© 2004 Foundation for Promotion of Cancer Research
Phase I Trial of Carboplatin and Weekly Paclitaxel in Patients With Advanced Non-small-cell Lung Cancer
1 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, 2 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo and 3 Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan
For reprints and all correspondence: Koichi Yamazaki, First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kitaku, Sapporo 060-8638, Japan. E-mail: kyamazak{at}med.hokudai.ac.jp
Received April 15, 2004; accepted June 20, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer.
Methods: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m2 and escalated in 10 mg/m2 increments.
Results: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m2) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m2. Nine of 21 (42.9%) patients demonstrated a therapeutic response.
Conclusion: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m2 of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.
Key Words: carboplatin • non-small-cell lung cancer • paclitaxel • phase I study
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer in the world. Unfortunately, when NSCLC is diagnosed most patients have locally advanced or disseminated cancers. The median survival of patients with stage IIIB and IV NSCLC ranges from 6 to 8 months and only 20–30% survive for 1 year.
Paclitaxel (Taxol; Bristol-Myers Squibb) is a clinically active anticancer drug that inhibits cell division by promoting the assembly of microtubules and stabilizing the tubulin polymers in the G2/M phase (1). Consequently, paclitaxel causes the formation of abnormal bundles of microtubules during the cell cycle, and it has antiangiogenic activity (2). Carboplatin (Paraplatin; Bristol-Myers Squibb) is a less toxic analog of cisplatin, which is thought to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules. Carboplatin is as efficacious as cisplatin in treating NSCLC.
A recent Eastern Cooperative Oncology Group (ECOG) study compared third-generation chemotherapy regimens, which included cisplatin with paclitaxel, cisplatin with gemcitabine, cisplatin with docetaxel and carboplatin with paclitaxel. The results showed that there were no differences in survival, and carboplatin with paclitaxel had the lowest degree of toxicity. Therefore, ECOG selected carboplatin with paclitaxel as its reference regimen (3). In addition, the combination of carboplatin [area under the curve (AUC) = 6] and paclitaxel (225 mg/m2) administered every 3 weeks is the most commonly used regimen in the USA. The response rate with this regimen ranges from 17% to 25%, with median survival times averaging 8 months (3–5). While the regimen is well tolerated, it is associated with a 10% to 17% incidence of grade 3 neuropathy (3–5).
Weekly regimens of paclitaxel and carboplatin were developed in an effort to increase efficacy and reduce toxicity. Belani et al. (6) studied various regimens and found that paclitaxel (paclitaxel 100 mg/m2 weekly for three of 4 weeks) plus carboplatin (AUC = 6 on day 1) was the most effective and least toxic. For example, this regimen had a response rate of 32%, a median survival time of 49 weeks, and a 1-year survival rate of 47%. Comparison with the previous studies using the standard every-3-week schedule of paclitaxel and carboplatin indicated that the weekly regimens achieved favorable efficacy with a highly tolerable toxicity profile.
In Japan, a phase I trial of carboplatin plus weekly paclitaxel was conducted in advanced NSCLC, and the recommended dose level of paclitaxel was 70 mg/m2 on days 1, 8 and 15 in combination with carboplatin (AUC = 6) on day 1 of a 4-week cycle (7). The dose level of paclitaxel was much lower than in Belani's study. In order to reconfirm the dose level of paclitaxel, we conducted a phase I trial of weekly paclitaxel (on days 1, 8 and 15) with carboplatin (on day 1) of a 4-week cycle for advanced NSCLC.
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SUBJECTS AND METHODS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT ELIGIBILITY
This phase I trial was designed to determine the maximum tolerated dose (MTD) and toxicity of paclitaxel administered on a weekly schedule to patients with advanced NSCLC. A secondary objective was the determination of efficacy. The ethics committee at Hokkaido University School of Medicine approved this study. Inclusion criteria were: (i) histological or cytological evidence of NSCLC with no prior chemotherapy; (ii) stage IIIB or IV disease that was not curable with chemoradiation as the first choice; (iii) measurable or assessable disease; (iv) ECOG performance status (PS)
1; (v) between 20 and 75 years of age with white blood cell (WBC) counts >4 x 109/l, hemoglobin (Hb) >9.5 g/dl, platelet (PLT) counts >100 x 109/l, bilirubin <1.5 mg/dl, GOT and GPT less than twice upper limits of normal, and creatinine <1.5 mg/dl, PaO2 >70 torr; (vi) anticipated survival at least 3 months and (vii) provided written informed consent. Exclusion criteria were: (i) serious concomitant systemic disorders; (ii) severe heart failure within 3 months, uncontrollable angina or hypertension; (iii) diabetes mellitus; (iv) interstitial pneumonia; (v) active infection, ulcer or second primary malignancy; (vi) history of severe hypersensitivity or hypersensitivity to the study drug or polioxyetilene and (vii) pregnancy. We also measured plasma paclitaxel concentrations during treatment to compare with those established for every-3-week regimens.
TREATMENT SCHEDULE
The trial was designed as a dose-escalation study of paclitaxel and carboplatin used in combination therapy scheduled every 4 weeks. The dose of carboplatin was fixed to target AUC 6 on day 1. The starting dose of paclitaxel was 60 mg/m2 given in 1-h i.v. infusions on days 1, 8 and 15 every 4 weeks. If treatment was well tolerated, then successive dose levels were increased in intervals of 10 mg/m2 in groups of three patients to 70, 80, 90 mg/m2, if there was no dose-limiting toxicity (DLT). DLT was defined as: (i) persistent (>4 days) leucopenia (<1000/µl); (ii) active infection or fever (>38°C) with grade 3/4 neutropenia; (iii) a PLT count <20 000/µl; (iv) any grade 3/4 non-hematological toxicities, except appetite loss, nausea and vomiting; (v) a delay of second cycle within 6 weeks. If no one encountered dose limiting toxicity, then subsequent patients entered the study at the next greater dose level. If one of the three patients encountered DLT, then subsequent patients entered at the same level, to a total of six patients. If more than one of three or more than two of six patients had DLT at a specific dose level, then that dose levels was defined as the maximum tolerated dose. Anaphylactic premedication included diphenhydramine (10 mg i.v.) and ranitidine (50 mg i.v.) and dexamethasone (20 mg i.v.) 1 h before paclitaxel infusion.
The National Cancer Institute (NCI) common toxicity scale (8) was used to grade side effects. The treatment plan was put on hold for any of the following reasons: (i) white blood cell (WBC) count <3000/µl or PLT count 75 000/µl within 24 h of the day of treatment; (ii) fever >38°C; (iii) PS 3 or (iv) grade 3/4 non-hematological toxicities. Treatment was discontinued when disease progressed, patient died, patient withdrew or experienced septic shock or grade 4 non-hematological toxicity, or decision of clinician. The dose modifications were made after the first 4 weeks of therapy as necessary. Repeated cycles were delivered as their assigned first-dose level unless modified for toxicity. If a patient developed hematologic DLT, each drug was reduced by 20% of previous cycle. The response was evaluated according to WHO criteria (9).
PHAMACOKINETIC ANALYSIS
The disposition of paclitaxel was determined in three patients who received 100 mg/m2. Blood samples were collected at 0, 2.5, 3.0, 6.0, 10, 24 and 48 h after infusion in tubes that contained potassium edetic acid. Plasma was immediately separated by centrifugation at 3000 r.p.m. for 3 min and stored at –20°C until analysis. Plasma paclitaxel concentrations were determined by high-performance liquid chromatography (HPLC) at SBS, Inc. (Sagamihara, Japan). The pharmacokinetic parameters were calculated using MOMENT (EXCEL), which was developed using Microsoft Excel.
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Twenty-one patients with NSCLC entered this trial through six dose levels (Table 1). There were 14 men and seven women with median age of 65 years (range, 44–75). Seven patients had stage IIIB disease and 14 patients had stage IV disease. Adenocarcinoma was the most common histology (n = 17) followed by squamous cell carcinoma (n = 4). Two patients were treated at relapse after surgical resection and 19 were treated during their initial presentation.
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Three patients entered at 60, 70, 80, 90 and 110 mg/m2 (Table 2). Six patients entered at 100 mg/m2, because one of the first three patients had a delayed second cycle of 6 weeks because of decrease in WBC counts. This patient developed asymptomatic neutropenia. Paclitaxel on day 15 was postponed to day 30. Since five of six patients completed the first cycle at the 100-mg/m2 dose level, the dose of paclitaxel was advanced to the next greater level. Two patients at the 110-mg/m2 dose level developed cases of pneumonia that were associated with grade 3/4 neutropenia that cleared with antibiotics. Thus, criteria of DLT were met in two of three patients treated with 110 mg/m2 (Table 2).
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Seven patients received one cycle of therapy, three completed two cycles, six completed three cycles, three completed four cycles, one completed five cycles and one completed seven cycles. Progression of disease was the most common reason for discontinuation. More than 148 doses of paclitaxel were administered to these 21 patients. The average cumulative dose of paclitaxel was 569 mg/m2, and the maximum dose was 1278 mg/m2. The longest duration of therapy was 13 months.
TOXICITIES OF THERAPY
Twenty-one patients and six dose levels were eligible for evaluation. The toxicities associated with this schedule were generally mild (Table 3). No significant (grade 3/4) red blood cell and PLT toxicities were noted. Although neuropathy is a complication of paclitaxel therapy, only one patient had grade 1 peripheral neuropathy. There was no anaphylaxis or hypersensitivity. Although no formal analysis of long-term toxicity was performed, no obvious cumulative hematologic, pulmonary or neurologic toxicity was noted.
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RESPONSE TO THERAPY
Of 21 assessable patients, one complete response (CR) and eight partial responses (PR) (42.9%) were observed. One occurred at level 1, two at level 2, two at level 3, one at level 4, one at level 5 and two at level 6 (Table 2). One patient attained a CR and he remained disease-free for 13 months. A minor response was also seen in five (23.8%) patients. Seven (33.3%) patients showed progression of their disease.
PHARMACOKINETICS
Pharmacokinetic studies were performed on three patients at 100 mg/m2. Their mean peak concentration was 5.3 ± 0.72 (±SD) µmol/l. Their average interval peak plasma paclitaxel concentrations are depicted graphically in Figure 1. The mean 48-h concentration was 0.02 ± 0.00 µmol/l. Plasma paclitaxel concentrations at 48-h were >0.01 µmol/l, which is the minimum for a therapeutic response. Plasma paclitaxel levels remained >0.01 µmol/l for more than 144 h and >0.05 µmol/l for 27.9 ± 4.11 h. Key pharmacokinetic characteristics are shown in Table 4.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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We conducted a phase I trial of weekly paclitaxel with carboplatin in advanced NSCLC. The recommended dose of paclitaxel in a phase II study was 100 mg/m2, and the DLT was infection with grade 3/4 neutropenia. While the 100 mg/m2 dose of paclitaxel was greater than doses previously reported in Japan (7), it was equivalent to the dose reported in Belani's study (6). Differences in the ratio of patients with PS 2 between another Japanese trial and the present may be a reason.
Since paclitaxel is a phase-specific agent, frequent or continuous schedules offer the greatest theoretical benefit (10). Depending on the duration of exposure, cellular cytotoxicity can be achieved at relatively low concentrations of this drug that are around 0.01 µmol/l (11,12). On the other hand, myelosuppression was related to the duration of exposure to plasma paclitaxel concentrations >0.05 µmol/l (13). In our study, the time that plasma paclitaxel concentrations remained >0.01 µmol/l was more than 144 h and the time it remained >0.05 µmol/l was 27.9 ± 4.11 h. Our results are similar to the findings in patients with metastatic breast cancer who received similar 1-h infusions of 100 mg/m2 paclitaxel (14). Thus, a weekly schedule of paclitaxel extended the duration >0.01 µmol/l and >0.05 µmol/l of plasma paclitaxel concentration, as compared to an every-3-week regimen. The pharmacokinetic data of paclitaxel might explain the favorable response rate of a weekly schedule despite weakened intensity of carboplatin every 4 weeks in comparison with an every-3-week regimen. In addition to exposure duration issues, cellular cytokinetic considerations imply that frequent exposure to cytotoxic agents with brief intervals between exposures affords less opportunity for the emergence and regrowth of drug-resistant cell clones (15). On the other hand, severe myelosuppression was not seen in this study, which was not compatible with pharmacokinetic data.
Weekly administration of paclitaxel is dose-intense, but it also has a favorable toxicity profile (16,17). Non-hematologic toxicity was less common with weekly paclitaxel regimens. In our study, no patients developed grade 3 or 4 peripheral neuropathy. A peripheral neuropathy may begin as soon as 24–72 h after treatment with higher doses (>250 mg/m2) but usually occurs only after multiple courses at conventional doses. Clinically, peripheral neurotoxicity occurs at cumulative doses of approximately 1500 mg/m2 given at weekly doses of >110 mg/m2 (18,19). Thus, weekly paclitaxel combination with carboplatin was a favorable regimen in the view of neuropathy, compared to a standard every-3-week regimen.
In conclusion, weekly paclitaxel and carboplatin were well tolerated and 100 mg/m2 of paclitaxel for 3 weeks of a 4-week cycle in combination with carboplatin was recommended for a phase II study. A multi-institutional phase II study of this treatment is currently underway.
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References |
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