Abstract
Aim: We evaluated the pharmacokinetics and quality of life of elderly patients with advanced non-small-cell lung cancer (NSCLC) treated with bi-weekly carboplatin and paclitaxel chemotherapy, and determined the maximum tolerated dose (MTD) of this treatment. Patients and Methods: Eligible patients had histologically- or cytologically-proven inoperable NSCLC, age of 70 years or older, no prior treatment, and Eastern Cooperative Oncology Group performance status 0-2. Paclitaxel was administered in combination with carboplatin under a bi-weekly schedule. We determined the plasma concentrations of both drugs during therapy. Results: The median patient age was 80 years. Using carboplatin at AUC 3, the MTD of paclitaxel was 100 mg/m2. Both hematological and non-hematological toxicities were mostly mild and manageable. Although paclitaxel is predominantly metabolized in the liver, clearance was decreased in patients with lower estimated glomerular filtration rate. Conclusion: Bi-weekly treatment, as described here, is feasible for elderly patients as a conventional regimen, particularly in the outpatient setting, due to its lower toxicity.
- Aged patient
- elderly
- non-small cell lung cancer
- chemotherapy
- pharmacokinetics
- quality of life
- carboplatin
- paclitaxel
- maximum tolerated dose
Lung cancer is the leading cause of cancer death worldwide, and the number of elderly patients with non-small cell lung cancer (NSCLC) is increasing in Japan. Lung cancer in elderly patients is an increasingly common problem faced by thoracic oncologists, and given Japan's position as one of the fasting aging societies in the world, Japanese oncologists have a duty to establish evidence supporting new treatments for lung cancer in elderly patients. A number of prospective trials specifically for such patients have clearly established the efficacy of single-agent chemotherapy in advanced NSCLC (1-3). However, a phase III trial (4) and subset analysis (5-7) conducted on patients aged over 70 years with advanced NSCLC, suggested that platinum-based doublet therapy may be an appropriate option for fit elderly individuals, although the frequency and severity of toxic effects associated with the combination therapy is generally high. In addition, the 2009 American Society of Clinical Oncology (ASCO) guidelines stated that the evidence does not support the selection of a specific first-line chemotherapy drug or combination based on patient age alone (8). However, the role of platinum-based doublet therapy on the benefit of survival and maintenance of quality of life (QOL) in elderly patients with NSCLC is unknown.
Currently, paclitaxel combined with carboplatin administered every three weeks (tri-weekly) is widely used as a standard first-line regimen for advanced NSCLC. Standard doses under this tri-weekly protocol in Japan are 200 mg/m2 for paclitaxel and area under the curve (AUC) of 6 mg/ml×min for carboplatin (9). The major clinical problem with this regimen is myelosuppression, which sometimes causes febrile neutropenia (FN) and treatment withdrawal. In their randomized phase II study, Sakakibara et al. showed that a weekly paclitaxel regimen was less toxic than the standard tri-weekly regimen in combination with carboplatin for elderly patients with NSCLC (10). As a result, patients receiving a weekly platinum-doublet regimen require weekly hospital visits for administration, and often require hospitalization for toxicity. To reduce hospital visits and toxicity, a bi-weekly carboplatin and paclitaxel (TC) regimen (drugs administered on day 1 and 15, respectively every four weeks) has been studied. Ichiki et al. (11) reported a recommended dose of paclitaxel of 140 mg/m2 for a bi-weekly regimen combined with carboplatin at an AUC of 3 mg/ml×min in non-elderly patients. This bi-weekly TC regimen was also considered superior in maintaining QOL, and in maintaining the dose intensity of the two drugs. These studies mainly enrolled patients who were not elderly (11), however, while optimum administration methods and dose of paclitaxel for elderly patients with NSCLC is still under investigation. Few studies have analyzed pharmacokinetic parameters for paclitaxel and carboplatin in the elderly.
Here, we conducted a phase I study to determine the maximum tolerated dose (MTD) and recommended dose of paclitaxel for a bi-weekly TC treatment regimen, and to evaluate not only the anti tumor response, toxicity, and QOL, but also the pharmacokinetics of both drugs in elderly patients with inoperable NSCLC. This trial is registered as UMIN 000005263, Tokyo, Japan.
Patients and Methods
Patient selection. Patients with histologically- or cytologically-proven NSCLC, aged 70 years or older, and with disease unsuitable for complete resection or concurrent chemoradiotherapy were eligible for the study. Other criteria included naïve to chemotherapy; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; adequate bone marrow, hepatic, and renal function; and normal blood coagulation parameters. Exclusion criteria included serious infections, clinically active brain metastasis or pleural effusion, or inability to metabolize alcohol. The protocol was approved by the Institutional Review Board of Shimane University Hospital. Each patient gave written informed consent before enrollment.
Study design. This study was designed as a single-center, prospective, single-arm phase I trial to determine the safety, tolerability, pharmacokinetics, tumor response, and QOL of bi-weekly TC administered to chemonaïve elderly patients with NSCLC. The primary endpoint was toxicity. A previous phase I trial had confirmed the safety and efficacy of bi-weekly TC with paclitaxel at 140 mg/m2 and of carboplatin at an AUC of 3 mg/ml×min in non-elderly patients with NSCLC (11). We have been using paclitaxel at 90 mg/m2 in bi-weekly TC treatment for elderly patients with NSCLC in our clinic, and have preliminary data of safety and tolerability. Based on these results, we set the starting dose of paclitaxel as 100 mg/m2, and escalated it in increments of 10 mg/m2. There was no dose escalation in individual patients. Carboplatin was administered at a fixed dose of AUC 3 mg/ml×min. The Calvert formula was used to calculate the dose of AUC for carboplatin. Paclitaxel and carboplatin were administered consecutively on days 1 and 15, with this treatment cycle was repeated every 28 days for six cycles, or until the occurrence of unacceptable toxicity, tumor progression, or death.
Patient evaluation. Toxicities were evaluated in the first cycle to determine the MTD. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia lasting four days or a grade 3 non-hematological toxicity, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (12), and cessation of treatment for more than eight days from the scheduled date due to toxicities. If more than three patients at the first level of paclitaxel experienced a DLT, the recommended dose of paclitaxel was determined as 90 mg/m2, and additional patients were to be enrolled to cohort II for pharmacokinetic study. All observations pertinent to safety were recorded, including the results of physical examinations, vital signs, adverse events, and laboratory data. Patients were monitored for adverse events, which were recorded with severity according to CTCAE version 3.0. Assessment of clinical response was performed radiologically according to the Response Evaluation Criteria in Solid Tumors (RECIST) (13).
Baseline characteristics of the study patients.
QOL was evaluated by the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire before the beginning of chemotherapy (baseline) and then every four weeks until 12 weeks after the start of treatment (four evaluations in total). The FACT-L instrument is a multidimensional questionnaire developed and validated for use in patients with lung cancer and which includes the 27-item FACT-General (FACT-G; version 4 in Japanese) questionnaire, which is targeted at general cancer patients, and seven questions specific to issues faced by patients with lung cancer (lung cancer subscale, LCS) (14). In this study, FACT-L was self-administered by the patients.
Pharmacokinetics. We collected blood samples for the pharmacokinetic study and determined the plasma concentrations of paclitaxel and platinum for carboplatin. For the pharmacokinetics of paclitaxel, samples were collected immediately after the infusion of paclitaxel and at 0.5, 1, 1.5, 2, 3, 5, 7, 9, and 24 h. For analysis of carboplatin, another sample was collected immediately after the infusion of carboplatin and at 0.5, 1, 3, 5, 7, 11, and 23 h. Paclitaxel concentration in plasma samples was determined using high-performance liquid chromatography (HPLC) assays (15). The platinum level in samples was measured by inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic parameters, including AUC, maximum concentration, and clearance for paclitaxel and carboplatin were calculated by WinNonlin Professional version 5.2 (Pharsight, Mountain View, CA, USA).
Adverse events for all courses and best overall response. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) version 3.0. Dose-limiting toxicity (DLT) was evaluated during the first cycle of treatment. DLT was defined as grade 4 neutropenia lasting four days or grade 3 non-hematological toxicity and cessation of treatment for more than eight days from the scheduled date due to toxicity.
Results
Patients' characteristics. A total of eight elderly chemonaïve patients with NSCLC were enrolled, five in cohort I and three in cohort II. Baseline demographics are shown in Table I. Median age was 80 years, ranging from 70 to 86 years. By histology, adenocarcinoma and squamous cell carcinoma accounted for four cases each. Seven patients had stage IIIB or IV disease. The one patient with stage IIIA disease had refused surgery, and showed radiological evidence of interstitial pneumonia and lung emphysema. The median number of administrations of bi-weekly TC was seven (3.8 cycles).
Safety and response. Table II summarizes the dosing regimens for the two cohorts together with toxicities and clinical response. Cohort I was treated with 100 mg/m2 of paclitaxel combined with AUC 3 mg/ml×min of carboplatin. Three out of five patients experienced DLTs during the first cycle of treatment, namely two with eight days' cessation of treatment due to prolonged neutropenia and liver dysfunction and one with grade 4 neutropenia lasting four days. The recommended dose of paclitaxel was therefore set at 90 mg/m2.
Best overall response was evaluated in all eight patients. One achieved a partial response (PR) (patient of cohort II), six had stable disease (SD), one progressive disease (PD) (patient of cohort I) and one could not be evaluated for response because he changed treatment regimen at the discretion of the attending physician, following one cycle of bi-weekly TC due to grade 2 allergic reaction.
Table III summarizes treatment-related adverse events for all courses. The most common hematological toxicity was neutropenia. Neutropenia of grade 4 occurred in one patient in cohort I and in one patient in cohort II. FN did not occur in either cohort. With regard to non-hematological toxicities, there was one case of grade 2 fatigue and grade 2 aspartate aminotransferase (AST)/alanine transaminase (ALT) elevation in cohort I, and one of grade 2 nausea and grade 2 allergic reaction in cohort II.
Assessment of QOL. QOL assessment using the FACT-L questionnaire was evaluated in all eight patients. Compliance with the FACT-L questionnaire was 100% at baseline, while three patients completed all three subsequent surveys, three patients completed two, and two patients completed one. Baseline QOL score and mean score are shown in Figure 1. FACT-L scores did not differ by treatment, indicating that QOL was maintained after the start of chemotherapy.
Pharmacokinetics. Pharmacokinetic analysis for paclitaxel and carboplatin was conducted for all eight patients on days 1 and 2 during the first cycle. Pharmacokinetic parameters for individual patients are listed in Table III. The targeted AUC of carboplatin was achieved with dose adjustment using the Calvert formula (Table IV). In terms of paclitaxel, systemic exposure to paclitaxel was increased in proportion to the increase in paclitaxel dose level (Table III, Figure 2). Marked inter-patient variation was observed in the clearance of paclitaxel, with no correlation with severe neutropenia. Although paclitaxel is predominantly metabolized in the liver, clearance was decreased in patients with lower estimated glomerular filtration rate (eGFR) (Figure 3).
Summary of hematological and non-hematological toxicities.
Discussion
In this phase I trial of bi-weekly TC for elderly patients with NSCLC, the recommended doses were determined to be 90 mg/m2 for paclitaxel and an AUC of 3 mg/ml×min for carboplatin. The overall response rate was 1/8, toxicity was acceptable and the QOL score was good. This regimen is therefore suitable for use in elderly patients with NSCLC in an outpatient setting. Furthermore, pharmacokinetic data suggest that the clearance of paclitaxel, which is predominantly metabolized in the liver, was associated with renal function.
To date, the optimal chemotherapy for the treatment of elderly patients with advanced NSCLC has remained undefined. Recently, a French group conducted phase III trials for elderly patients with NSCLC, and showed that carboplatin and weekly paclitaxel doublet chemotherapy was associated with a survival benefit comparable to monotherapy with third-generation chemotherapeutic agents (4). However, toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group, the most frequent of which was neutropenia. Similarly, neutropenia was the most common hematological toxicity in the present study. Although neutropenia of grade 4 occurred in two out of eight patients, FN did not occur. The incidence of grade 4 neutropenia in this study was lower than that with a weekly paclitaxel with carboplatin regimen, and the non-hematological toxicities were mostly mild and manageable. In particular, there were no cases of severe peripheral neuropathy. The PR rate was lower (1/8) than in a previous phase II study of bi-weekly TC (41.0%) (11) and a phase III study of conventional tri-weekly TC treatment (32.4%) (9) in Japanese non-elderly patients with advanced NSCLC; the reason for this difference remains unclear because of the substantial differences in sample size and patient profiles between these studies. Dose reduction or cessation of treatment due to toxicity was thought to be less frequent than with the tri-weekly regimen, likely because dose intensities of carboplatin and paclitaxel were only 75% and 67.5%, respectively, of those of that regimen. Moreover, assessment using the FACT-L questionnaire indicated that QOL was maintained after chemotherapy started. This bi-weekly TC regimen is therefore suitable for elderly patients with NSCLC, particularly in outpatient settings. Nevertheless, it is clear that some elderly patients have a higher incidence of toxic events with chemotherapy, and a method to distinguish these groups is necessary.
Summary of pharmacokinetic parameters. Pharmacokinetic study of PTX and CBDCA were performed on day 1 during the first cycle. Pharmacokinetic parameters were calculated using WinNonlin Professional version 5.1.
Regarding pharmacokinetics, the targeted AUC of carboplatin was achieved with dose adjustment using the Calvert formula. This result suggests that the calculation of treatment dose for carboplatin using the Calvert formula was acceptable for elderly patients. With regard to paclitaxel, hematological toxicity has been reported to be related to the plasma paclitaxel concentration (16, 17). In the present study, however, we found no relationship between plasma paclitaxel concentration and hematological or non-hematological toxicity, likely due to the small number of involved patients. Paclitaxel is predominantly metabolized in the liver by the cytochrome P450 (CYP) 2C8 pathway to 6-hydroxy-paclitaxel and is also metabolized by CYP3A4 (18), undergoing biliary excretion as the main route of elimination (19). Paclitaxel is accordingly recognized as an anticancer agent which can be used without the need for dose reduction for renal impairment. Gelderblom et al. (20) reported that systemic exposure to paclitaxel in patients with severe renal dysfunction is approximately 1.5- to 2-fold higher than in those with normal renal function, which most likely relates to decreased renal metabolism and urinary excretion of unchanged drug. In the present study, clearance was associated with eGFR, suggesting that the plasma concentration of paclitaxel may increase to greater-than-expected levels in elderly patients with renal impairment. This finding may be due to increased levels of circulating uremic toxins which inhibit the function of organic anion transporting peptide (OATP) 1B3, a transporter in the hepatocellular uptake of paclitaxel (21, 22). Franke et al. (22) showed that one such toxin directly inhibits the hepatic uptake of imatinib, another substrate for OATP1B3, and hypothesized that an inhibitory effect would also be seen with paclitaxel. Our data support the possibility that uremic toxins directly reduce hepatic uptake of paclitaxel by OATP1B3. Further elucidation of this mechanism and the pharmacokinetics of paclitaxel in elderly patients warrant investigation.
Effect of chemotherapy on quality of life (QOL) score. QOL was evaluated by the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire before chemotherapy and every four weeks thereafter.
Relationship of area under the curve (AUC) and paclitaxel dose.
Correlation of clearance of paclitaxel and estimated glomerular filtration rate (eGFR).
In conclusion, this study shows that bi-weekly TC treatment for elderly patients with inoperable NSCLC is feasible as a conventional regimen, particularly in outpatient settings, because of its low toxicity. We are now conducting an additional pharmacokinetic study to evaluate the association of clearance of paclitaxel with renal function, as well as a phase II study of this bi-weekly TC regimen with bevacizumab in elderly patients with advanced NSCLC.
Footnotes
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Financial Disclosures
There are no financial disclosures from any of the Authors.
- Received October 7, 2012.
- Revision received November 8, 2012.
- Accepted November 9, 2012.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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