year
6.5%
9%
0.37
2-Year
0.5%
2%
0.04
8.15 Months
8.25 Months
1-Year Overall Survival
32.8%
35.2%
0.53
2-Year Overall Survival
11%
14%
0.24
Overall Response Rate Progression-Free Survival
Median Survival
Abbreviation: ECOG = Eastern Cooperative Oncology Group
ease stage, weight loss, tumor histology, and ability to complete radiation therapy. Patients were followed up for a median of 4.5 years. Survival rates were similar between the age groups (Table 1). The 1-year and 5year survival rates were 59% and 13%, respectively, in patients ≥ 70 years of age, compared to 58% and 17%, respectively, in patients < 70 years of age. Median survival was 1.13 years and 1.25 years, respectively (P = 0.43). The 2 age groups also had similar progression-free survival and local and distant failure rates. There was increased toxicity seen with the elderly patients (Table 1). Grade 4 toxicities were observed in 81% of elderly patients compared with 62% of younger patients (P = 0.007). Grade 4 leukopenia occurred more frequently in elderly patients (56% vs. 31%; P = 0.0005).
Single-Agent Chemotherapy Leong and colleagues carried out a randomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in NSCLC in elderly patients and those with poor PS.7 The study enrolled chemotherapy-naive patients with stage III/IV NSCLC disease who were ≥ 70 years of age or had an Eastern Cooperative Oncology Group (ECOG) PS of 2/3. Patients
were stratified by age (< 70 years vs. ≥ 70 years) and PS (0/1 vs. 2/3) and randomized to receive gemcitabine 800 mg/m2, vinorelbine 25 mg/m2, or docetaxel 30 mg/m2. Chemotherapy was administered on days 1, 8, and 15. A total of 84 patients were eligible for randomization, of whom 55 patients (65%) were aged ≥ 70 years. Sixty patients (71%) had stage IV disease. The majority of patients were considered frail, with 48% of patients having a PS of 3 and 20% having a PS of 2. Although 27 patients (32%) required dose omissions or reductions, 21 patients (25%) received all 6 cycles of therapy. The response rate was 18%, consisting of 15 partial responses. Patients with a PS of 1 had a response rate of 22% and patients with a PS of 2/3 had a response rate of 16%. Twenty-four patients (29%) had stabilization of disease. Treatment was well tolerated, with the most severe hematologic toxicity being grade 3/4 neutropenia in 17% of patients. The most frequent grade 3/4 nonhematologic adverse events were fatigue in 25% of patients and dyspnea in 20% of patients. Analysis of quality of life showed a trend toward improvement in global health, physical function, and emotional function during the course of treatment.
An age-specific analysis of the ECOG 1594 trial was carried out by Langer and colleagues.9 The study enrolled 1207 patients, 227 of whom (19%) were ≥ 70 years of age. The baseline demographics were similar for patients < 70 and ≥ 70 years of age. There were no statistically significant differences in response rates or survival between patients < 70 years of age and patients ≥ 70 years of age (Table 2). The overall response rates were 22.1% and 24.5%, respectively (P = 0.76). The median survival times for younger and elderly patients were 8.15 months and 8.25 months, and the 1-year survival rates were 32.8% and 35.2%, respectively (P = 0.53). There was a marginally statistically significant increase in grade 4 toxicities, occurring in 66% of young patients and 71% of elderly patients (P = 0.04). A total of 9 patients were ≥ 80 years of age. This group of patients experienced poor outcomes, with no responses to therapy. Median and progression-free survival times were approximately half those seen in patients aged 70-79 years.
research in brief
ECOG 1594 Trial
Table 2: Outcomes of ECOG 1594 by Age Group9
ECOG 1599 Trial Although progress has been made in prolonging survival of patients with advanced NSCLC, patients with a PS ≥ 2 have not benefited to the same extent as patients with a PS of 0/1. The assumption that patients with poor PS would experience increased toxicity from treatment has often led to the exclusion of this subset of patients from clinical trials. A subset analysis of patients with a PS of 2 in the ECOG 1594 trial, however, showed that the overall rate of toxicity in patients with a PS of 2 was not significantly higher than that in patients with a PS of 0/1.12 Median survival was only 4.1 months for patients with a PS of 2,12 however, underscoring the need to explore alternative approaches to treatment for this group of patients. Therefore, Langer and colleagues carried out a PS 2–specific study of dose-attenuated chemotherapy in NSCLC.8 Patients with advanced, chemotherapynaive NSCLC and a PS of 2 were eligible
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for the study. Treatment consisted of either carboplatin to an area under the curve of 6 plus paclitaxel 200 mg/m2 every 3 weeks or gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 every 3 weeks. The paclitaxel/carboplatin combination was chosen because of its low toxicity in the ECOG 1594 trial, and the gemcitabine/cisplatin doublet was selected because it yielded a median survival of 7.9 months in patients with a PS of 2 in the ECOG 1594 trial.8,12 Patient characteristics were similar for both arms. The median age was approximately 66 years. Forty-six percent of patients had weight loss of ≥ 5%, and 88% of patients had stage IV or recurrent disease. Twenty-one percent of patients on the gemcitabine/cisplatin arm responded, including 1 complete response, and the response rate was 10% in the carboplatin/paclitaxel group (Table 3). The disease control rate (response plus stable disease) was approximately 50% in both groups. Median time to progression was similar between the 2 regimens (4.8 months and 4.2 months, respectively), as was the median overall survival time (6.8 months and 6.1 months, respectively). The 2 regimens had different patterns of grade 3/4 adverse events (Table 3). There was a trend toward increased neutropenia with carboplatin/paclitaxel compared with gemcitabine/cisplatin (77% vs. 44%). Sensory neuropathy occurred in 8% of patients and no patients, respectively. Other toxicities included thrombocytopenia (12% vs. 38%), nausea/vomiting (6% vs. 23%), and fatigue (12% vs. 22%).
TAX 326 To further evaluate the efficacy of docetaxel/cisplatin and docetaxel/carboplatin in advanced NSCLC, the TAX 326 trial compared docetaxel/cisplatin and docetaxel/carboplatin to the reference regimen of vinorelbine/cisplatin as first-line treatment for NSCLC.13 Belani led an elderly patient–specific analysis of survival and toxicity data from the TAX 326 study to determine the benefit of platinum-based chemotherapy for elderly patients with NSCLC.10
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Patients were enrolled from 28 coun- (Table 4). The 1- and 2-year survival rates tries and 140 institutions between July for docetaxel/cisplatin were 52% and 1998 and January 2000. Eligible patients 24%, respectively. Patients on the docewere ≥ 18 years of age and had histolog- taxel/carboplatin and vinorelbine/cisplatin ically or cytologically confirmed stage arms experienced similar survival rates at 1 IIIB or IV NSCLC and a Karnofsky PS year (38% and 41%, respectively) and at 2 of ≥ 70%. No previous chemotherapy was years (19% and 17%, respectively). A comparison of survival data from eldallowed. This analysis stratified patients into 2 age groups: elderly (≥ 65 years of erly versus young patients treated with docetaxel/cisplatin showed that elderly paage) and young (< 65 years of age). Patients were randomized to receive 1 of tients actually had a longer median survival 3 regimens: docetaxel 75 mg/m2 intra- time (12.6 months) than did young pavenously (I.V.) over 1 hour followed by cis- tients (11.0 months; Table 4). One- and 2platin 75 mg/m2 I.V. every 3 weeks, doce- year survival rates were also higher in eldertaxel 75 mg/m2 I.V. over 1 hour followed ly versus young patients. There was little by carboplatin to an area under the curve difference in survival between age groups of 6 I.V. over 1 hour every 3 weeks, or vi- who received docetaxel/carboplatin or vinorelbine 25 mg/m2 I.V. on days 1, 8, 15, norelbine/cisplatin. There was a moderate trend toward inand 22 followed by cisplatin 100 mg/m2 creased grade 3/4 adverse events in elderly I.V. on day 1 every 4 weeks. Of the 1218 patients enrolled in the patients, even though elderly patients toltrial, 401 were aged ≥ 65 years. Baseline erated the 3 regimens well (Table 4). patient characteristics were well balanced Grade 3/4 asthenia, infection, and pain among the 3 treatment arms and, with the were more frequent in elderly patients in exception of age, were similar to those of all 3 regimens. Grade 3/4 nausea/vomitthe overall patient population. The medi- ing was less frequent on the docetaxel/ an ages were 69 years in the docetaxel/ platinum arms and occurred less frequentplatinum arms and 68 years in the vinorelbine/ Table 3: Efficacy and Safety Results cisplatin arm. Most pain ECOG 15998 tients had a Karnofsky PS ≥ 80%; only 2%-3% of Carboplatin/ Gemcitabine/ Paclitaxel Cisplatin patients had a Karnofsky PS of 70%. Approximately Efficacy two thirds of the patients 21%* 10% ORR had stage IV disease. The mean combined relative 50% 52.5% Disease control† dose intensity of treatment 4.8 Months 4.2 Months Time to progression was 0.93 for docetaxel/cisplatin and docetaxel/car6.8 Months 6.1 Months Median survival boplatin and 0.76 for vin = 47 n = 51 Grade 3/4 Toxicity norelbine/cisplatin, similar to those in the overall Neutropenia 44% 77% study population. Thrombocytopenia 38% 12% Docetaxel/cisplatin was the most efficacious regiNausea/vomiting 23% 6% men in patients aged ≥ 65 Neuropathy 0 8% years, with a median survival time of 12.6 months, Fatigue 22% 12% compared with 9.0 *Includes 1 complete response. months for docetaxel/car†Disease control was defined as overall response plus stable disease. boplatin and 9.9 months Abbreviation: ECOG = Eastern Cooperative Oncology Group for vinorelbine/cisplatin
Docetaxel/Cisplatin
Docetaxel/Carboplatin
Vinorelbine/Cisplatin
Aged ≥ 65 Years
Aged < 65 Years
Aged ≥ 65 Years
Aged < 65 Years
Aged ≥ 65 Years
Aged < 65 Years
n = 149
n = 259
n = 118
n = 288
n = 134
n = 270
Median survival, months
12.6
11.0
9.0
9.7
9.9
10.1
1-Year survival
52%
44%
38%
37%
41%
41%
2-Year survival
24%
19%
19%
17%
17%
13%
n = 148
n = 258
n = 114
n = 287
n = 128
n = 268
Nausea/vomiting
12%
13%
3%
9%
26%
18%
Asthenia
14%
11%
13%
10%
17%
13%
Infection
12%
7%
18%
8%
10%
7%
Pain
10%
7%
11%
8%
12%
7%
Efficacy
Grade 3/4 Toxicities
ly in elderly patients than in young patients. Overall, the rate of grade 3/4 toxicities was lower with the docetaxel/platinum regimens than with vinorelbine/cisplatin. There were also fewer discontinuations of treatment by elderly patients on the docetaxel/cisplatin (20%) and docetaxel/carboplatin arms (15%) than on the vinorelbine/cisplatin arm (32%).
Conclusion Data from several clinical trials indicate that elderly patients and those with poor PS with NSCLC indeed benefit from active treatment, with response and survival rates similar to those in young patients. Despite the pessimism surrounding chemotherapy and radiation therapy in this subgroup of patients, the data indicate that even these modalities can be used safely. This report indicates that age alone should not be the basis for denying elderly patients the potential benefits of active
treatment. Additionally, with appropriate dose attenuation, patients with a PS of 2 should be given the option of receiving such treatment in addition to supportive care. However, more data are needed regarding patients > 80 years of age.
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research in brief
Table 4. Efficacy and Safety in TAX 326 Study by Age Group10
treatment of elderly and/or poor performance state patients with non-small-cell lung cancer (NSCLC). Lung Cancer 2003; 41(suppl 2):S18-S19 (Abstract #O-53). Langer CJ, Stephenson P, Schiller J, et al. ECOG 1599: randomized phase II study of paclitaxel/carboplatin vs cisplatin/gemcitabine in performance status (PS) 2 patients with treatment-naive advanced NSCLC. Lung Cancer 2003; 41(suppl 2):S18 (Abstract #O-52). Langer CJ, Vangel M, Schiller J, et al. Age-specific subanalysis of ECOG 1594: Fit elderly patients (70-80 yrs.) with NSCLC do as well as younger patients (<70). Lung Cancer 2003; 41(suppl 2):S17 (Abstract #O-49). Belani CP, Fossella FV, on behalf of the TAX 326 Study Group. Phase III study (TAX 326) of docetaxelcisplatin (DC) and docetaxel-carboplatin (DCB) versus vinorelbine-cisplatin (VC) for the first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC): analyses in elderly patients. Lung Cancer 2003; 41(suppl 2):S18 (Abstract #O-51). Schild SE, Stella PJ, Geyer SM, et al. Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 54:370-378. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic non-small-cell lung carcinoma. Cancer 2001; 92:2639-2647. Fossella FV, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus cisplatin for advanced non–small-cell lung cancer: the TAX 326 Study Group. J Clin Oncol 2003; 21:3016-3024.
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