Japanese Journal of Clinical Oncology 31:100-106 (2001)
© 2001 Foundation for Promotion of Cancer Research
Phase I Studies of Cisplatin and Docetaxel Administered by Three Consecutive Weekly Infusions for Advanced Non-small Cell Lung Cancer in Elderly and Non-elderly Patients
1Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba and 2Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: To determine the maximum tolerated dose and recommended dose of cisplatin and docetaxel administered by three consecutive weekly infusions in both non-elderly (
74 years) and elderly (
75 years) patients, we conducted two independent phase I studies for non-elderly and elderly patients with non-small cell lung cancer. Methods: Between April 1998 and September 1999, 26 non-elderly (median, 54 years; range, 44–73 years) and 12 elderly (median, 76 years; range, 75–80 years) patients with non-small cell lung cancer were entered in these studies. The eligibility criteria of both cohorts were identical except for age. Chemotherapy consisted of cisplatin 25 mg/m2 and an escalated dose of docetaxel on days 1, 8 and 15 every 4 weeks. The initial dose of docetaxel was 20 mg/m2 and it was increased by 5 mg/m2 at each dose level.
Results: In the non-elderly and elderly cohorts, up to 45 or 25 mg/m2 of docetaxel, respectively, were administered. Dose-limiting toxicities were neutropenia, liver damage, pneumonia and omission of treatment on day 15 by leukopenia and refusal in the non-elderly cohort; pneumonia and omission of treatment on day 15 by refusal due to fatigue/asthenia or fever in the elderly cohort. We considered the recommended doses for phase II studies were cisplatin 25 mg/m2 and docetaxel 35 mg/m2 on days 1, 8 and 15 for non-elderly patients and cisplatin 25 mg/m2 and docetaxel 20 mg/m2 on days 1, 8 and 15 for elderly patients. Seven of 26 (27%) and seven of 12 (58%) patients achieved a partial response, median survival times were 8.7 and 7.2 months and 1 year survival rates were 27 and 27% in the non-elderly and elderly cohorts, respectively.
Conclusions: Further evaluation of this combination chemotherapy is warranted for both non-elderly and elderly patients with non-small cell lung cancer but the dose of docetaxel should be lower for elderly than non-elderly patients.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Docetaxel is a hemisynthetic compound derived from 10-deacetylbaccatin III, a non-cytotoxic precursor extracted from the needles of the European yew tree, Taxus baccata L. (1,2). Members of the taxoid family, such as docetaxel and paclitaxel, promote microtubule assembly and inhibit depolymerization to free tubulin, which results in the blockage of the cells in the M phase of the cell cycle (1,2). Docetaxel has a broad spectrum of antitumor activity in clinical trials for several kinds of cancers such as breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer and head and neck cancer (1,3).
Docetaxel has demonstrated antitumor activity in patients with NSCLC that are not only chemotherapy-naive but also with a progressed stage after receiving cisplatin-based regimens (4–8). Docetaxel with cisplatin is one of the most promising chemotherapy regimens for NSCLC. In phase II studies, the response rates and median survival times have been reported to be 32–48% and 8–13 months, respectively (9). Several phase III studies including docetaxel with cisplatin regimen are ongoing. The commonly used dose and schedule of docetaxel are 60–100 mg/m2 every 3 weeks; however, moderate to severe neutropenia is frequently observed (4–8). Recently, studies have shown that weekly administration of docetaxel produces a higher dose intensity and less myelotoxicity (10–12). Recommended doses of six consecutive or long-term weekly infusions of docetaxel alone were reported to be 35–40 mg/m2/week (10–12). The dose-limiting toxicities (DLTs) of docetaxel administered in six consecutive weekly infusions were reported to be fatigue and asthenia (10). Moreover, a weekly schedule may be safer than a triweekly schedule because we could omit the treatment on day 8 and/or day 15 if we observed severe toxicity.
We have demonstrated that standard cisplatin-based chemotherapy regimens, such as cisplatin 80 mg/m2 on day 1 with etoposide 100 mg/m2 on days 1–3 and cisplatin 80 mg/m2 on day 1 with vindesine 3 mg/m2 on days 1 and 8, cause severe myelotoxicity for elderly patients aged 75 years or older with NSCLC (13). We set very restricted eligibility criteria to select the patients who could tolerate cisplatin-based standard chemotherapy. Of 34 elderly patients only 10 fitted the eligibility criteria. In spite of granulocyte colony-stimulating factor (G-CSF) support, of the 10 eligible patients, nine experienced grade 4 neutropenia and six had infectious episodes (13). Thus, we hypothesized that the recommended dose for elderly patients aged 75 years or older should be determined in a specific phase I study only for elderly patients.
To determine the maximum tolerated dose (MTD) and recommended dose for phase II studies and to evaluate the safety and efficacy of cisplatin and docetaxel administered in three consecutive weekly infusions in both non-elderly (74 years) and elderly (75 years) patients, we conducted two independent phase I studies for elderly and non-elderly patients with NSCLC.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Selection
Eligibility criteria of both cohorts, elderly and non-elderly, were identical except for age. Patients with histologically and/or cytologically documented NSCLC were eligible for these studies. Each patient was required to meet the following criteria: clinical stage IV or IIIB (including only the patients with no indication for curative radiotherapy), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, age
20 years, no prior chemotherapy, evaluable or measurable lesion, adequate hematological function (WBC 4000–12 000/mm3, neutrophil 2000/mm3, platelets 100 000/mm3, Hb 9.0 g/dl), adequate hepatic function (total bilirubin <1.1 mg/dl, AST and ALT <60 IU/l) and adequate renal function (creatinine 1.2 mg/dl, creatinine clearance 60 ml/min). Patients with active infection, severe heart disease, uncontrollable hypertension or diabetes mellitus, active concomitant malignancy or pleural and/or pericardial effusion that required drainage and pregnant/nursing women were excluded. These studies were approved by the Institutional Review Board at National Cancer Center and written informed consent was obtained from each patient.
Patient Evaluation
Pretreatment evaluation consisted of complete blood cell counts, differential, routine chemistry measurements, chest radiograph, chest computed tomographic (CT) scan, abdominal ultrasound or CT scan, whole-brain magnetic resonance imaging (MRI) or CT scan and isotope bone scan. Complete blood cell counts and differential and routine chemistry measurements were performed at least twice a week during the first course of chemotherapy.
Treatment Schedule
All patients were admitted to hospital during the first course of chemotherapy. Chemotherapy consisted of cisplatin 25 mg/m2 on days 1, 8 and 15 and an escalated dose of docetaxel on days 1, 8 and 15 every 4 weeks. The initial dose of docetaxel was 20 mg/m2 and it was increased by 5 mg/m2 at each dose level. Intrapatient dose escalation was not allowed. Docetaxel was infused over 30 min with 16 mg of dexamethasone and 3 mg of granisetron just before the docetaxel infusion. Ninety minutes after the completion of docetaxel infusion, 25 mg/m2 of cisplatin were administered over 15 min with 1500 ml of normal saline over 3.5 h. Prophylactic administration of G-CSF was not permitted. Administration of G-CSF was permitted for patients with grade 4 neutropenia and/or leukopenia and grade 3 febrile neutropenia. The administrations of both cisplatin and docetaxel were omitted on day 8 and/or day 15 if patients met the criteria WBC <2000/mm3 and/or platelets <50 000/mm3. No dose modification of cisplatin and docetaxel was performed on day 8 and/or day 15. If the DLT was observed, only the dose of docetaxel was reduced by 5 mg/m2 in the next course of chemotherapy. Treatment was to be performed for at least two courses, unless unacceptable toxicity or disease progression occurred.
The DLT was defined as follows: grade 4 hematological toxicity, grade 3 or grade 4 febrile neutropenia, grade 3 non-hematological toxicity except for nausea/vomiting, omission of the treatment on day 8 and/or day 15. Initially, three patients were treated at each dose level. If DLT was not observed in any of three patients, dose escalation was made. If DLT was observed in one or two of three patients, an additional three patients were entered at the same dose level. If DLT was observed in three or more of six patients or all of the initial three patients, we considered the dose was the MTD. If DLT was observed in one or two of six patients, dose escalation was also made. The patients who could not receive at least one course of treatment due to disease progression or coincidental disease were not included in the evaluation of MTD. Dose escalation was decided by the data based only on the first course of chemotherapy. Dose escalation and determinations of MTD and recommended dose were performed independently for the elderly and non-elderly cohorts.
Response and Toxicity Evaluation
Response was evaluated according to WHO criteria (14). Complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. Partial response (PR) was defined as a 50% reduction in the product of the largest perpendicular diameters of one or more clearly measurable lesions or as a >50% reduction in evaluable malignant disease lasting for more than 4 weeks with no new area of malignant disease. No change (NC) included: regression of indicator lesions insufficient to meet the criteria for response, a <25% increase in any measurable lesion and no new lesions of malignant disease. Progressive disease (PD) indicated an increase in any measurable lesion by >25% or a new lesion of malignant disease. Survival times from the start of treatment were calculated by the Kaplan–Meier method. Toxicity grading criteria of the Japan Clinical Oncology Group (JCOG) were used for evaluation of toxicity (15).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients’ Characteristics
Between April 1998 and September 1999, 26 non-elderly (median, 54 years; range, 44–73 years) and 12 elderly (median, 76 years; range, 75–80 years) patients with NSCLC were entered in these studies (Table 1). All patients were assessable for response, survival and toxicity. The majority of patients had untreated stage IV NSCLC and scored PS 1. In the non-elderly cohort, 24 of the 26 patients were found to have an adenocarcinoma of the lung.
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Treatment Received
The initial dose of docetaxel was 20 mg/m2 and it was increased by 5 mg/m2 at each dose level (Table 2). Up to 45 or 25 mg/m2 of docetaxel were administered in non-elderly and elderly cohorts, respectively. The total numbers of cycles of treatment were 54 (median, 2; range, 1–5) and 29 (median, 2.5; range, 1–3) in the non-elderly and elderly cohorts, respectively. In the non-elderly cohort, four, four, three and three patients were treated at levels 1, 2, 3 and 4, respectively. After the treatment of three patients at level 6, an additional three patients were treated at level 4. In the elderly cohort, three and six patients were treated at levels 1 and 2, respectively. After the treatment of six patients at level 2, an additional three patients were treated at level 1. Two patients could not complete the first course of treatment owing to disease progression and bacterial colitis at levels 1 and 2, respectively, in the non-elderly cohort.
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Toxicity, Maximum Tolerated Dose and Recommended Dose in Non-elderly Patients
The worst grades for each patient in all courses of hematological and non-hematological toxicities in non-elderly patients are listed in Table 3. Leukopenia and neutropenia were observed dose dependently, but they were relatively mild. Grade 4 neutropenia was observed in only one patient at level 5 and another two patients omitted the treatment on day 15 owing to leukopenia (<2000/mm3) at level 4. Anemia and thrombocytopenia were very mild. No peripheral neuropathy and no edema were observed. Renal toxicity was also very mild; grade 1 renal toxicity was observed in only three of 26 patients. No DLT was observed in the first course of treatment at levels 1–3. However, grade 3 liver toxicity and grade 3 infection, pneumonia, were observed in the third course at level 1 and in the fourth course at level 2, respectively. At level 5, grade 3 liver damage and refusal of the treatment on day 15 owing to fatigue/asthenia were observed in the first course for the first and second patients, respectively. Three patients entered at level 6, because DLT was observed in only two of six patients in the first course of treatment at level 5. However, grade 4 neutropenia was observed in the second course with another patient at level 5. Finally, DLTs were observed in three of six patients at level 5. Therefore, we entered three additional patients at level 4 to confirm the safety and finally DLTs were observed in only two of six patients at level 4. No treatment-related deaths were observed at any level. We considered MTD was level 5, cisplatin 25 mg/m2 and docetaxel 40 mg/m2 on days 1, 8 and 15 every 4 weeks and the recommended dose for phase II study was level 4, cisplatin 25 mg/m2 and docetaxel 35 mg/m2 on days 1, 8 and 15 every 4 weeks for non-elderly patients.
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Toxicity, Maximum Tolerated Dose and Recommended Dose in Elderly Patients
The worst grades for each patient in all courses of hematological and non-hematological toxicities in elderly patients are listed in Table 4. Leukopenia and neutropenia were relatively mild. However, leukopenia and neutropenia at level 2 in the elderly cohort were more dominant than that in the non-elderly cohort. Anemia was severe at level 2 in the elderly cohort, three grade 3 and three grade 2 anemia were observed in six patients. At level 2, three of six patients omitted the treatment on day 15 owing to fever or refusals due to fatigue/asthenia. Pneumonia occurred in another patient at level 2. DLTs were observed in four of six patients at level 2. Therefore, we entered three additional patients at level 1 to confirm the safety and one patient refused the treatment on day 15 owing to fatigue/asthenia in the third course. Finally, DLT was observed in only one of six patients at level 1. No treatment-related deaths were observed at either level. We considered MTD was level 2, cisplatin 25 mg/m2 and docetaxel 25 mg/m2 on days 1, 8 and 15 every 4 weeks and the recommended dose for phase II study was level 1, cisplatin 25 mg/m2 and docetaxel 20 mg/m2 on days 1, 8 and 15 every 4 weeks for elderly patients.
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Objective Tumor Response and Overall Survival
Objective tumor responses in the non-elderly and elderly cohorts at each dose level are shown in Table 5. Seven of 26 (27%) and seven of 12 (58%) patients achieved PR in the non-elderly and elderly cohorts, respectively. Overall survivals of all patients treated in the non-elderly and elderly cohorts are shown in Fig. 1. The median follow-up times for eight and three censored patients were 11.9 and 17.8 months, the median survival times were 8.7 and 7.2 months and the 1 year survival rates were 27 and 27% in the non-elderly and elderly cohorts, respectively. In spite of the lower dose of docetaxel, a relatively higher response rate was observed in elderly patients.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Phase I studies of cisplatin and docetaxel administered in three consecutive weekly infusions were conducted in non-elderly and elderly patients with advanced NSCLC. We demonstrated that the recommended doses for phase II studies were cisplatin 25 mg/m2 and docetaxel 35 mg/m2 on days 1, 8, 15 for non-elderly patients and cisplatin 25 mg/m2 and docetaxel 20 mg/m2 on days 1, 8, 15 for elderly patients. DLTs were neutropenia, liver toxicity, pneumonia and omission of treatment on day 15 by leukopenia and refusal due to fatigue/asthenia in the non-elderly cohort and pneumonia and omission of treatment on day 15 owing to refusal due to fatigue/asthenia or fever in the elderly cohort. The toxicity profile of cisplatin and docetaxel can be markedly altered when administered using a weekly schedule. Not only myelotoxicity but also renal toxicity and nausea/vomiting were mild. No peripheral neuropathy and no edema were observed. However, cumulative toxicity such as peripheral neuropathy and edema could not be precisely evaluated because the median cycles of treatment were only 2 and 2.5 in the non-elderly and elderly cohorts, respectively. In our studies, toxicity in the first course was mild, but toxicities in the second or later courses were more severe. We consider that a higher dose could be administered only in the first course of treatment and could not be repeated. Recommended doses of six consecutive or long-term weekly infusions of docetaxel alone were reported to be 35–40 mg/m2/week (10–12). Surprisingly, the recommended dose of docetaxel with cisplatin was similar to that of docetaxel alone administered as six consecutive weekly infusions followed by 2 weeks of rest. Our schedule was three consecutive weekly infusions followed by 1 week of rest repeated every 4 weeks. This earlier rest from treatment may reduce the fatigue and asthenia. Moreover, only chemotherapy-naive and PS 0 or 1 patients were eligible for our studies.
In spite of the lower dose of docetaxel, a comparable efficacy was observed in elderly patients. Seven of 26 (27%) and seven of 12 (58%) patients achieved PR; the median survival times were 8.7 and 7.2 months in the non-elderly and elderly cohorts, respectively. Several papers have reported results of chemotherapy for elderly patients aged 70 years with NSCLC (16–18). The response rate in the present study for elderly patients aged 75 years was markedly higher than the reported results. We consider that the combination of cisplatin and docetaxel administered as three consecutive weekly infusions is safe and active in both non-elderly and elderly patients with NSCLC. However, owing to the small number of patients, it will be necessary to confirm these findings in further studies.
Our hypothesis based on our previous study was that the recommended dose for elderly patients aged 75 years should differ from that for non-elderly patients. In the current studies we demonstrated the difference in the recommended dose of docetaxel combined with cisplatin administered in three consecutive weekly infusions between non-elderly and elderly patients. The recommended doses of docetaxel with 25 mg/m2 of cisplatin were 35 and 20 mg/m2 on days 1, 8 and 15 for non-elderly and elderly patients, respectively. One reason for the difference was related to the patience level regarding toxicity effects such as fatigue and asthenia. Because an objective evaluation of fatigue and asthenia was very difficult and no criteria to evaluate them were available in the JCOG toxicity criteria, we considered that refusal of the treatment on day 8 and/or day 15 due to fatigue and asthenia was comparable to grade 3 non-hematological toxicity (15). No patients refused the treatment at levels 1–4 in the non-elderly cohort, but two of six patients refused the treatment on day 15 at level 2 in the elderly cohort. We speculate that this difference might partially depend on the difference in the level of patience. However, anemia was more severe in the elderly cohort; three grade 3 and three grade 2 anemia were observed in six patients at level 2. Moreover, in spite of the lower dose of docetaxel, the efficacy was not diminished in the elderly patients. Advanced age and small body surface area were reported as factors decreasing the clearance of docetaxel (19). Thus, we speculate that the main reason for the difference in recommended dose was dependent on the different pharmacokinetics. In elderly patients, a comparable plasma concentration or area under the concentration versus time curve (AUC) might be obtained in spite of the lower dose of docetaxel.
We consider that this combination chemotherapy is warranted for further evaluation not only for non-elderly but also for elderly patients with NSCLC, although the dose of docetaxel should be reduced in the elderly patients. To clarify the reasons for the difference in recommended dose in the two groups and to confirm the efficacy and safety, phase II studies with pharmacokinetic evaluation are ongoing in both non-elderly and elderly patients with NSCLC using each recommended dose.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by a grant from the Ministry of Health and Welfare for 2nd-term Comprehensive Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Yuichiro Ohe, Department of Internal Medicine, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yohe@ncc.go.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received September 28, 2000; accepted December 18, 2000.
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