Annals of Oncology Advance Access originally published online on May 2, 2006
Annals of Oncology 2006 17(7):1128-1133; doi:10.1093/annonc/mdl084
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© 2006 European Society for Medical Oncology
A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer
1 Cancer Therapeutics Research Group, Department of Haematology-Oncology; 2 Department of Pharmacology, National University Hospital, Singapore; 3 Cancer Therapeutics Research Group, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; 4 Clinical Trials & Epidemiology Research Unit, Ministry of Health, Singapore
* Correspondence to: Dr B. C. Goh, Department of Haematology-Oncology, 5 Lower Kent Ridge Road, National University Hospital, Singapore, 119074. Tel: +65 6772 4621; Fax: +65 6777 5545; E-mail: gohbc{at}nuh.com.sg
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Abstract |
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Background: Intracellular gemcitabine triphosphate (dFdCTP) levels can be optimised by administering gemcitabine at a fixed dose rate infusion.
Patients and methods: Patients with chemonaive advanced non-small cell lung cancer (NSCLC) were randomised to receive gemcitabine at a fixed dose rate gemcitabine 750 mg/m2 over 75 min (arm A) or gemcitabine 1000 mg/m2 over 30 min (arm B) on days 1 and 8 every three week cycle. Carboplatin at AUC of 5 was administered in both treatment arms on day 1 of each cycle. End points were activity, tolerability and pharmacokinetics of plasma and intracellular gemcitabine.
Results: 76 patients were randomised. Response rate was 34% in arm A and 42% in arm B. Toxicity and quality of life scores were similar for both treatment arms. Mean plasma Cmaxgemcitabine and mean dFdCTP AUC in arm A was 20.8 µM ± 17.2 µM and 35 079 ± 18 216 µM*min respectively and in arm B, 41.2 ± 13.9 µM and 32 249 ± 11 267 µM*min respectively. dFdCTP saturation was reached in Arm B but not in Arm A.
Conclusion: The saturability of dFdCTP accumulation in Arm A suggests optimal delivery of gemcitabine is achieved using fixed rate infusion compared to 30-min infusion. Fixed dose rate gemcitabine is active and feasible, supporting the concept of fixed dosing rate of gemcitabine in advanced NSCLC. However, this entails a longer infusion time with associated higher costs involved.
Key words: gemcitabine, non-small cell lung cancer, pharmacokinetics
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Platinum-based chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) has improved survival compared to best supportive care alone [1
]. The combination of gemcitabine (2', 2'-difluorodeoxycytidine, dFdC) and carboplatin has been shown in randomised phase III studies to be active and tolerable in advanced stage NSCLC [2–4]. Gemcitabine, a nucleoside anti-metabolite prodrug, requires phosphorylation intracellularly to its active form gemcitabine triphosphate (dFdCTP). The rate-limiting step in the activation of gemcitabine is the phosphorylation of gemcitabine to its monophosphate form by deoxycytidine kinase, and a plasma gemcitabine concentration between 10–20 µmol/l results in optimal rate of accumulation of dFdCTP [5]. In phase I studies, this concentration range of plasma dFdC and continuous saturation of dFdCTP levels were attained when gemcitabine was infused at a fixed dose rate of 10 mg/m2/min [6–9]. Furthermore, the infusion of gemcitabine at 10 mg/m2/min has been reported in a randomised phase II study to have clinical benefit in patients with pancreatic adenocarcinoma, and achieved higher intracellular dFdCTP in peripheral blood mononuclear cells compared to the standard 30-min infusion arm [10].
Based on the favourable activity of gemcitabine and carboplatin in advanced NSCLC, the preclinical and clinical data supporting the prolonged infusion schedule of gemcitabine, we conducted a randomised phase II study of carboplatin and gemcitabine in patients with advanced NSCLC utilizing two different infusion rates of gemcitabine. In arm A (fixed-dose rate 10 mg/m2/min) gemcitabine was infused at 750 mg/m2 over 75 min and in arm B, gemcitabine was administered at the standard infusion duration of 30 min. The dose for arm A was based on our previous phase I study [11].
The primary objective was to evaluate the response rate of carboplatin and gemcitabine given at a fixed dose-rate and standard 30-minute infusion. Secondary objectives were time to progression (TTP), overall survival, quality of life (QoL) and plasma and cellular pharmacokinetics of gemcitabine.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patient selection
Eligibility criteria included histologically or cytologically confirmed NSCLC with measurable disease, stage IIIB unsuitable for radical radiotherapy or stage IV disease. Patients were required to have a Karnofsky performance status (KPS) of
70%, age 18 years, life expectancy > 3 months, hemoglobin 9g/dl, white blood cell count 3500/µl, neutrophils 2000/µl, platelet count 100 000/µl, serum creatinine < 133 µmol/l or creatinine clearance > 30 ml/min (based on the Cockcroft formula), serum bilirubin 
1.5 times the upper limit of normal (ULN), and serum transaminase levels two times ULN or five times ULN if hepatic metastases were present. The study was approved by the institutional review board of each participating centre and all patients gave written informed consent. Previous chemotherapy for advanced disease was not allowed. Prior neoadjuvant or adjuvant chemotherapy or chemotherapy given with radiotherapy for non-metastatic disease was allowed if the last dose was administered 6 months before study entry. Patients were excluded if they had received prior gemcitabine therapy or had symptomatic central nervous system metastases requiring steroids. Prior radiotherapy was allowed provided the indicator site(s) had not been irradiated and the last dose of radiation therapy had been completed 3 weeks before study entry.
treatment plan
Patients were randomly assigned to the following two treatment arms: gemcitabine 750 mg/m2 over 75 min (arm A) or gemcitabine 1000 mg/m2 over 30 min (arm B) on days 1 and 8 every 3 weeks. An infusion pump was used to ensure exact infusion time. In both arms, carboplatin targeting an AUC of 5 mg/ml*min was given over 1 h on day 1 prior to the gemcitabine infusion. Randomisation was conducted through the central randomisation office of Clinical Trials and Epidemiology Research Unit, Singapore, by means of a telephone call, randomisation list, and web randomisation. Stratified randomisation was performed using the minimisation method based on study site, KPS (90–100% versus 70–80%), and disease stage (IIIB versus IV).
Dose modifications were based on weekly blood counts and toxicity. On day 22 of each cycle, for grade 1 neutropaenia and/or platelets < 100 000/µl, treatment was delayed for 1 week. On day 8 of each cycle, for grade 3 neutropaenia and grade 2 thrombocytopaenia, the dose of gemcitabine was reduced by 25% and maintained for the next cycle, and for grade 4 neutropaenia and/or grade 3/4 thrombocytopaenia, gemcitabine was omitted and decreased by 25% for the next cycle following marrow recovery and carboplatin was also reduced by 10% for the next cycle. Gemcitabine was also reduced by 25% and carboplatin by 10% for a grade 4 neutropenic fever or grade 4 neutropaenia for > 7 days or thrombocytopaenia grade 3 with bleeding or platelets < 25 000/µl. Patients requiring a third dose reduction, or experienced a non-haematologic toxicity of > 3 (except for nausea, fatigue, or reversible elevation of transaminases) were taken off study.
patient evaluation
Prior to chemotherapy, patients underwent a history and physical examination, chest X-ray, chest and abdominal computed tomography (CT) scans, complete blood count (CBC), serum biochemistry, urinalysis, and ECG. Additional radiological imaging was performed if clinically indicated. A physical examination, recording of toxicities, serum biochemistry was performed prior to each cycle of therapy. Weekly CBC was obtained during each cycle.
response and toxicity analysis
Tumour response was evaluated after every two cycles according to the RECIST criteria [12]. Patients with stable disease or better continued with treatment to a maximum of six cycles. Confirmed responses required repeat CT scans at least 4 weeks later. Toxicities were evaluated every cycle using to the National Cancer Institute Common Toxicity Criteria, version 2.0 and as a percentage decrease in neutrophils and platelets using the following equation:
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quality of life
Quality of life was measured with the EORTC QLC C-30 and QLQ-LC13 questionnaire. The questionnaire was completed at baseline prior to therapy, on day 1, cycle 1 of treatment, and every 2 months post-study for responding patients.
pharmacokinetic study
Pharmacokinetic studies were performed on all patients from Singapore. Venous blood for plasma gemcitabine and intracellular dFdCTP were drawn at the following times: before initiation of gemcitabine (baseline), 10 min, 30 min, 10 min before completion of infusion, and 30 min, 1 h, and 2 h after completion of the infusion. At each point, 10 ml of blood was drawn into tubes containing heparin and 5 µmol tetrahydrouridine. Plasma was obtained by centrifugation and gemcitabine levels were assayed by ion-pair reversed-phase high-performance liquid chromotography (HPLC) [13]. Intracellular dFdCTP was determined by anion-exchange HPLC as previously described [14] with minor modifications. In brief, white blood cells (WBC) were isolated from blood buffy coat by Ficoll-Paque step density centrifugation and stored at –80°C. Nucleotide extraction was processed with 0.8 M HClO4. The resultant supernatant was neutralised with 1M KOH and the precipitated KClO4 was removed by centrifugation. Baseline separation and fast quantification was achieved with a gradient Anion-Exchange HPLC-UV analysis.
statistical analysis
The sample size was calculated based on the statistical selection theory [15, 16] Assuming a 90% probability of correctly choosing the best treatment, and anticipating a baseline response rate of 40%, to detect a 15% superiority of the best treatment, a sample size of 37 patients per treatment arm was needed. Efficacy parameters were evaluated according to intent-to-treat (ITT) analysis. Survival and TTP were calculated using the Kaplan-Meier technique. Survival was calculated from the date of randomisation to the date of death or last follow up. TTP was defined as the time from randomisation until disease progression, or last contact. For each QoL dimension, changes in score over time were compared between treatment arms by longitudinal data analysis technique. No interim analysis was performed.
pharmacokinetics
Noncompartmental analysis was performed using Kinetica 4.3 (InnaPhase Corp., Philadelphia, PA) to calculate the pharmacokinetic parameters, clearance (CL), half-life of the terminal disposition phase (t
), and volume of distribution at steady state (Vss) for gemcitabine and dFdCTP. Area under the concentration-time curve (AUC) was estimated using the log-linear trapezoidal option from time 0 to infinity. Derivation of the rate constant for the terminal phase, k, was done with extrapolation of the last measured concentration to infinity, by including the final three sampling time points. Clearance (CL), half-life (t) and steady state volume of distribution (Vss), were computed.
Pharmacokinetic data between the two treatment arms were evaluated using the Student's t-test and Mann–Whitney test. Pearson's Correlation was used to test for correlation between the percentage change in neutrophils or platelets during the first cycle of chemotherapy with gemcitabine and dFdCTP pharmacokinetics. A P value of <0.05 was considered to be statistically significant.
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results |
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patient characteristics
Between July 2001 to February 2004, 76 patients were accrued from Singapore and Australia (Table 1). One patient withdrew consent after randomisation and did not receive treatment.
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treatment received
A total of 322 cycles of chemotherapy was administered (150 in arm A and 172 in arm B) with a median number of four cycles (range 0 to 6). In arm A, gemcitabine was omitted in 3.7% and reduced in 21.3% of courses. In arm B, 2% and 15.7% of gemcitabine doses were omitted or reduced respectively. In both treatment arms, the most common reasons for dose omission and reduction was neutropaenia and thrombocytopaenia. Carboplatin was reduced in 18.7% of doses in arm A and 12.8% in arm B. The relative dose intensity (RDI) of gemcitabine was 83% and 84% in arms A and B respectively.
efficacy
Five patients (three in arm A, two in arm B) did not undergo tumour assessment because of early disease progression (three patients), lost to follow-up (one patient) and withdrawal of consent (one patient). All patients were included in the response assessment as per ITT analysis. No patient had a complete response. Thirteen patients (34%, 95% CI, 26–59%) in the fixed dose rate arm and 16 patients (42%, 95% CI, 20–51%) in the 30-minute arm had partial responses.
The median follow up was 233 days. The median TTP was 160 days (95% CI 96–210 days) in arm A and 157 days (95% CI, 116–214 days) in arm B (Figure 1). No significant difference was seen between the two treatment groups (P = 0.73, log-rank test HR 1.08, 95% CI 0.68–1.73)
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The median survival and one year survival rate was 212 days (95% CI 176–263 days) and 31.6% respectively for patients in arm A and 287 days (95% CI 191–394 days) and 35.6% respectively for patients in arm B.
toxicity
Seventy-five patients were assessed for toxicity (Arm A, n = 38, Arm B, n = 37). Grade 3/4 anaemia and neutropaenia was similar in both treatment arms (Table 2) whilst grade 
thrombocytopaenia was more frequent in arm A (69% versus 50%), this, however, was not statistically significant (P = 0.10). Two episodes of neutropaenic fever were reported, one in each treatment arm. Significant non-haematologic toxicities were infrequent and tolerable in both treatment arms (Table 3). There were no treatment related deaths.
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quality of life
Role and social function improved and there was less pain, dyspnoea and insomnia in both treatment arms. Other QoL parameters were unchanged. There were no differences in functional or symptom scores between the two treatment groups.
pharmacokinetic analysis
Plasma gemcitabine were analysed in 58 patients (29 in each arm, all from Singapore) and intracellular dFdCTP was determined in 33 patients (arm A 15 patients, arm B 18 patients). Peak plasma gemcitabine concentrations occurred earlier in arm B than in arm A (Figure 2A). In arm A, Cmax gemcitabine was 20.8 ± 17.2 µM at 51 min compared to 41.2 ± 13.9 µM at 29 min in arm B (Table 4A). Mean gemcitabine AUC was 1345.9 ± 1112.6 µM*min and 1432.4 ± 528.9 µM*min in arm A and B respectively. Terminal elimination was similar, with a mean clearance of 164.0 ± 64.0 l/h/m2 in arm A and 181.6 ± 74.5 l/h/m2 in arm B (Table 4A). The volume of distribution of gemcitabine was 65.0 ± 37.2 L in arm A and 74.5 ± 41.2 L in arm B, indicating that irrespective of the infusion rate, gemcitabine was widely distributed in the tissues.
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In arm B, saturability of intracellular dFdCTP was observed with blunting of Cmax dFdCTP relative to the peak observed for plasma gemcitabine (Figure 2A, 2B). In addition, the ratio of Cmax gemcitabine/Cmax dFdCTP was 8.4 and 5.5 and AUC dFdCTP/AUC gemcitabine was 35 and 28 for arms A and B respectively, consistent with saturability of dFdCTP in arm B. Intracellular dFdCTP AUC was similar at 35 079 ± 18 216 µM*min and 32 249 ± 11 267 µM*min in arms A and B respectively (Table 4B).
pharmacokinetic-pharmacodynamic relationships
Pharmacokinetic parameters were tested for association with degree of neutropaenia or thrombocytopaenia as measured by percentage change in neutrophils or platelets. No correlation between the percent change in neutrophils or platelets with plasma gemcitabine AUC (r = –0.066, P = 0.62), Cmax (r = –0.024, P = 0.859), CL (r = –0.232, P = 0.08), or intracellular dFdCTP Cmax (r = 0.051, P = 0.781), AUC r = 0.068, P = 0.712) was seen.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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This randomised phase II study compared the pharmacokinetics of plasma gemcitabine and intracellular dFdCTP in a large set of patients receiving gemcitabine either as a standard infusion rate or as a fixed dose rate in combination with carboplatin. Similar outcome measures of response rates, time to disease progression, survival and toxicities were found using carboplatin with gemcitabine at 1000 mg/m2 in a 30-min infusion or at 750 mg/m2 in a 75-min infusion in the treatment of advanced NSCLC.
The response rate in both study arms is consistent with the established efficacy of this regimen in NSCLC with response rates ranging from 29% to 42% in studies using carboplatin and 30-min infusion gemcitabine [2–4] and 34% to 47% in studies of gemcitabine administered at 10 mg/m2/min with carboplatin or cisplatin [17, 18]. However, the sample size of each arm of this study was not designed to compare efficacy or test non-inferiority.
Whilst significant myelosuppression was seen in both treatment arms, the frequency of neutropaenic fever and bleeding from thrombocytopaenia was low. The RDI of gemcitabine in arm A of 83% was similar to that in arm B (84%) and compared favourably with the 75% for gemcitabine reported in a phase II study of carboplatin and gemcitabine 1200 mg over 120 min in NSCLC [17]. Therefore, a fixed dose rate infusion of gemcitabine with carboplatin is feasible without major cumulative toxicities. Previous studies using a prolonged gemcitabine infusion schedule have reported elevation in hepatic transaminases [19, 20]; this, however, was not seen in our study and may be related to duration of the infusion. Non-haematologic toxicities in both treatment arms were similar and improvements in the EORTC QoL questionnaire on both schedules were also similar, suggesting tolerability and similar clinical benefits.
A secondary objective of this study was to evaluate the pharmacokinetics plasma gemcitabine and intracellular dFdCTP between the two treatment arms. The AUC of intracellular dFdCTP was similar in both treatment arms despite the dose of gemcitabine being 25% higher in the 30-min arm. Consistent with previously reported studies [6, 9, 22], the pharmacokinetic data demonstrates that the 30-minute infusion arm is a pharmacologically less efficient method of administering gemcitabine compared to a fixed dose rate of 10 mg/m2/min. In arm B, a higher mean plasma gemcitabine Cmax of 41.2 µM was reached, a value that is well outside the concentration range known to optimise the rate of gemcitabine phosphorylation [6–9]. The blunting of Cmax dFdCTP relative to the peak for plasma gemcitabine (Figure 2A, 2B), and higher ratios of Cmax dFdCTP/Cmax gemcitabine and AUC dFdCTP/AUC gemcitabine in arm A compared to arm B provides evidence of intracellular dFdCTP saturability in arm B.
As phosphorylation of gemcitabine was more efficient in the fixed-dose rate arm, a lower dose of gemcitabine could be administered, with the resultant benefit of reduced chemotherapy costs. This advantage however may be offset by increased charges associated with a longer infusion time and nursing costs as well as greater inconvenience. In comparison, the infusion of gemcitabine over 30 min was pharmacologically less efficient with greater drug wastage but is more convenient with a shorter infusion time.
A potential strategy to achieve more efficient activation of gemcitabine and to reduce the infusion period of the fixed dose regimen is to administer an initial rapid bolus of gemcitabine to saturate deoxycytidine kinase activity, followed by an infusion at 10 mg/m2/min. Theoretically, a reduction in excessive gemcitabine levels would be attained and a higher dFdCTP AUC could be achieved in a shorter duration of infusion and, assuming similar cellular transport characteristics in tumours, should lead to increased cytotoxicity. This approach to gemcitabine dosing is supported by recent work using pharmacokinetic modelling where a reduction in excessive gemcitabine levels was reported when using a loading dose of gemcitabine followed by a maintenance infusion [23].
In summary, by using a 25% lower dose of gemcitabine at an infusion rate of 10 mg/m2/min in combination with carboplatin in NSCLC, a similar clinical efficacy and safety profile was achieved compared to standard 30-min infusion regimen. Pharmacokinetic sampling of gemcitabine and dFdCTP suggests that the 30 min infusion is a pharmacologically less efficient method of administering gemcitabine compared to a fixed dose rate of 10 mg/m2/min. These results provide evidence on the benefits of exploring a pharmacologic approach to optimise clinical administration of gemcitabine and illustrate the importance of incorporating pharmacodynamic-pharmacokinetic correlates in early phase clinical trials to determine an optimal dosing strategy.
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Acknowledgements |
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This work was supported by grants from the Agency for Science, Technology and Research, (BMRC 01/1/26/18/060 and SCS-PN0022) and Eli Lilly Company.
Received for publication January 12, 2006. Revision received March 15, 2006. Accepted for publication March 17, 2006.
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References |
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