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Dose escalation study of carboplatin–pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer
original articles
Annals of Oncology Annals of Oncology 24: 980–985, 2013 doi:10.1093/annonc/mds544 Published online 7 November 2012
Dose escalation study of carboplatin–pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer
1 Department of Internal Medicine, Kinki-Chuo Chest Medical Center, Osaka; 2Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka, Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka; 3Department of Clinical Research Center, Kinki-Chuo Chest Medical Center, Osaka, Japan
Received 11 August 2012; revised 11 September 2012; accepted 14 September 2012
Background: This study was designed to determine the recommended dose of carboplatin–pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC).
Patients and methods: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. Results: The combination of carboplatin at an area under the concentration–time curve (AUC) of 5, and 500 mg/m2 pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68–216 days) and the median overall survival time was 461 days (95% CI 168–754 days). Conclusions: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m2) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC. Key words: carboplatin, elderly, maintenance therapy, nonsmall-cell lung cancer, pemetrexed
introduction Nonsmall-cell lung cancer (NSCLC) accounts for >80% of all lung cancers, and the risk of lung cancer clearly increases with advancing age. Because of the progressive aging of the population, the number of elderly patients with NSCLC is increasing, and the disease is becoming an increasing public health problem worldwide [1, 2]. Platinum-based chemotherapy is the standard first-line treatment of advanced NSCLC, based on the moderate improvements in survival and quality of life that it confers compared with the best supportive care alone [3–5]. However, elderly people are underrepresented in clinical trials [6, 7] and, therefore, might not receive the most appropriate treatment in practice. The under*Correspondence to: Dr M. Tamiya, Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino 3–7-1, Habikino City, Osaka 583-8588, Japan. Tel: +81-72957-2121; Fax: +81-72-957-8002; E-mail: [email protected]
representation of the elderly in clinical trials may be the result of the pessimism of the doctors, patients, and their relatives about the relevance of the treatment or drug-related toxic effects [8]. Retrospective analyses, conducted on subsets of patients >70 years old in several phase III NSCLC trials, have suggested that platinum-based doublet therapy may be an appropriate option for fit, elderly patients [9–13]. In addition, many elderly specific prospective trials have clearly established the efficacy of single-agent chemotherapy in ≥70-year-old patients with advanced NSCLC [14–17]. Further, a recent French phase III trial, specifically designed for the elderly, showed that carboplatin–paclitaxel conferred a significant improvement on overall survival (OS), compared with single agents vinorelbine or gemcitabine, with moderate toxicity [18]. This study has shed new light on platinum-doublet chemotherapy for elderly patients with advanced NSCLC. Pemetrexed is a multitargeted, antifolate cytotoxic agent that has been demonstrated to be efficacious in combination with
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A. Tamiya1, M. Tamiya2*, T. Shiroyama2, M. Kanazu1, A. Hirooka1, T. Tsuji1, N. Morishita2, K. Asami1, H. Suzuki2, N. Okamoto2, K. Okishio3, T. Kawaguchi1, T. Hirashima2, S. Atagi3 & I. Kawase2
original articles
Annals of Oncology
patients and methods study design The present dose-escalation study was conducted to examine the safety of carboplatin–pemetrexed combinations for chemo-naive elderly (≥75 years) patients with advanced nonsquamous NSCLC. The primary objectives of this study were to evaluate the incidence, type, and severity of adverse events and determine the recommended dose of carboplatin for use in combination with pemetrexed. Patients were divided into three cohorts: cohort 0 patients were treated with carboplatin at an AUC of 4 plus 500 mg/m2 pemetrexed; cohort 1 patients received carboplatin at an AUC of 5 plus 500 mg/m2 pemetrexed; and cohort 2 patients received carboplatin at an AUC of 6 plus 500 mg/m2 pemetrexed. In each cohort, if one instance of DLT was observed among three patients, three additional patients were treated at the same dose level. Dose escalation continued if DLT was observed in no more than one of six patients. If two of three patients, or at least two of six patients, showed DLT at a given dose level, that level was considered the MTD and one dose level below that was considered the RD. Dose escalation was decided by the toxicity data in the first cycle of chemotherapy. The recommended dose was determined based on these initial results from cohorts 0, 1, and 2.
eligibility Elderly (≥75 years) patients with histologically or cytologically confirmed nonsquamous NSCLC were eligible for the study. Each patient was required to meet the following criteria: (i) clinical stage IIIB, IV, or postoperative recurrent disease; (ii) lesions not amenable for curative radiation; (iii) no prior chemotherapy; (iv) age, ≥75 years; (v) Eastern
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Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (vi) measurable lesions by Response Evaluated Criteria in Solid Tumors (RECIST ver1.1); (vii) adequate functioning of major internal organs (lung: SpO2, ≥90%; bone marrow: hemoglobin ≥9.5 g/dl, white blood cell count ≥3500/mm3, neutrophil count ≥2000/mm3, platelet count ≥100 000/mm3; liver: aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤2.5 times upper limit of normal, total bilirubin ≤1.5 mg/dl; kidney: serum creatinine ≤1.2 mg/dl, predicted creatinine clearance or 24 h creatinine clearance ≥45 ml/min, as estimated by the Cockcroft and Gault formula [23]); and (viii) life expectancy of at least 3 months. Peripheral blood and biochemistry examinations were repeated at least once every 2 weeks after the initial evaluation. This study followed the ethical principles in the Declaration of Helsinki, and the local institution review board approved this protocol before initiation of the study. All patients provided written informed consent before study-related procedures were carried out.
study treatments All patients received 500 mg/m2 pemetrexed by 10-min intravenous infusion, followed by intravenous infusion of carboplatin over at least 30 min (to an AUC of 4, 5, or 6) on day 1 of a 21-day cycle. Combination chemotherapy was repeated every 3 weeks for a maximum of four cycles. After the completion of four cycles, only patients with controlled disease were eligible for maintenance therapy; and continued pemetrexed treatment was possible, at the discretion of the investigator, until progressive disease (PD) was observed. Subsequent cycles of treatment were withheld until the following criteria were observed: neutrophil counts ≥1500/mm3, platelet count ≥100 000/mm3, PS ≤ 1, SpO2 ≥ 90%, AST/ ALT ≤ 2.5 times upper limit of normal, serum creatinine ≤1.2 mg/dl, other nonhematological toxicity was ≤grade 2, and recommendation by the physician. If the toxicity had not resolved within 43 days, the patient was excluded from further participation in the study. Treatment doses during induction and maintenance therapies were to be modified as follows: in cases of toxicity, the pemetrexed dose was to be reduced from 500 to 400 mg/m2, and the carboplatin dose was to be reduced from AUC 6 to 5 (or 5 to 4) during induction therapy, or the pemetrexed dose was to be reduced from 500 to 400 mg/m2 during maintenance therapy. The toxic effects requiring dose reduction were set as grade 4 leukopenia and thrombocytopenia, febrile neutropenia, and grade 3 nonhematological toxic effects, excluding fatigue, nausea, and anorexia. When further dose reduction was required because of continuing evidence of toxicity during either the induction or maintenance therapy, the patient discontinued the protocol. While the patients were on study, they received supplemental folic acid and vitamin B12. All patients underwent comprehensive baseline assessments including clinical laboratory tests and imaging studies. Patients also received follow-up assessments and monitoring at regular intervals. Toxicity evaluations were based on the Common Terminology Criteria for Adverse Events, version 4.0.
definition of DLT DLT was defined as a toxicity occurring in cycle 1 that met one of the following criteria and for which a causal relationship with the study drugs could not be ruled out: grade 4 leukopenia, febrile neutropenia, grade 4 thrombocytopenia, or grade 3 nonhematological toxicity that did not resolve within 43 days (the following events were DLT, if the event did not recover to ≤grade 2, despite standard/optimal supportive treatment: nausea, vomiting, anorexia, fatigue, constipation, diarrhea, transient increase in AST/ALT, or transient electrolyte abnormality). If the patients
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cisplatin for first-line treatment of nonsquamous NSCLC in randomized phase III clinical studies [19]. This phase III study reported noninferior efficacy and better tolerability for cisplatin–pemetrexed than for cisplatin–gemcitabine in the first-line setting. In addition, OS was statistically superior for cisplatin–pemetrexed versus cisplatin–gemcitabine in patients with nonsquamous NSCLC [20]. Another phase III clinical study demonstrated superior progression-free survival (PFS) and OS when pemetrexed was used in a maintenance setting following four cycles of cisplatin–pemetrexed [21]. These study results indicated that pemetrexed-based platinum doublet induction therapy followed by pemetrexed maintenance therapy deserves to be evaluated as a treatment option for elderly (≥75 years old) patients with advanced nonsquamous NSCLC. Because carboplatin-based regimens have been shown to be less toxic, convenient, and capable of being administered on an outpatient basis, they have been widely used as a substitute for cisplatin regimens in clinical practice. In a previous Japanese dose-escalation study of carboplatin–pemetrexed in a first-line setting for <75-year-old patients, carboplatin doses (AUC of 6) and pemetrexed (500 mg/m2) were recommended [22] and used in clinical settings. However, carboplatin dose-escalation has not been evaluated in chemotherapy-naive elderly (≥75year old) patients with advanced nonsquamous NSCLC. Therefore, we conducted this study to determine the recommended dose of carboplatin in combination with pemetrexed and assess the feasibility of pemetrexed maintenance therapy.
original articles
Annals of Oncology
experienced toxic effects that met the DLT criteria, treatment doses were modified in subsequent courses.
rearrangement. Stage IIIB and IV disease was found in 2 and 11 patients, respectively; four had suffered a relapse after surgical resection.
assessment procedures and efficacy evaluation
statistical methods Kaplan–Meier (K-M) plots were used for OS and PFS analysis; the median and 95% confidence intervals were determined. The incidence of the adverse events was calculated for each dose group, and the distribution of the best overall responses was summarized in patients with target lesions.
results patient characteristics Between October 2010 and May 2012, 17 patients from two institutions were enrolled into this study. Table 1 shows the characteristics of the 17 assessable patients, nine of whom were men. The median patient age was 78 years (range 75–83 years). The majority of the patients (12 individuals) had a PS of 1. Histologically, there were 15 adenocarcinomas and 2 nonsmall-cell carcinomas; three of the patients harbored epidermal growth factor receptor (EGFR) mutations and one had an anaplastic lymphoma kinase (ALK) gene Table 1. The characteristics of 17 assessable patients Characteristics
Cohort 0 (n = 3)
Cohort 1 (n = 7)
Cohort 2 (n = 7)
Total (N = 17)
Age (median) Male gender (%) PS: 0/1 Histology: Ad/large/NOS Stage: NIB/IV/relapse EGFR mutation+/ALK+ Exon 19/Exon 21 EGFR wild/unknown ALK positive
76–82 (79) 2 (66.7) 0/3 2/0/1 0/2/1
76–83 (78) 2(28.6) 3/4 6/0/1 1/5/1
75–81 (79) 5(71.4) 2/5 7/0/0 1/4/2
75–83 (78) 9(52.9) 5/12 15/0/2 2/11/4
0/0 2/1 0
0/0 6/0 1
2/1 4/0 0
2/1 12/1 1
| Tamiya et al.
dose escalation The profile of the major toxic effects observed during the DLT period is shown in Table 2. In dose cohort 0, DLT was not observed in the first three patients. In dose cohort 1, DLT was also not observed in the first three patients. In dose cohort 2, DLT was observed in one of three patients (grade 4 thrombocytopenia). Therefore, another four patients were assigned to receive the same dose. Of those four patients, one patient developed grade 4 thrombocytopenia and one patient developed grade 3 febrile neutropenia. Thus, DLTs were observed in three of the seven patients in the dose cohort. As a result, dose cohort 2 (carboplatin, AUC of 6, and 500 mg/m2 pemetrexed) was determined to be the maximum tolerated dose. Further, in dose cohort 1, another four patients received the treatment, without any observed DLT. Therefore, the recommended dose was carboplatin at an AUC of 5 and 500 mg/m2 pemetrexed. Figure 1 summarizes the determination of the recommended dose.
toxic effects The profile of the major toxic effects observed during the total treatment period is shown in Table 3. The hematological adverse events that were ≥grade 3 included neutropenia (47%), anemia (29%), and thrombocytopenia (35%). Of these events, grade 4 thrombocytopenia and neutropenia were observed in two patients; no grade 4 leukopenia events were observed. Few toxic effects were observed during the maintenance period, which were characterized by good tolerability. The major adverse events were anemia (60%), fatigue (70%), anorexia (40%), and elevated transaminase (AST/ALT) (50%). Adverse events ≥grade 3, including grade 4 neutropenia, grade 3 infection, and a grade 3 transaminase elevation, were observed in one patient. One of the 10 patients discontinued treatment because of adverse events (grade 2 fatigue and grade 3 transaminase elevation), and one patient needed dose reduction because of adverse events (grade 3 infection). There was one treatment-related death (TRD). In this case, the patient was a 79-year-old man (EGFR mutation negative) without comorbidity who died suddenly during the third cycle. Although a clear cause could not be determined, sudden death due to arrhythmia was unlikely. The adverse events observed in the study were well managed, and most of the patients recovered from such adverse events following dose adjustment or discontinuation of the study treatment. Nonhematological toxic effects (grade 3 or higher) included, fatigue and infection (12% each).
efficacy The observed efficacy during the total treatment period is shown in Table 4. The overall response rate was 47.1%. There were eight partial responses (one of the three patients in cohort 0, 4 of the seven patients in cohort 1, and three of the seven patients in cohort 2) and no complete responses. Ten of the 17 patients received maintenance therapy, following a median of
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Within the 4 weeks before study entry, all patients underwent computed tomography CT or magnetic resonance imaging (MRI) of the brain, and a bone scan. Within the 2 weeks before study entry, all patients underwent chest radiography, a complete blood cell count, and measurement of blood chemistry values. Within the week before study entry, all patients had their history taken, physical examination, measurement of body weight, and assessment of performance status. Evaluations were conducted at least every 2 weeks throughout the study and were conducted at least every week during the first administration course (DLT period), and evaluations included a complete history, physical examination, complete blood cell count, and measurement of blood chemistry values; CT scans of all involved sites was carried out every 6–8 weeks. If there was clinical doubt about the involvement of a new site, a CT, MRI, or bone scan for this potential new site was also required, according to the RECIST guidelines [24]. The efficacy end points were tumor response, PFS time, and OS. PFS was defined as the time from enrollment to the date of confirmation of PD or the date of death from any cause. OS was defined as the time from study registration until death from any cause. For patients not known to have died and to have had progression, the patients were censored at the date of the last progression-free assessment. The cutoff date was 30 July 2012.
original articles
Annals of Oncology Table 2. The profile of major toxic effects during the DLT period Cohort 0 (n = 3) grade ≤ 2/ ≥ 3 (4)
Cohort 1 (n = 7) grade ≤ 2/ ≥ 3 (4)
Cohort 2 (n = 7) grade ≤ 2/ ≥ 3 (4)
Total (N = 17) grade ≤ 2/ ≥ 3 (4)
Leucopenia Neutropenia Anemia (Hb) Thrombocytopenia Febrile Neutropenia AST/ALT Creatinine Anorexia/nausea Fatigue Skin trouble Constipation Stomatitis Pneumonitis Infection
0/0 0/0 2/0 2/0 −/0 1/0 1/0 1/0 1/0 1/0 1/0 1/0 0/0 1/0
2/1 2/2 5/1 4/0 −/0 2/0 2/0 3/0 1/0 0/0 4/0 1/0 0/0 0/0
4/0 2/4 3/0 1/4 (2) (2 DLT) −/1 (1 DLT) 3/0 1/0 3/0 3/0 0/0 2/1 0/0 0/0 2/0
6/1 4/6 10/1 7/4 (2) −/1 6/0 4/0 7/0 5/0 1/0 7/1 2/0 0/0 3/0
Figure 1. The flow chart of the present study.
five cycles. All 17 patients were assessable for PFS and OS. At a median follow-up period of 14.4 months (range 2.2–20.6 months), nine patients are alive. The median PFS for all patients was 5.1 months (95% CI 2.4–7.7 months; supplementary Table 1, available at Annals of Oncology online), whereas the median OS was 16.5 months (95% CI 7.7–26.9 months; supplementary Table 2, available at Annals of Oncology online).
post chemotherapy Six of the 17 patients (35.3%) received after first-line chemotherapy. All of the three patients harboring the EGFR mutation received gefitinib monotherapy as a second-line chemotherapy. Seven of the 17 (41.1%) patients discontinued chemotherapy because of disease progression, whereas four patients remained on the maintenance pemetrexed chemotherapy.
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discussion Phase III studies have demonstrated that first-line pemetrexedbased platinum doublet therapy, followed by pemetrexed maintenance therapy, is efficacious, and may be an alternative treatment option for patients with advanced nonsquamous NSCLC [21]. Further, phase III studies have also demonstrated that first-line platinum-based therapy is more efficacious in elderly patients than is monotherapy (vinorelbine and gemcitabine), and that platinum-based therapy is an alternative treatment option for elderly patients with advanced NSCLC. This was the first dose-escalation study to investigate the recommended dose of carboplatin–pemetrexed as a first-line therapy for ≥75-year-old patients with advanced nonsquamous NSCLC. In Japan, the inclusion criterion for a previous pivotal study using platinum doublet chemotherapy was <75 years old [25], so there was insufficient safety and efficacy data available for patients ≥75 years. Nonplatinum monotherapy was
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Toxicity
original articles
Annals of Oncology
Table 3. The profile of major toxic effects during the total treatment period Cohort 0 (n = 3) grade ≤ 2/ ≥ 3 (4)
Cohort 1 (n = 7) grade ≤ 2/ ≥ 3 (4)
Cohort 2 (n = 7) grade ≤ 2/ ≥ 3 (4)
Total (N = 17) grade ≤ 2/ ≥ 3 (4)
Leucopenia Neutropenia Anemia (Hb) Thrombocytopenia Febrile neutropenia AST/ALT Creatinine Anorexia/nausea Fatigue Skin trouble Constipation Stomatitis Pneumonitis Infection
0/0 1 10 3/0 3/0 −/0 2/0 1/0 2/0 2/0 2/0 1/0 1/0 1/0 1/0
4/1 2/3 3/4 6/1 −/0 3/0 4/0 6/0 6/0 2/0 4/0 3/0 0/0 1/1
6/0 1/5 (1) 5/1 2/5 (2) −/1 3/1 2/0 3/0 3/2 1/0 3/1 1/0 1/0 1/1
10/1 4/8 (1) 11/5 11/6 (2) −/1 6/1 7/0 11/0 11/2 5/0 8/1 5/0 2/0 3/2
Table 4. The efficacy during the total treatment period
Best efficacy CR/PR/SD/PD Response rate (%) Disease control rate (%) Progression-free survival median PFS (months) 95% CI (months) Overall survival median (months) 95% CI (months) Maintenance case (n) Extraction rate (%)
Cohort 0 (n = 3)
Cohort 1 (n = 7)
Cohort 2 (n = 7)
Total (N = 17)
0/1/1/1 33.3 66.7 —
0/4/2/1 57.1 85.7 —
0/3/2/2 42.9 71.4 —
0/8/5/4 47.1 76.5 5.1
—
—
—
2.4–7.7 16.5
1/3 33.3
5/7 76.5
4/7 57.1
7.7–26.9 10/17 58.8
considered to be standard therapy; therefore, this study was planned to investigate whether carboplatin can be added to pemetrexed, and to determine its RD. Therefore, only the carboplatin dose was modified, not the pemetrexed dose. The present study was able to identify the recommended therapeutic dose for carboplatin and pemetrexed therapy in an elderly population. Three patients were treated with carboplatin at an AUC of 4 plus 500 mg/m2 pemetrexed (cohort 0); seven were treated with carboplatin at an AUC of 5 plus the same dose of pemetrexed (cohort 1); and another seven were treated with carboplatin at an AUC of 6 in addition to the same dose of pemetrexed (cohort 2). DLTs were not observed in either cohort 0 or 1, but three patients in cohort 2 were observed to experience DLT. Two of the 3 DLTs were grade 4 thrombocytopenia, and the other was a grade 3 febrile neutropenia. Therefore, the recommended dose for this elderly population was determined to be carboplatin at an AUC of 5, in combination with 500 mg/m2 pemetrexed. This dose is different from that recommended for patients <75 years old, which is carboplatin at an AUC of 6, combined with 500 mg/ m2 pemetrexed [22]. This difference suggests that ≥75-year-old patients should be distinguished from those <75 years when
| Tamiya et al.
they are treated with these therapeutic agents; the need for such a distinction may also apply to patients receiving other platinum-based chemotherapies. The distinction in therapeutic dosing regimens may reflect declines in physiological functions in elderly patients, who typically have more comorbidities and take more concomitant medications than younger patients. In the present study, 10 patients (cohort 0, 1; cohort 1, 5; and cohort 2, 4) continued pemetrexed as a maintenance therapy after four cycles of the combined therapy. The median number of cycles of pemetrexed maintenance therapy was 5. One of the 10 patients discontinued treatment due to adverse events (grade 2 fatigue), and one needed dose reduction, due to adverse events (grade 3 infection). However, no unexpected adverse events or cumulative toxic effects were observed during the maintenance phase. This indicated that pemetrexed maintenance therapy was tolerable, following carboplatin–pemetrexed therapy. Although only a small number of patients received maintenance therapy, pemetrexed is still considered to have good tolerability for maintenance therapy in elderly patients. These results constitute the first safety report for pemetrexed maintenance therapy for this population of patients. The observed response rate of 47.1%, the median PFS of 5.1 months (95% CI 2.4–7.7 months), and the OS of 16.5 months (95% CI 7.7–26.9 months) was demonstrative of good efficacy, even though it involved only a small sample size. Previous Japanese phase I and II studies of carboplatin–pemetrexed, followed by pemetrexed maintenance therapy, showed response rates of 60.0% and 39.0% [22, 26], respectively, in a younger population of patients. For elderly nonsquamous NSCLC patients, carboplatin–pemetrexed followed by pemetrexed might be similarly effective as in younger patients with advanced nonsquamous NSCLC. In the present study, the combination of carboplatin at an AUC of 5 plus 500 mg/m2 pemetrexed as the RD was confirmed to be reasonably well tolerated and effective for chemotherapy naïve, elderly (≥75 years) Japanese patients with advanced nonsquamous NSCLC; this regimen is recommended for the target population. Pemetrexed maintenance therapy,
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Toxicity
Annals of Oncology
following the combination therapy, was well tolerated. This trial provides the rationale for larger scale trials of carboplatin– pemetrexed for elderly patients with advanced nonsquamous NSCLC. A multicenter, phase II trial is now ongoing to confirm these findings.
acknowledgements The authors thank all the participants of this study.
disclosure The authors have declared no conflicts of interest.
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references
original articles
Annals of Oncology Annals of Oncology 24: 980–985, 2013 doi:10.1093/annonc/mds544 Published online 7 November 2012
Dose escalation study of carboplatin–pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer
1 Department of Internal Medicine, Kinki-Chuo Chest Medical Center, Osaka; 2Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka, Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka; 3Department of Clinical Research Center, Kinki-Chuo Chest Medical Center, Osaka, Japan
Received 11 August 2012; revised 11 September 2012; accepted 14 September 2012
Background: This study was designed to determine the recommended dose of carboplatin–pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC).
Patients and methods: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. Results: The combination of carboplatin at an area under the concentration–time curve (AUC) of 5, and 500 mg/m2 pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68–216 days) and the median overall survival time was 461 days (95% CI 168–754 days). Conclusions: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m2) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC. Key words: carboplatin, elderly, maintenance therapy, nonsmall-cell lung cancer, pemetrexed
introduction Nonsmall-cell lung cancer (NSCLC) accounts for >80% of all lung cancers, and the risk of lung cancer clearly increases with advancing age. Because of the progressive aging of the population, the number of elderly patients with NSCLC is increasing, and the disease is becoming an increasing public health problem worldwide [1, 2]. Platinum-based chemotherapy is the standard first-line treatment of advanced NSCLC, based on the moderate improvements in survival and quality of life that it confers compared with the best supportive care alone [3–5]. However, elderly people are underrepresented in clinical trials [6, 7] and, therefore, might not receive the most appropriate treatment in practice. The under*Correspondence to: Dr M. Tamiya, Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino 3–7-1, Habikino City, Osaka 583-8588, Japan. Tel: +81-72957-2121; Fax: +81-72-957-8002; E-mail: [email protected]
representation of the elderly in clinical trials may be the result of the pessimism of the doctors, patients, and their relatives about the relevance of the treatment or drug-related toxic effects [8]. Retrospective analyses, conducted on subsets of patients >70 years old in several phase III NSCLC trials, have suggested that platinum-based doublet therapy may be an appropriate option for fit, elderly patients [9–13]. In addition, many elderly specific prospective trials have clearly established the efficacy of single-agent chemotherapy in ≥70-year-old patients with advanced NSCLC [14–17]. Further, a recent French phase III trial, specifically designed for the elderly, showed that carboplatin–paclitaxel conferred a significant improvement on overall survival (OS), compared with single agents vinorelbine or gemcitabine, with moderate toxicity [18]. This study has shed new light on platinum-doublet chemotherapy for elderly patients with advanced NSCLC. Pemetrexed is a multitargeted, antifolate cytotoxic agent that has been demonstrated to be efficacious in combination with
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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A. Tamiya1, M. Tamiya2*, T. Shiroyama2, M. Kanazu1, A. Hirooka1, T. Tsuji1, N. Morishita2, K. Asami1, H. Suzuki2, N. Okamoto2, K. Okishio3, T. Kawaguchi1, T. Hirashima2, S. Atagi3 & I. Kawase2
original articles
Annals of Oncology
patients and methods study design The present dose-escalation study was conducted to examine the safety of carboplatin–pemetrexed combinations for chemo-naive elderly (≥75 years) patients with advanced nonsquamous NSCLC. The primary objectives of this study were to evaluate the incidence, type, and severity of adverse events and determine the recommended dose of carboplatin for use in combination with pemetrexed. Patients were divided into three cohorts: cohort 0 patients were treated with carboplatin at an AUC of 4 plus 500 mg/m2 pemetrexed; cohort 1 patients received carboplatin at an AUC of 5 plus 500 mg/m2 pemetrexed; and cohort 2 patients received carboplatin at an AUC of 6 plus 500 mg/m2 pemetrexed. In each cohort, if one instance of DLT was observed among three patients, three additional patients were treated at the same dose level. Dose escalation continued if DLT was observed in no more than one of six patients. If two of three patients, or at least two of six patients, showed DLT at a given dose level, that level was considered the MTD and one dose level below that was considered the RD. Dose escalation was decided by the toxicity data in the first cycle of chemotherapy. The recommended dose was determined based on these initial results from cohorts 0, 1, and 2.
eligibility Elderly (≥75 years) patients with histologically or cytologically confirmed nonsquamous NSCLC were eligible for the study. Each patient was required to meet the following criteria: (i) clinical stage IIIB, IV, or postoperative recurrent disease; (ii) lesions not amenable for curative radiation; (iii) no prior chemotherapy; (iv) age, ≥75 years; (v) Eastern
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Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (vi) measurable lesions by Response Evaluated Criteria in Solid Tumors (RECIST ver1.1); (vii) adequate functioning of major internal organs (lung: SpO2, ≥90%; bone marrow: hemoglobin ≥9.5 g/dl, white blood cell count ≥3500/mm3, neutrophil count ≥2000/mm3, platelet count ≥100 000/mm3; liver: aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤2.5 times upper limit of normal, total bilirubin ≤1.5 mg/dl; kidney: serum creatinine ≤1.2 mg/dl, predicted creatinine clearance or 24 h creatinine clearance ≥45 ml/min, as estimated by the Cockcroft and Gault formula [23]); and (viii) life expectancy of at least 3 months. Peripheral blood and biochemistry examinations were repeated at least once every 2 weeks after the initial evaluation. This study followed the ethical principles in the Declaration of Helsinki, and the local institution review board approved this protocol before initiation of the study. All patients provided written informed consent before study-related procedures were carried out.
study treatments All patients received 500 mg/m2 pemetrexed by 10-min intravenous infusion, followed by intravenous infusion of carboplatin over at least 30 min (to an AUC of 4, 5, or 6) on day 1 of a 21-day cycle. Combination chemotherapy was repeated every 3 weeks for a maximum of four cycles. After the completion of four cycles, only patients with controlled disease were eligible for maintenance therapy; and continued pemetrexed treatment was possible, at the discretion of the investigator, until progressive disease (PD) was observed. Subsequent cycles of treatment were withheld until the following criteria were observed: neutrophil counts ≥1500/mm3, platelet count ≥100 000/mm3, PS ≤ 1, SpO2 ≥ 90%, AST/ ALT ≤ 2.5 times upper limit of normal, serum creatinine ≤1.2 mg/dl, other nonhematological toxicity was ≤grade 2, and recommendation by the physician. If the toxicity had not resolved within 43 days, the patient was excluded from further participation in the study. Treatment doses during induction and maintenance therapies were to be modified as follows: in cases of toxicity, the pemetrexed dose was to be reduced from 500 to 400 mg/m2, and the carboplatin dose was to be reduced from AUC 6 to 5 (or 5 to 4) during induction therapy, or the pemetrexed dose was to be reduced from 500 to 400 mg/m2 during maintenance therapy. The toxic effects requiring dose reduction were set as grade 4 leukopenia and thrombocytopenia, febrile neutropenia, and grade 3 nonhematological toxic effects, excluding fatigue, nausea, and anorexia. When further dose reduction was required because of continuing evidence of toxicity during either the induction or maintenance therapy, the patient discontinued the protocol. While the patients were on study, they received supplemental folic acid and vitamin B12. All patients underwent comprehensive baseline assessments including clinical laboratory tests and imaging studies. Patients also received follow-up assessments and monitoring at regular intervals. Toxicity evaluations were based on the Common Terminology Criteria for Adverse Events, version 4.0.
definition of DLT DLT was defined as a toxicity occurring in cycle 1 that met one of the following criteria and for which a causal relationship with the study drugs could not be ruled out: grade 4 leukopenia, febrile neutropenia, grade 4 thrombocytopenia, or grade 3 nonhematological toxicity that did not resolve within 43 days (the following events were DLT, if the event did not recover to ≤grade 2, despite standard/optimal supportive treatment: nausea, vomiting, anorexia, fatigue, constipation, diarrhea, transient increase in AST/ALT, or transient electrolyte abnormality). If the patients
doi:10.1093/annonc/mds544 |
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cisplatin for first-line treatment of nonsquamous NSCLC in randomized phase III clinical studies [19]. This phase III study reported noninferior efficacy and better tolerability for cisplatin–pemetrexed than for cisplatin–gemcitabine in the first-line setting. In addition, OS was statistically superior for cisplatin–pemetrexed versus cisplatin–gemcitabine in patients with nonsquamous NSCLC [20]. Another phase III clinical study demonstrated superior progression-free survival (PFS) and OS when pemetrexed was used in a maintenance setting following four cycles of cisplatin–pemetrexed [21]. These study results indicated that pemetrexed-based platinum doublet induction therapy followed by pemetrexed maintenance therapy deserves to be evaluated as a treatment option for elderly (≥75 years old) patients with advanced nonsquamous NSCLC. Because carboplatin-based regimens have been shown to be less toxic, convenient, and capable of being administered on an outpatient basis, they have been widely used as a substitute for cisplatin regimens in clinical practice. In a previous Japanese dose-escalation study of carboplatin–pemetrexed in a first-line setting for <75-year-old patients, carboplatin doses (AUC of 6) and pemetrexed (500 mg/m2) were recommended [22] and used in clinical settings. However, carboplatin dose-escalation has not been evaluated in chemotherapy-naive elderly (≥75year old) patients with advanced nonsquamous NSCLC. Therefore, we conducted this study to determine the recommended dose of carboplatin in combination with pemetrexed and assess the feasibility of pemetrexed maintenance therapy.
original articles
Annals of Oncology
experienced toxic effects that met the DLT criteria, treatment doses were modified in subsequent courses.
rearrangement. Stage IIIB and IV disease was found in 2 and 11 patients, respectively; four had suffered a relapse after surgical resection.
assessment procedures and efficacy evaluation
statistical methods Kaplan–Meier (K-M) plots were used for OS and PFS analysis; the median and 95% confidence intervals were determined. The incidence of the adverse events was calculated for each dose group, and the distribution of the best overall responses was summarized in patients with target lesions.
results patient characteristics Between October 2010 and May 2012, 17 patients from two institutions were enrolled into this study. Table 1 shows the characteristics of the 17 assessable patients, nine of whom were men. The median patient age was 78 years (range 75–83 years). The majority of the patients (12 individuals) had a PS of 1. Histologically, there were 15 adenocarcinomas and 2 nonsmall-cell carcinomas; three of the patients harbored epidermal growth factor receptor (EGFR) mutations and one had an anaplastic lymphoma kinase (ALK) gene Table 1. The characteristics of 17 assessable patients Characteristics
Cohort 0 (n = 3)
Cohort 1 (n = 7)
Cohort 2 (n = 7)
Total (N = 17)
Age (median) Male gender (%) PS: 0/1 Histology: Ad/large/NOS Stage: NIB/IV/relapse EGFR mutation+/ALK+ Exon 19/Exon 21 EGFR wild/unknown ALK positive
76–82 (79) 2 (66.7) 0/3 2/0/1 0/2/1
76–83 (78) 2(28.6) 3/4 6/0/1 1/5/1
75–81 (79) 5(71.4) 2/5 7/0/0 1/4/2
75–83 (78) 9(52.9) 5/12 15/0/2 2/11/4
0/0 2/1 0
0/0 6/0 1
2/1 4/0 0
2/1 12/1 1
| Tamiya et al.
dose escalation The profile of the major toxic effects observed during the DLT period is shown in Table 2. In dose cohort 0, DLT was not observed in the first three patients. In dose cohort 1, DLT was also not observed in the first three patients. In dose cohort 2, DLT was observed in one of three patients (grade 4 thrombocytopenia). Therefore, another four patients were assigned to receive the same dose. Of those four patients, one patient developed grade 4 thrombocytopenia and one patient developed grade 3 febrile neutropenia. Thus, DLTs were observed in three of the seven patients in the dose cohort. As a result, dose cohort 2 (carboplatin, AUC of 6, and 500 mg/m2 pemetrexed) was determined to be the maximum tolerated dose. Further, in dose cohort 1, another four patients received the treatment, without any observed DLT. Therefore, the recommended dose was carboplatin at an AUC of 5 and 500 mg/m2 pemetrexed. Figure 1 summarizes the determination of the recommended dose.
toxic effects The profile of the major toxic effects observed during the total treatment period is shown in Table 3. The hematological adverse events that were ≥grade 3 included neutropenia (47%), anemia (29%), and thrombocytopenia (35%). Of these events, grade 4 thrombocytopenia and neutropenia were observed in two patients; no grade 4 leukopenia events were observed. Few toxic effects were observed during the maintenance period, which were characterized by good tolerability. The major adverse events were anemia (60%), fatigue (70%), anorexia (40%), and elevated transaminase (AST/ALT) (50%). Adverse events ≥grade 3, including grade 4 neutropenia, grade 3 infection, and a grade 3 transaminase elevation, were observed in one patient. One of the 10 patients discontinued treatment because of adverse events (grade 2 fatigue and grade 3 transaminase elevation), and one patient needed dose reduction because of adverse events (grade 3 infection). There was one treatment-related death (TRD). In this case, the patient was a 79-year-old man (EGFR mutation negative) without comorbidity who died suddenly during the third cycle. Although a clear cause could not be determined, sudden death due to arrhythmia was unlikely. The adverse events observed in the study were well managed, and most of the patients recovered from such adverse events following dose adjustment or discontinuation of the study treatment. Nonhematological toxic effects (grade 3 or higher) included, fatigue and infection (12% each).
efficacy The observed efficacy during the total treatment period is shown in Table 4. The overall response rate was 47.1%. There were eight partial responses (one of the three patients in cohort 0, 4 of the seven patients in cohort 1, and three of the seven patients in cohort 2) and no complete responses. Ten of the 17 patients received maintenance therapy, following a median of
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Within the 4 weeks before study entry, all patients underwent computed tomography CT or magnetic resonance imaging (MRI) of the brain, and a bone scan. Within the 2 weeks before study entry, all patients underwent chest radiography, a complete blood cell count, and measurement of blood chemistry values. Within the week before study entry, all patients had their history taken, physical examination, measurement of body weight, and assessment of performance status. Evaluations were conducted at least every 2 weeks throughout the study and were conducted at least every week during the first administration course (DLT period), and evaluations included a complete history, physical examination, complete blood cell count, and measurement of blood chemistry values; CT scans of all involved sites was carried out every 6–8 weeks. If there was clinical doubt about the involvement of a new site, a CT, MRI, or bone scan for this potential new site was also required, according to the RECIST guidelines [24]. The efficacy end points were tumor response, PFS time, and OS. PFS was defined as the time from enrollment to the date of confirmation of PD or the date of death from any cause. OS was defined as the time from study registration until death from any cause. For patients not known to have died and to have had progression, the patients were censored at the date of the last progression-free assessment. The cutoff date was 30 July 2012.
original articles
Annals of Oncology Table 2. The profile of major toxic effects during the DLT period Cohort 0 (n = 3) grade ≤ 2/ ≥ 3 (4)
Cohort 1 (n = 7) grade ≤ 2/ ≥ 3 (4)
Cohort 2 (n = 7) grade ≤ 2/ ≥ 3 (4)
Total (N = 17) grade ≤ 2/ ≥ 3 (4)
Leucopenia Neutropenia Anemia (Hb) Thrombocytopenia Febrile Neutropenia AST/ALT Creatinine Anorexia/nausea Fatigue Skin trouble Constipation Stomatitis Pneumonitis Infection
0/0 0/0 2/0 2/0 −/0 1/0 1/0 1/0 1/0 1/0 1/0 1/0 0/0 1/0
2/1 2/2 5/1 4/0 −/0 2/0 2/0 3/0 1/0 0/0 4/0 1/0 0/0 0/0
4/0 2/4 3/0 1/4 (2) (2 DLT) −/1 (1 DLT) 3/0 1/0 3/0 3/0 0/0 2/1 0/0 0/0 2/0
6/1 4/6 10/1 7/4 (2) −/1 6/0 4/0 7/0 5/0 1/0 7/1 2/0 0/0 3/0
Figure 1. The flow chart of the present study.
five cycles. All 17 patients were assessable for PFS and OS. At a median follow-up period of 14.4 months (range 2.2–20.6 months), nine patients are alive. The median PFS for all patients was 5.1 months (95% CI 2.4–7.7 months; supplementary Table 1, available at Annals of Oncology online), whereas the median OS was 16.5 months (95% CI 7.7–26.9 months; supplementary Table 2, available at Annals of Oncology online).
post chemotherapy Six of the 17 patients (35.3%) received after first-line chemotherapy. All of the three patients harboring the EGFR mutation received gefitinib monotherapy as a second-line chemotherapy. Seven of the 17 (41.1%) patients discontinued chemotherapy because of disease progression, whereas four patients remained on the maintenance pemetrexed chemotherapy.
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discussion Phase III studies have demonstrated that first-line pemetrexedbased platinum doublet therapy, followed by pemetrexed maintenance therapy, is efficacious, and may be an alternative treatment option for patients with advanced nonsquamous NSCLC [21]. Further, phase III studies have also demonstrated that first-line platinum-based therapy is more efficacious in elderly patients than is monotherapy (vinorelbine and gemcitabine), and that platinum-based therapy is an alternative treatment option for elderly patients with advanced NSCLC. This was the first dose-escalation study to investigate the recommended dose of carboplatin–pemetrexed as a first-line therapy for ≥75-year-old patients with advanced nonsquamous NSCLC. In Japan, the inclusion criterion for a previous pivotal study using platinum doublet chemotherapy was <75 years old [25], so there was insufficient safety and efficacy data available for patients ≥75 years. Nonplatinum monotherapy was
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Annals of Oncology
Table 3. The profile of major toxic effects during the total treatment period Cohort 0 (n = 3) grade ≤ 2/ ≥ 3 (4)
Cohort 1 (n = 7) grade ≤ 2/ ≥ 3 (4)
Cohort 2 (n = 7) grade ≤ 2/ ≥ 3 (4)
Total (N = 17) grade ≤ 2/ ≥ 3 (4)
Leucopenia Neutropenia Anemia (Hb) Thrombocytopenia Febrile neutropenia AST/ALT Creatinine Anorexia/nausea Fatigue Skin trouble Constipation Stomatitis Pneumonitis Infection
0/0 1 10 3/0 3/0 −/0 2/0 1/0 2/0 2/0 2/0 1/0 1/0 1/0 1/0
4/1 2/3 3/4 6/1 −/0 3/0 4/0 6/0 6/0 2/0 4/0 3/0 0/0 1/1
6/0 1/5 (1) 5/1 2/5 (2) −/1 3/1 2/0 3/0 3/2 1/0 3/1 1/0 1/0 1/1
10/1 4/8 (1) 11/5 11/6 (2) −/1 6/1 7/0 11/0 11/2 5/0 8/1 5/0 2/0 3/2
Table 4. The efficacy during the total treatment period
Best efficacy CR/PR/SD/PD Response rate (%) Disease control rate (%) Progression-free survival median PFS (months) 95% CI (months) Overall survival median (months) 95% CI (months) Maintenance case (n) Extraction rate (%)
Cohort 0 (n = 3)
Cohort 1 (n = 7)
Cohort 2 (n = 7)
Total (N = 17)
0/1/1/1 33.3 66.7 —
0/4/2/1 57.1 85.7 —
0/3/2/2 42.9 71.4 —
0/8/5/4 47.1 76.5 5.1
—
—
—
2.4–7.7 16.5
1/3 33.3
5/7 76.5
4/7 57.1
7.7–26.9 10/17 58.8
considered to be standard therapy; therefore, this study was planned to investigate whether carboplatin can be added to pemetrexed, and to determine its RD. Therefore, only the carboplatin dose was modified, not the pemetrexed dose. The present study was able to identify the recommended therapeutic dose for carboplatin and pemetrexed therapy in an elderly population. Three patients were treated with carboplatin at an AUC of 4 plus 500 mg/m2 pemetrexed (cohort 0); seven were treated with carboplatin at an AUC of 5 plus the same dose of pemetrexed (cohort 1); and another seven were treated with carboplatin at an AUC of 6 in addition to the same dose of pemetrexed (cohort 2). DLTs were not observed in either cohort 0 or 1, but three patients in cohort 2 were observed to experience DLT. Two of the 3 DLTs were grade 4 thrombocytopenia, and the other was a grade 3 febrile neutropenia. Therefore, the recommended dose for this elderly population was determined to be carboplatin at an AUC of 5, in combination with 500 mg/m2 pemetrexed. This dose is different from that recommended for patients <75 years old, which is carboplatin at an AUC of 6, combined with 500 mg/ m2 pemetrexed [22]. This difference suggests that ≥75-year-old patients should be distinguished from those <75 years when
| Tamiya et al.
they are treated with these therapeutic agents; the need for such a distinction may also apply to patients receiving other platinum-based chemotherapies. The distinction in therapeutic dosing regimens may reflect declines in physiological functions in elderly patients, who typically have more comorbidities and take more concomitant medications than younger patients. In the present study, 10 patients (cohort 0, 1; cohort 1, 5; and cohort 2, 4) continued pemetrexed as a maintenance therapy after four cycles of the combined therapy. The median number of cycles of pemetrexed maintenance therapy was 5. One of the 10 patients discontinued treatment due to adverse events (grade 2 fatigue), and one needed dose reduction, due to adverse events (grade 3 infection). However, no unexpected adverse events or cumulative toxic effects were observed during the maintenance phase. This indicated that pemetrexed maintenance therapy was tolerable, following carboplatin–pemetrexed therapy. Although only a small number of patients received maintenance therapy, pemetrexed is still considered to have good tolerability for maintenance therapy in elderly patients. These results constitute the first safety report for pemetrexed maintenance therapy for this population of patients. The observed response rate of 47.1%, the median PFS of 5.1 months (95% CI 2.4–7.7 months), and the OS of 16.5 months (95% CI 7.7–26.9 months) was demonstrative of good efficacy, even though it involved only a small sample size. Previous Japanese phase I and II studies of carboplatin–pemetrexed, followed by pemetrexed maintenance therapy, showed response rates of 60.0% and 39.0% [22, 26], respectively, in a younger population of patients. For elderly nonsquamous NSCLC patients, carboplatin–pemetrexed followed by pemetrexed might be similarly effective as in younger patients with advanced nonsquamous NSCLC. In the present study, the combination of carboplatin at an AUC of 5 plus 500 mg/m2 pemetrexed as the RD was confirmed to be reasonably well tolerated and effective for chemotherapy naïve, elderly (≥75 years) Japanese patients with advanced nonsquamous NSCLC; this regimen is recommended for the target population. Pemetrexed maintenance therapy,
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Toxicity
Annals of Oncology
following the combination therapy, was well tolerated. This trial provides the rationale for larger scale trials of carboplatin– pemetrexed for elderly patients with advanced nonsquamous NSCLC. A multicenter, phase II trial is now ongoing to confirm these findings.
acknowledgements The authors thank all the participants of this study.
disclosure The authors have declared no conflicts of interest.
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references
original articles