Japanese Journal of Clinical Oncology 32:48-53 (2002)
© 2002 Foundation for Promotion of Cancer Research
A Feasibility Study of Paclitaxel 225 mg/m2 and Carboplatin AUC = 6 in Untreated Advanced Non-small Cell Lung Cancer Patients in Japan
1Department of Internal Medicine, National Kinki-Central Hospital for Chest Diseases, Sakai, Osaka and 2Division of Biostatistics, Toyama Medical and Pharmaceutical University, Toyama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The combination of paclitaxel (225 mg/m2, 3 h infusion) and carboplatin [area under the curve (AUC) 6 mg/mlxmin] is used widely for non-small cell lung cancer in the USA and is one of the standard regimens in the Southwest Oncology Group. In Japan, however, the upper limit of the approved dose for single-use paclitaxel is 210 mg/m2 and the optimum dose of this agent in combination with carboplatin has not yet been established. This study was designated to determine whether the paclitaxel dose of 225 mg/m2 plus carboplatin (AUC = 6) is tolerable for Japanese patients with untreated advanced non-small cell lung cancer.
Methods: Ten patients were enrolled between October 1999 and June 2000 and all of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin (AUC = 6 mg/ml xmin) and 225 mg/m2 of paclitaxel on day 1 every 3 weeks.
Results: Neutropenia was the major toxicity and grade 4 neutropenia was observed in seven of the 10 patients (70%), but febrile neutropenia was not observed. Grade 4 anemia as a dose-limiting toxicity was observed in two patients. This was due to gastric ulcer bleeding in both patients. Only one patient experienced grade 3 peripheral neuropathy. No grade 3 or more myalgia or arthralgia was reported. Overall, 44 courses of chemotherapy were administered in 10 patients. Partial responses were observed in six of the 10 patients (60%). Median survival time was 7.7 months.
Conclusion: Paclitaxel at 225 mg/m2 in a 3 h infusion and carboplatin AUC = 6 appears to be tolerable in Japanese patients with untreated advanced non-small cell lung cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is currently the most common cause of cancer deaths in many countries, including Japan. Although meta-analyses have proved that cisplatin-based chemotherapy improves survival compared with the best supportive care, the benefits have been modest (1–3). During the past few years, several new chemotherapeutic drugs with novel mechanisms of action, including paclitaxel, have demonstrated promising activity in patients with advanced non-small cell lung cancer (NSCLC).
Paclitaxel, an antimicrotubule agent, interferes with mitosis during cell division (4–8). It binds preferentially, promotes assembly and stabilizes microtubules. In the USA, the combination of paclitaxel and carboplatin has been a widely used regimen for NSCLC because of its low toxicity profile and efficacy (7,9,10). Moreover, compared with cisplatin, carboplatin does not affect the pharmacokinetics of paclitaxel due to the sequence of these two drugs (11).
The Southwest Oncology Group (SWOG) reported a phase III trial of the combination of paclitaxel (225 mg/m2, 3 h infusion) plus carboplatin [area under the concentration–time curve (AUC) 6 mg/mlxmin] versus the SWOG standard regimen with vinorelbine plus cisplatin (12). There was no significant difference in response rate, median survival time (MST) or 1-year survival rate between the two regimens, but neutropenia and nausea were significantly higher in the vinorelbine plus cisplatin arm whereas peripheral neuropathy was also increased in the paclitaxel plus carboplatin arm. It was concluded that both regimens are effective, but the paclitaxel plus carboplatin regimen was preferred for future studies because of its favorable toxicity profile and better tolerability and compliance.
The Eastern Cooperative Oncology Group (ECOG) 1594 trial had four arms, including 24 h infusion of paclitaxel plus cisplatin, 3 h infusion of paclitaxel plus carboplatin, docetaxel plus cisplatin and gemcitabine plus cisplatin (13). The fewest patients with grade 3 or 4 toxicity were in the paclitaxel (225 mg/m2, 3 h infusion) plus carboplatin (AUC 6) arm and this arm also had significantly less nausea, vomiting and febrile neutropenia. These SWOG and ECOG trials led to the decision that the combination of paclitaxel and carboplatin was the standard regimen because of its lower toxicity profile and ease of administration.
The phase III study reported by Kosmidis et al. (14), evaluating the dose of paclitaxel combined with carboplatin, indicated that the median time to progression was significantly longer in the higher dose of paclitaxel arm (225 mg/m2) than the lower dose (175 mg/m2) arm. The better response rate, overall survival and 1-year survival rate observed in the higher dose of paclitaxel were not statistically significant.
In Japan, a phase I study of paclitaxel infused over 3 h demonstrated the maximum tolerated dose (MTD) to be 240 mg/m2 and that the recommended dose for the phase II study should be 210 mg/m2 (15). A phase II study of paclitaxel at 210 mg/m2 revealed that 38% of patients achieved a partial response, MST was 11.2 months and the 1-year survival rate was 48% (16). Although the dose of paclitaxel was 225 mg/m2 when combined with carboplatin in the USA, the approved maximum dose of paclitaxel for single-agent use in Japan was 210 mg/m2, i.e. lower than the standard dose (225 mg/m2) in other countries.
The optimum dose of paclitaxel has not yet been defined for Japanese patients when paclitaxel and carboplatin are combined. We therefore conducted a phase I trial and pharmacokinetic study of a combination of 3 h infusion of 225 mg/m2 of paclitaxel with carboplatin (AUC 6 mg/mlxmin) in Japanese patients with untreated advanced NSCLC. The purpose of this study was to assess the feasibility of 225 mg/m2 paclitaxel treatment with carboplatin (AUC 6 mg/mlxmin) in Japanese patients for the future Japan–SWOG common arm trial for advanced NSCLC using the same regimen and the same entry criteria.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Eligibility criteria included the following: (1) patients with histologically or cytologically defined NSCLC; (2) stage IIIB (with malignant pleural effusion or multiple metastasis in the same lobe or stage IV); (3) age 18 years or over; (4) ECOG performance status 0–1; (5) measurable or evaluable lesion; (6) adequate bone marrow function (granulocyte
1500/µl, hemoglobin 9.5g/dl, platelets 100 000/µl), renal function [creatinine 
1.1 mg/dl (male), 0.8 mg/dl (female)] and calculated creatinine clearance {Cockcroft’s equation: predictive creatinine clearance = [(140 – age) x body weight/72 x serum creatinine] x 1 (male) or x 0.85 (female) 50 mg/mlxmin} and liver function (transaminase 2xupper normal limit, total bilirubin 1.5 mg/dl); (7) no brain metastases; (8) no prior chemotherapy; and (9) written informed consent. The Institutional Review Board at our hospital approved this study.
Pretreatment and Follow-up Evaluations
Before enrollment, detailed medical histories were obtained and all patients underwent physical examinations and performance status assessments. Blood samples were obtained for complete blood counts (CBCs), electrolytes and renal and liver function. Required radiographs included baseline chest X-ray, computed tomography (CT) scan of the chest and CT and/or ultrasound of the abdomen. A CT scan and/or magnetic resonance imaging (MRI) scan of the brain and a bone scan were also required.
After initiating chemotherapy, physical examinations were performed daily. CBCs were repeated weekly or two or three times per week if necessary. Routine serum chemistry studies, including total protein, albumin, total cholesterol, electrolytes, blood urea nitrogen, creatinine, total bilirubin, AST, ALT, LDH, alkaline phosphatase and urinalysis, were performed weekly. Chest radiographs for tumor measurement were required once per week and CT scans after two courses of treatment. Pharmacokinetic study served for measurement of actual AUC of carboplatin in the first cycle.
Treatment Plan
The patients received chemotherapy with paclitaxel (225 mg/m2) and carboplatin (AUC 6 mg/mlxmin) on day 1. Paclitaxel was administered as a 3 h intravenous infusion followed by a 1 hour infusion of carboplatin. The total dose of paclitaxel was diluted in 500 ml of saline. Polyethylene-lined nitroglycerine tubing and in-line filtration with a 0.22 µm filter were used for all infusions. To prevent hypersensitivity reactions, all patients received premedication with (1) 20 mg of dexamethasone intravenously, 14 and 6 h before paclitaxel, (2) famotidine (20 mg) intravenously, 30 min before paclitaxel, and (3) D-chlorpheniramine maleate (8 mg) orally, 30 min before paclitaxel infusion. The carboplatin dose was calculated as the target AUC 6 mg/mlxmin, using the Calvert equation (17). The total carboplatin dose was diluted in 300 ml of 5% dextrose in water. Antiemetic regimens were devised by attending physicians individually. Chemotherapies were planned to be repeated every 3 weeks for six courses, unless a patient had progressive disease or intolerable toxicity. After the first course of chemotherapy the patients with no hypersensitivity reactions were given dexamethasone administered only once, 1 h before paclitaxel infusion. Granulocyte colony-stimulating factor (G-CSF) was subsequently allowed for patients who developed grade 4 leukopenia and/or neutropenia or grade 3 leukopenia and/or neutropenia with fever (38.0°C). Both paclitaxel and carboplatin were reduced by 25% if febrile neutropenia occurred or the platelet count fell below 20 000/µl. If a patient did not recover to WBC count 4000/µl, neutrophil count 2000/µl and platelet count 100 000/µl within the 6 weeks from the start of chemotherapy, the study protocol was discontinued. Toxicities were evaluated and scored according to SWOG criteria (18).
MTD was defined as dose-limiting toxicities (DLT) for two out of five patients during the whole courses. DLTs were defined as (1) grade 3 febrile neutropenia with or without G-CSF, (2) grade 4 neutropenia or leukopenia with prophylactic G-CSF and (3) grade 4 other than the above toxicity.
Sample size was determined in order to detect the DLT at least 40% incidence with a confidence level >95%.
Patients with measurable lesions were evaluable for the response to therapy. Responses were evaluated using WHO criteria. A complete response (CR) was defined as the disappearance of all measurable and evaluable disease without evidence of new lesions for at least 4 weeks. A partial response (PR) required a 50% decrease in the sum of the products of perpendicular diameters of all measurable lesions under the baseline without progression of evaluable disease or evidence of new disease for at least of 4 weeks. No change (NC) was <50% regression or <25% increase in the sum of the diameters of measurable lesions without evidence of new lesions for at least of 4 weeks. Progressive disease (PD) was reported if there was a 25% increase in the sum of the products of measurable lesions over the smallest sum observed or if there was clear worsening of evaluable disease, the appearance of any new lesion or failure to return for evaluation owing to deterioration. Patients who could not continue the treatment were considered not evaluable (NE) for response before tumor re-evaluation in the absence of PD.
Pharmacokinetic Study
Methods of Blood Sampling
Blood samples (3 ml) were obtained at the following times in relation to carboplatin administration: before infusion, at 30 min (end of infusion) and at 1, 2, 4, 8 and 24 h after the start during the first course. Serum was harvested from blood samples with half of the serum centrifuged through an Amicon Centfree ultrafree filter (Amicon Division, W.R. Grace, Danvers, MA) to obtain a serum ultrafiltrate. The remaining serum and serum ultrafiltrate were stored at –20°C until analyzed for total platinum and free platinum, respectively.
Measurement of Platinum Concentration
Total platinum in serum and ultrafiltrate platinum in serum were measured by flameless atomic absorption spectrometry. Samples were diluted in duplicate with 0.2% nitric acid containing 0.1% (v/v) Triton X-100 and injected (20 µl) into a Perkin-Elmer/Cetus Model 3100 atomic absorption spectrometer equipped with an HGA 600 graphite furnace. Platinum concentrations were determined relative to a freshly prepared calibration curve for elemental platinum (0.2–4.0 ng). The limit of detection was 0.01 µg/ml (19).
Calculation of the AUC
Ultrafiltrate platinum (recalculated as carboplatin) concentration–time curves were modeled (two-compartment open model) with the Kinfit computer program (20). Carboplatin AUCs were determined on the basis of the fitted curve as the exact integral of the concentration versus time plots from 0 to 24 h.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Ten patients (five male, five female) were enrolled in this study between October 1999 and June 2000. All patients were eligible and received chemotherapy. The characteristics of the patients are presented in Table 1. Nine patients had performance status 1. The patients were between 35 and 74 years old, mean 57.3 years. Seven patients had stage IV disease. The number of patients with adenocarcinoma and squamous cell carcinoma were in the same proportion (50% each).
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Hematological Toxicity
Hematological toxicities in all courses are summarized in Table 2. There was no grade 4 leukopenia. Grade 4 neutropenia was observed in seven patients (70%), but febrile neutropenia (
38.0°C) was not observed. No patients required anitibiotics or developed documented infections. Grade 4 anemia was experienced in two patients, both of whom had bleeding from gastric ulcer during the second course. They recovered uneventfully with medical treatment and were able to continue further courses. No grade 3 or more thrombocytopenia was observed. Overall, dose-limiting hematological toxicity was experienced in two patients with grade 4 anemia.
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Non-hematological Toxicity
Non-hematological toxicities in all courses were mild, as shown in Table 2. Clinically significant hypersensitivity reactions were not observed. Nausea or vomiting was observed in seven patients although only one patient had grade 3. Alopecia was common. There were no other cardiac toxicities related to paclitaxel, such as hypotension, bradycardia or conduction disturbance. All of the patients experienced peripheral neuropathy, but only one patient had grade 3. Arthralgia were observed in eight patients (80%) but was grade 2 or less.
None of the patients experienced dose-limiting non-hematological toxicity. There was no treatment-related death.
Response and Compliance
Responses are shown in Table 3. Six patients had a PR and four NC. The overall response rate (ORR) in the 10 patients was 60.0% (95% confidence interval: 26.2–87.8%). The median follow-up time was 8 months. The median survival time (MST) was 7.7 months.
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As shown in Table 3, 44 courses of chemotherapy were administered in this trial. The median number of chemotherapy courses in a patient was four. Three patients completed six courses. Two, three, four and five courses were given in 1, 1, 4 and 1 patient, respectively. One patient discontinued after two courses because of long-lasting neutropenia. One patient stopped chemotherapy after three courses owing to the decline of performance status (PS 3). One patient was transferred to another hospital to pursue alternative medicine, at her own volition. Three patients discontinued therapy after four courses because of paresthesia. One patient stopped therapy after five courses owing to the development of brain metastasis during treatment. No dose reduction was required in any patient.
The delivered dose intensity of carboplatin (CBDCA) ranged from 3.8 to 6.0 mg/mlxmin/3weeks; the median was 5.3 mg/mlxmin/3weeks and the mean was 5.2 mg/mlxmin/3weeks. The delivered dose intensity of paclitaxel ranged from 146 to 225 mg/m2/3weeks; the median was 198 mg/m2 /3weeks and the mean was 194 mg/m2/3weeks. Treatment delays were observed in 12 out of 36 courses after the first course. Most of them (8/12) were within 7 days. Three courses were delayed 2 weeks. Only one course was delayed over 2 weeks (21 days).
Pharmacokinetics
A pharmacokinetic study of carboplatin was performed for the purpose of verifying Cockcroft’s predictive equation for creatinine clearance. The serum platinum concentration was measured in eight patients. The actual AUCs of carboplatin are shown in Table 4. The range of the actual AUC varied from 3.7 to 8.0 mg/mlxmin. The actual AUC values of six patients were <6.0 mg/mlxmin, and in two further patients >6.0 mg/mlxmin (7.6 and 8.0).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This feasibility study showed that the combination of paclitaxel 225 mg/m2 infused over 3 h and carboplatin (AUC 6 mg/mlxmin) can be given to Japanese patients with advanced NSCLC with acceptable toxicity. The most frequent toxicities produced by short infusion of the paclitaxel plus carboplatin regimen were leukopenia and neutropenia (21,22). Also in this study, neutropenia was the major toxicity. Seven of the 10 patients had grade 4 neutropenia. This is incompatible with the SWOG’s data, which showed 36% of 188 patients. ECOG reported that 42% of 272 patients showed grade 4 neutropenia (13), whereas the Hellenic Cooperative Oncology Group reported that only 1% of 99 patients showed grade 4 neutropenia (14). These data from different studies indicate a widely ranging incidence of neutropenia. The 95% confidence interval of our results ranged from 35 to 93%. Therefore, there is not a statistically significant difference between our data and the SWOG data (p = 0.3). One of the reasons for our high incidence of grade 4 neutropenia may be related to the more frequent (weekly) measurement of CBC in our study than those in other countries. Further clarification is needed as to whether this difference is due to the small number of patients in our study, ethnic differences or other reasons. Of note, there was neither febrile neutropenia nor antibiotic use. No patient died from any toxicity related to neutropenia. Other studies have reported peripheral neuropathy, arthralgia and myalgia to be DLTs when paclitaxel was combined with either cisplatin or carboplatin (22,23). In our study, these toxicities were relatively mild and they were not a dose-limiting factor. Moreover, these toxicities were reversible. We experienced two grade 4 anemias due to gastric ulcer. They were, however, able to be continued to receive the same chemotherapy with no recurrence of gastrointestinal bleeding caused by gastric ulcer. Therefore, gastrointestinal bleeding caused by gastric ulcer seen in these two cases was considered to be accidental.
In several studies, investigators have noted that thrombocytopenia was much milder than anticipated in the case of carboplatin alone and suggested that paclitaxel appeared to offer some protective effect against carboplatin-induced thrombocytopenia (21,22,24,25). Studies evaluating the pharmacokinetics of these two drugs identified no drug interactions (26–28). Some reports have suggested that this platelet-sparing effect is attributable to the paclitaxel-induced release of hematopoietic growth factors and megakaryocyte colony-forming units in the bone marrow (28–30). In this study, thrombocytopenia was not severe, which is consistent with the results of previous studies. In addition to thrombocytopenia, our combination chemotherapy with paclitaxel and carboplatin was less likely to cause serious toxicity when compared with phase I and II studies of single-use paclitaxel in Japan (15,16). Grade 3 and 4 hypotension and grade 3 peripheral neuropathy were DLTs in the phase I study (15), whereas grade 4 neutropenia, neutropenic fever and neuromuscular toxicity were common in the phase II study (16). No hypotension, severe neuropathy or neutropenic fever was seen in our study.
Our response rate was relatively higher than in paclitaxel-alone phase II studies (16), but the numbers of patients studied was too small to allow comparison with the response rate in other studies. Although the actual AUC values varied, there was no severe toxicity related to carboplatin. For the early-entered patients, these values were relatively lower than those with late-entered patients. This may have been due to the technical problems (e.g. delay) in serum preparation. There was no significant relationship between measured AUC and severity of neutropenia or thrombocytopenia in during the first course.
In conclusion, combination chemotherapy with paclitaxel 225 mg/m2 infused over 3 h and carboplatin AUC = 6, calculated with Cockcroft’s equation, was useful and feasible in Japanese patients presenting with untreated advanced NSCLC despite a high incidence of neutropenia. A randomized phase III study of this regimen with three courses of vinorelbine and gemcitabine followed by three courses of docetaxel (sequential non-platinum triplet) is under way in Japan as a Japan–SWOG common arm trial.
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FOOTNOTES |
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+ For reprints and all correspondence: Mitsumasa Ogawara, Department of Internal Medicine, National Kinki-Central Hospital for Chest Diseases, 1180 Nagasone-cho, Sakai, Osaka 591-8555, Japan. E-mail: ogawaram@kinchu.hosp.go.jp
Abbreviations: NSCLC, non-small cell lung cancer; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group; AUC, area under the concentration–time curve; MST, median survival time; MTD, maximum tolerated dose; CBC, complete blood count; CT, computed tomography; MRI, magnetic resonance imaging; G-CSF, granulocyte colony-stimulating factor; DLT, dose-limiting toxicity; CR, complete response; PR, partial response; NC, no change; PD, progressive disease; NE, not evaluable; ORR, overall response rate; CBDCA, carboplatin
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Received August 27, 2001; accepted November 13, 2001.
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