Japanese Journal of Clinical Oncology 32:512-516 (2002)
© 2002 Foundation for Promotion of Cancer Research
A Phase I Study of Carboplatin and Docetaxel for Advanced Non-small Cell Lung Cancer Using the Continual Reassessment Method
1 Respiratory Medicine, School of Medicine, Kanazawa University, Kanazawa, 2 Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, 3 Division of Respiratory Medicine, Kouseiren Takaoka Hospital, Takaoka, Toyama and 4 Respiratory Medicine, Komatsu Municipal Hospital, Komatsu, Ishikawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Purpose: This phase I study was designed to determine the maximum tolerated dose of carboplatin combined with a fixed dose of docetaxel (60 mg/m2) and the safety and efficacy of this combination chemotherapy in unresectable non-small cell lung cancer.
Methods: Patients received a 60 min intravenous infusion of docetaxel followed by a 90 min infusion of carboplatin with dose escalation using the continual reassessment method. The starting dose of carboplatin was targeted to an area under the plasma concentration curve of 3 using Calvert’s equation and dose escalation was based on course 1 toxicities.
Results: From January 1999 to February 2000, 16 patients entered this trial. The major dose-limiting toxicity was neutropenia. Thrombocytopenia was rare and major non-hematological toxicities included fever that was not associated with neutropenia and grade 2 nausea and vomiting. Objective responses were seen in five patients (response rate 31.3%).
Conclusions: Based on this phase I clinical trial, the maximum tolerated dose of carboplatin combined with 60 mg/m2 of docetaxel was a target area under the plasma concentration curve (tAUC) of 6 and the recommended tAUC for further trials is 5.5. This combination appeared to be effective for non-small cell lung cancer. A phase II clinical trial is recommended using 60 mg/m2 of docetaxel and carboplatin with a tAUC of 5.5.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Non-small cell lung cancer (NSCLC) is the leading cause of death of men in Japan. Unfortunately, at the time of diagnosis the majority of patients with NSCLC present with locally advanced or disseminated disease. The median survival of patients with stage IIIB and IV NSCLC ranges from 6 to 8 months and only 10–20% survive for 1 year.
Docetaxel, partially synthesized from 10-deacetylbaccatin III, was isolated from the needles of the European yew tree, Taxus baccata (1,2). It promotes tubulin assembly, thus disrupting the normal dynamic recognition of the microtubule network, essential for vital interphase and mitotic function (1,2). A phase I trial of docetaxel was conducted in Japan and the dose-limiting toxic reaction was neutropenia (3). The recommended dose for phase II study is 60 mg/m2 at 3–4 week intervals. In Japan, two phase II studies of docetaxel at a dose of 60 mg/m2 by 1 h intravenous infusion every 3 weeks were conducted (4,5). Neutropenia (>grade 3) was observed in 87% of patients receiving this dose of docetaxel. A 60 mg/m2 dose of docetaxel was demonstrated to be active against NSCLC with tolerable side effects.
Carboplatin, a less toxic analogue of cisplatin, has marginal but consistent antitumor effects in NSCLC. In the Eastern Cooperative Oncology Group (ECOG) study that compared three cisplatin-based combination regimens, single-agent therapy of carboplatin or iproplatin, the best survival was observed with carboplatin (6). The dose-limiting toxic effect of carboplatin is thrombcytopenia, which is prominent in chemotherapy with docetaxel as a single agent. Carboplatin is likely to be a suitable agent for combination with docetaxel.
The objectives of this phase I study were as follows: (1) to determine the maximum tolerated dose (MTD) of carboplatin in combination with docetaxel; (2) to describe and quantify the toxic effects of the combination of carboplatin and docetaxel; and (3) to propose a safe dose for a phase II clinical trial in chemotherapy-naive NSCLC.
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PATIENTS AND METHODS |
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Patient Eligibility
Patients were required to have histologically or cytologically proven stage IIIB or IV NSCLC. No prior therapy including chemotherapy or radiotherapy was permitted. Other eligibility criteria were age
75 years, performance status (ECOG) 0–2, Hb 
9.5 g/dl, WBC count 4.0 x 109/l, actual neutrophil count 2 x 109/l, platelets 100 x 109/l, AST and ALT 2 x normal, ALP 2.5 x normal, T. bilirubin normal, urea and creatinine normal and PaO2 70 Torr. Written informed consent was obtained from all patients and the protocol was approved by the institutional ethics committees of the participating centers. Patients were excluded from the trial for any of the following: severe complication such as unstable cardiac disease and diabetes mellitus, active double cancer, uncontrolled infection, pericardial, pleural and peritoneal effusion requiring treatment, pregnancy, lactation and interstitial pneumonia.
Pretreatment and Follow-up Evaluations
Before enrollment into the trial, all patients underwent a full history and clinical examination, which included performance status, complete blood cell count (CBC) with differentials, electrolytes, glucose, liver function tests, urea, creatinine, urinalysis, ECG and chest X-ray. Computed tomographies of chest and abdomen and bone scans were performed in all patients. Additional imaging investigations were performed if clinically indicated or to measure areas of known disease. During the study, all patients were reviewed for symptoms of toxicity and had clinical examinations, including weight and performance status daily. CBC was performed two or three times weekly. Electrolytes, glucose, liver function tests, urea, creatinine, urinalysis and chest X-ray were performed weekly. ECG and CT scan for all measurable diseases were performed every 3 weeks.
Drug Administration
Docetaxel was diluted in 500 ml of 5% glucose and infused over 60 min. Carboplatin was dissolved in 500 ml of 0.9% saline solution and infused over 90 min immediately following docetaxel infusion. All patients received intravenous 5-HT3-receptor antagonists and dexamethasone 10 mg before the docetaxel infusion. Additional antiemetic treatment was given as necessary. Prophylactic recombinant colony-stimulating factor support was not permitted.
Dose Level and Dose Escalation
In this study, we intended to increase carboplatin target area under the plasma concentration curve (tAUC) against a fixed dose of docetaxel (60 mg/m2). The dose of docetaxel used was the recommended dose for a phase II study based on phase I studies in Japan (4,5) and for combination chemotherapy in the USA (7). The dose of carboplatin was calculated using Calvert’s equation (8):
carboplatin dose = tAUC x [glomerular filtration rate (GFR) + 25]
GFR was calculated with the estimated creatinine clearance by the Jelliffe’s equation (9):
GFR = {[(98 – 0.8 x age)] x body surface area}/(serum creatinine x 1.73)
Dose escalation was based on the continual reassessment method (CRM) (10,11). Based on the predicted probability of development of DLT in phase II of docetaxel, in Japan (4,5), ECOG phase III trial (6), data on carboplatin dosage (8), phase I of docetaxel and carboplatin combination therapy (12), a logistic distribution was assumed in the dose–response relationship and the slope was assumed from single regression analysis. The target incidence of toxicity was assumed to be 50% and the gamma distribution of r (0.308781 x 10, 1/10), which has a slope assumed from single regression analysis, was considered as an advance distribution of the slope.
The starting dose (level 1) was carboplatin tAUC of 3 mg/ml/min. The dose of carboplatin was increased to the tAUC 3.5 (level 2), 4 (level 3), 4.5 (level 4), 5 (level 5), 5.5 (level 6), 6 (level 7), 6.5 (level 8) and 7 (level 8) mg/ml/min. Before each new patient was treated, an estimated MTD was calculated based on the toxicity experienced by all previously treated patients. The MTD was defined as the dose at which a probability of 50% of the patient population showing unacceptable reversible toxicity (grade 4 hematological toxicity lasting for 3 days or longer or grade 3 or 4 non-hematological toxicity) would be more than 33.3%. The recommended dose for phase II clinical trial would be the dose one level below the MTD that caused moderate reversible toxicity in most patients.
Response and Toxicity Criteria
Tumor response and treatment toxicity were graded according to the standard World Health Organization (WHO) toxicity criteria (13).
Prediction of Thrombocytopenia
Reduction in platelet counts, the percentage decrease in platelets and nadir platelets were predicted by the equation advocated by Egorin et al. (14):
carboplatin dosage = 0.091 x (Ccr/Abs)(Pred) + 86
where Ccr is creatinine clearance, Abs is the body surface area and Pred is the predicted percentage reduction in platelets counts.
Statistical Analysis
Statistical analyses were done with the Stat View Program for Apple Macintosh computers. The comparisons of quantitative and qualitative data were made with the Wilcoxon signed-rank test or simple regression analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
From January 1999 to February 2000, 16 patients were enrolled in this study. Patients’ characteristics are listed in Table 1. The number of patients entered at each level is listed in Table 2. The median age was 68.5 years. Fourteen patients had a performance status of 0–1. The most common histological subtype was adenocarcinoma (68.8%). Twelve patients (75%) had unresectable stage III disease, seven had malignant pleural effusion without necessity for treatment, four had poor pulmonary function and could not receive radiotherapy and one had a giant tumor greater than half of the right lung and could not receive radiotherapy (Table 1).
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Toxicity
All patients were assessed for toxicity. The number of patients who experienced DLT in the first cycle at each level is listed in Table 2. No patients who entered at levels 1, 2, 3, 4 and 5 had experienced DLT. At level 6, when two cases were registered, because DLT occurred in one case (severe pneumonia without neutropenia), we registered one more patient. The patient had not experienced DLT, so the level proceeded to level 7. At level 7, however, all three cases showed DLT (one experienced grade 4 liver dysfunction and two experienced grade 4 neutropenia lasting for more than 3 days). Because the predicted probability of the development of DLT at level 7 was 49.2% at that time, the level was decreased to level 6 for confirmation, which was registered. However, patients experienced febrile neutropenia and DLT was considered, and consequently the preliminary probability of development of DLT at level 7 became 53.3%, so level 7 was considered as the MTD. Hematological toxicity is listed in Table 3. Neutropenia was the predominant hematological toxicity. Of the 16 patients entered in this trial, three experienced grade 3 neutrocytopenia and six experienced grade 4 neutropenia. The median time to nadir was 9 days and no grade 4 neutropenia lasted for 5 days or longer. Severe thrombocytopenia did not occur in any patients. At level 6, one patient experienced grade 1 thrombocytopenia. We calculated predicted values of platelet decrease based on Egorin’s equation. In 13 patients, the 24 h creatinine clearance was examined just before chemotherapy. The predicted decrease in platelet count was 138 ± 54 x 109/l and the actual decrease was 66 ± 42 x 109/l. The actual decreases in platelet counts were significantly lower than the predicted values (P = 0.0017; sign test) (Fig. 1). The most common non-hematological toxicity was drug-induced fever. Four of the 16 patients experienced grade 1 and one experienced grade 2 fever. Nausea and vomiting of grade 2 or worse occurred in two patients at levels 4 and 6. Asthenia, diarrhea, neurotoxicity or severe hypersensitivity reactions were not observed.
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Response to Chemotherapy
Of the 16 patients who received this combination chemotherapy, there were five PR (response rate 31.3%, Table 2). No dose-dependent effects regarding efficacy were documented in our preliminary data. However, because there was only a small number of patients, it is impossible to draw a definite conclusion from the present results.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Docetaxel is a promising chemotherapeutic agent for the treatment of NSCLC. A report of the results obtained with 60 mg/m2 of docetaxel every 3 weeks in chemotherapy-naive patients with NSCLC showed a response rate of 21.8% in Japan (4). In addition to NSCLC, docetaxel has activity in a range of other solid tumors, including breast cancer, cisplatin-resistant ovarian cancer, head and neck cancer, gastric cancer and soft tissue sarcomas. In this study, we conducted a phase I clinical trial on combination chemotherapy of carboplatin and docetaxel in NSCLC using CRM. The traditional dose escalation design of a phase I investigation involves a minimum of three patients at a base level before dose escalation. When significant toxicity is observed, more patients are added to the dose level. These procedures continue until the MTD is determined. The CRM proposed by O’Quigley et al. (10) allows more rapid dose escalation compared with the traditional dose-escalation schedule and a decrease in patients who are treated with low doses of the drug. The duration of the study was not short and dose escalation not rapid; the number of patients treated with a relatively low dose of carboplatin (tAUC <5) was seven. Nine patients were treated with a relatively high dose of carboplatin (tAUC
5). The dose-limiting toxic effect of this combination chemotherapy was neutropenia, with an MTD of carboplatin tAUC of 6. The MTD with this combination consisting of carboplatin and docetaxel was relatively low compared with previous studies by Belani et al. (12) and Giannakakis et al. (15). Belani et al. reported that the recommended dose of this combination in non-hematological malignancy was 80 mg/m2 of docetaxel and carboplatin tAUC 6.0 mg/ml/min. Giannakakis et al. reported that the recommended dose was 100 mg/m2 of docetaxel and carboplatin tAUC 6.0 mg/ml/min in patients with advanced NSCLC. A precise reason for this discrepancy is not clear. In this study, three patients given 60 mg/m2 of docetaxel and carboplatin AUC 6 experienced grade 3 or 4 neutropenia. CRM analysis showed that the probability of emergence of DLT in level 6 was 43.6% [Pro (P > 0.5) = 0.319] and that in level 7 was 53.3% [Pro (P > 0.5) = 0.581]. We finally decided that the MTD of a fixed dose of docetaxel with carboplatin was tAUC 5.5 mg/ml/min in this study. Thrombocytopenia was rare; only one patient experienced grade 1 toxicity, which did not last for 3 days. Thrombocytopenia has not been commonly seen in patients who received combined chemotherapy with carboplatin and paclitaxel. Bunn and Kelly (16) reported that grade 4 thrombocytopenia was observed in only one patient treated with this combination chemotherapy (carboplatin 250–400 mg/m2 and paclitaxel 135–225 mg/m2). The decreases in observed platelet counts were significantly lower than those predicted. Our findings suggest that both docetaxel and paclitaxel may have a protective effect against thrombocytopenia induced by carboplatin administration. This platelet-sparing effect appears to be one of the reasons that docetaxel is preferable as a suitable drug for combination use with carboplatin.
Non-hematological toxicities of this combination were relatively mild. One patient experienced grade 4 liver dysfunction at level 7. No patients experienced hypersensitivity reaction, asthenia, diarrhea, neurotoxicity or fluid retention. The low incidence of adverse effects might be attributed to the dose of docetaxel, 60 mg/m2. The combination chemotherapy with carboplatin and docetaxel produced encouraging antitumor activity in this phase I study. Although it is too early to estimate the duration of response or the overall survival, this combination chemotherapy appears to be well tolerated, with favorable results in patients with NSCLC, and a phase II trial is warranted.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (10770264). We thank Dr Mikio Nishikawa (Bristol-Myers Squibb, Tokyo, Japan) for his assistance with the statistical analysis.
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FOOTNOTES |
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+ For reprints and all correspondence: K. Kasahara, Respiratory Medicine, School of Medicine, Kanazawa University, Takara-machi 13–1, Kanazawa 920-8641, Japan. E-mail: kasa1237@med3.m.kanazawa-u.ac.jp
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Received May 7, 2002; accepted September 24, 2002
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