Japanese Journal of Clinical Oncology 30:429-434 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Phase II Study of Single-agent Docetaxel Chemotherapy for Non-small Cell Lung Cancer
Chest Department, Veterans General Hospital – Taipei, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Docetaxel is an active agent used in the treatment of non-small cell lung cancer (NSCLC).
Methods: A phase II trial of single-agent docetaxel chemotherapy was conducted in Chinese patients with NSCLC, as either a first- or second-line treatment, to assess response and toxicity. The treatment scheme was docetaxel 75 mg/m2 intravenous infusion for 1 h every 3 weeks for up to nine cycles. Dexamethasone was routinely given for 3 days, beginning 1 day before chemotherapy.
Results: From August 1996 to December 1997, 48 patients were enrolled, including 34 chemo-naive patients and 14 patients previously treated with one chemotherapeutic regimen. All patients were evaluable for toxicity profiles and 47 patients were evaluable for response rate. As expected, the major toxicity was myelosuppression. Grade 3 or 4 neutropenia occurred in 41 of 48 (85.5%) patients during treatment. Twenty patients (41.7%) experienced febrile neutropenia and accounted for two toxic deaths. Only one patient suffered from grade 3 thrombocytopenia and two patients from grade 3 anemia. Moderate or severe asthenia occurred in 30 patients (62.5%). Moderate fluid retention (peripheral edema) was observed in five patients (10.4%) and severe fluid retention in three; all were reversible. No grade 3 or 4 neurosensory toxicity was observed. After two cycles of treatment, 14 of 47 evaluable patients attained a partial response (29.8%, 95% CI 16.7–42.9%), including 30.3% (95% CI 14.6–46%) of those in first-line treatment and 28.6% (95% CI 4.9–52.3%) of those in second-line treatment. The median time to disease progression was 13 weeks in first-line patients and 19 weeks in second-line patients. Median survival time was 7.1 and 11.7 months in first- and second-line patients, respectively.
Conclusion: Docetaxel is active and has an acceptable toxicity profile, in both first- and second-line treatments, in Chinese patients with inoperable NSCLC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lung cancer is the leading cause of cancer deaths in Taiwan. Over 75% of non-small cell lung cancer (NSCLC) patients are inoperable at diagnosis because of either metastatic disease or disease confined to one hemithorax with one or more criteria of unresectability. Local recurrence or metastases also occurred in more than half of the patients who received surgical intervention. The high proportion of disseminated disease in these patients has justified the numerous attempts to improve systemic treatment that have progressed for several years now.
Recently, many chemotherapeutic agents have been developed which show promising activity in the treatment of NSCLC, including vinorelbine, gemcitabine, taxanes (paclitaxel, docetaxel) and topoisomerase I inhibitor (1). Docetaxel enhances microtubule assembly and inhibits the depolymerization of tubulin. As with paclitaxel, this can lead to bundles of microtubules in the cell, which, by blocking cells in the M phase of the cell cycle, result in the inability of the cells to divide (2). This contrasts with the action of other spindle poisons in clinical use, such as Vinca alkaloids, which inhibit tubulin assembly in microtubules. Single-agent docetaxel, used either as a first- or second-line treatment, has been found active against NSCLC in medical journal reports since 1994 (3–15). Objective response rates range from 21 to 38% in chemo-naive patients and the average response rate is 29% with a median survival of nearly 11 months (9,14). The response rate of single agent docetaxel in second-line treatment is between 15 and 27%, with a median survival of up to 9 months in one report (8,9,12,13).
There has been no previous report of single-agent docetaxel treatment in Chinese NSCLC patients, in either first- or second-line treatment. The response rate and safety profile in Chinese NSCLC patients are unknown. Therefore, a phase II trial of single-agent docetaxel treatment to evaluate its efficacy and toxicity profile in Chinese stage IIIb/IV NSCLC patients was performed.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study was conducted according to the Helsinki Declaration and existing rules for good clinical practice. The protocol was approved by the local ethics committee and the Department of Health. Registration was done using the central registration office outside the hospital. Patients with stage IIIb or stage IV NSCLC,
18 years old, were entered into the study after obtaining written informed consent. Eligibility criteria were as follows: histological or cytological diagnosis of stage IIIb or IV NSCLC; no prior immunotherapy or radiotherapy on target lesions; performance status of 0–1 on the Zubrod scale; clinically measurable disease, defined as two-dimensionally measurable lesions with clearly defined margins on X-ray, scan or physical examination; an estimated life expectancy of at least 12 weeks; adequate bone marrow reserve with white blood cell (WBC) count 4000/mm3, platelets 100 000/mm3 and hemoglobin 10 g/dl; appropriate contraceptive methods in female patients; and those patients previously treated by surgery needed to demonstrate progressive disease. Exclusion criteria were as follows: previous history of more than one regimen of chemotherapy or an active infection; ALT and/or AST >2.5 times the upper normal limit or alkaline phosphatase >5; an inadequate renal function with creatinine >1.5 times the upper normal limit; pregnancy or not using appropriate birth control during the study; breast feeding; second primary malignancy except in situ carcinoma of the cervix or appropriately treated basal cell carcinoma of the skin; and neurological conditions which could interfere with the evaluation of neurological toxicity. Initial work-up included documentation of the patient’s history, a physical examination and a performance score. Complete blood cell counts, urinalysis, serum biochemistry profile, ECG, chest roentgenography, whole body bone scan and chest (including liver and adrenal glands) CT scan were also performed. A brain CT scan was performed if clinically indicated.
Eligible patients were treated with docetaxel, up to nine cycles, at 3-weekly intervals. The treatment consisted of docetaxel 75 mg/m2 intravenous infusion for 1 h. Dexamethasone 8 mg p.o. b.i.d. was given on days –1, 1 and 2 (day 1 being the day of docetaxel administration).
Courses were repeated every 3 weeks. Before and after each injection of the chemotherapeutic agent, the patient’s vital signs and temperature were recorded. A complete blood cell count was checked between day 8 and day 15 of each cycle. Serum biochemistry studies were performed before every course of chemotherapy and if clinically indicated. Adverse events and toxicities were also recorded using the US National Cancer Institute (NCI) grading system. A granulocyte colony-stimulating factor was used to treat patients suffering from grade 4 or febrile neutropenia.
The docetaxel dose was reduced to 55 mg/m2 in subsequent cycles if the patient suffered from febrile neutropenia, if grade 4 hematological toxicity persisted longer than 1 week or in cases of grade 2 neurological or grade 3 non-hematological toxicity (except nausea/vomiting). In the case of grade 3 neurological toxicity or grade 4 non-hematological toxicity (except nausea/vomiting), the patient was removed from the study.
A response evaluation was performed after the first two courses of chemotherapy and every two courses thereafter according to established WHO criteria (16). Patients were considered evaluable for response if they completed two courses of chemotherapy with at least one follow-up tumor assessment, unless there was early tumor progression. If the patient died before the first follow-up tumor assessment, this was considered progressive disease. Responding patients and those in a stable condition were continued until disease progression or through nine courses of treatment.
A two-stage phase II design was used to estimate patient accrual targets. A response rate of 20% to single-agent docetaxel would be of interest in both chemo-naive and previously chemotherapy-treated NSCLC patients. Initially, 14 patients were evaluated for response and if none of the 14 patients experienced a partial or complete response, then the study was terminated. If the true response rate was 20%, the chance of rejection error was <5%. However, in the event of one response among the first 14 patients, further accrual was continued to a total of 50 evaluable patients to estimate the response rate more precisely, with a standard error of no more than 7%. Hence the maximum accrual in this study would be 50 evaluable patients. With a response rate of 29.8% and 47 evaluable patients in our study, the standard error was 6.7%. Time to disease progression was calculated from the first infusion of docetaxel to the first documentation of progression. Survival was measured from administration of the first dose of docetaxel until the date of death or last follow-up.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between August 1996 and December 1997, 48 patients were brought into this study, including 32 males and 16 females. Thirty-four patients were chemo-naive and 14 patients had previously received systemic chemotherapy. Among the 14 patients who had previously received chemotherapy, 12 had received cisplatin-based combination chemotherapy (their prior response to chemotherapy was partial response in three, stable disease in five and progressive disease in four) and the remaining two patients had received single-agent gemcitabine treatment (prior response was one partial response and the other stable disease). The clinical characteristics of these patients are shown in Table 1. All were assessable for toxicity profiles and 47 patients were evaluable for treatment response. The only patient who was not evaluable for response was one with protocol violation (double cancer) who was off-study after one cycle of docetaxel treatment.
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A total of 227 cycles of docetaxel were given to all patients, including 156 cycles to the first-line patients and 71 cycles to the second-line patients. Docetaxel 100 mg/m2 was given to the first seven patients (11 cycles in all) and reduced to 75 mg/m2 later in all patients owing to a high incidence of serious adverse events in two patients who died (one patient with tumor bleeding-induced massive hemoptysis and the other with pneumonia, septic shock and acute renal failure) and in a third patient who was critically ill with pneumonia after febrile neutropenia. The median number of cycles received per patient was four in both first- and second-line patients. Dose reduction to 55 mg/m2 was necessary in five patients, with a total of 13 cycles, due to toxicity. The median dose intensity in overall, first-line and second-line patients was 23.1, 23.5 and 22.3 mg/m2/week, respectively.
After two cycles of treatment, 14 of 47 patients achieved a partial response, with a response rate of 29.8% [95% confidence interval (CI) 16.7–42.9%]. None achieved a complete response (Table 2). The overall response rate was 30.3 and 28.6% in first- and second-line patients, respectively. The response rate in first-line treatment was significantly higher in patients with a performance status of 0 than in those with 1 (Table 2). There was no significant difference in the response rate for first-line treatment regarding staging and histology subtype (Table 2). The median time to disease progression was 13 weeks in the first-line patients and 19 weeks in the second-line patients. Median survival time was 7.1 and 11.7 months in first- and second-line patients, respectively. The survival curve of 34 chemo-naive patients treated with docetaxel is shown in Fig. 1.
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All patients enrolled into the study were eligible for toxicity evaluation. The main toxicities were hematological (Table 3). Neutropenia was the main hematological toxicity with 4.2% of the patients having grade 3 toxicity and 81.3% having grade 4 toxicity. Grade 3 or 4 neutropenia occurred in 72 of 99 evaluable cycles (72.7%). The median nadir by patient was 0.2 x 109/l and the median time to nadir was 8 days. Grade 3 or 4 leukopenia occurred in 75% of the patients or in 57.8% of 102 evaluable cycles. The median nadir was 1.3 x 109/l and the median time to nadir was 7 days. Febrile neutropenia occurred in 20 patients (41.7%) or 22 cycles (9.7%), including four of 11 cycles (36.4%) treated with 100 mg/m2 and 18 of 203 cycles (8.9%) treated with 75 mg/m2 and did not occur in cycles of 55 mg/m2. There were five documented infections in five patients during neutropenia that accounted for two toxic deaths in this study. The incidence of grade 3 anemia was 4.2% of the patients or 1.9% (two of 103) of the evaluable cycles. There was no grade 4 anemia. Grade 3 thrombocytopenia occurred in one of the patients or in one out of 101 evaluable cycles. There was no grade 4 thrombocytopenia.
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There were several other non-hematologic toxicities (Table 4), which, for the most part, was not a limiting factor in the administration of docetaxel. Asthenia occurred in 35 patients (72.9%), including mild in five patients (10.4%), moderate in 22 patients (45.8%) and severe in eight patients (16.7%). Fluid retention was observed in 21 patients (43.8%). Five patients had moderate fluid retention (peripheral edema) and three patients had severe fluid retention. All these cases of fluid retention were reversible. Neurosensory toxicity was the most frequent neurotoxicity (29.2% of the patients). However, no grade 3 or 4 neurosensory toxicity was observed. Hypersensitivity reaction (allergy) occurred in 19 cycles (8.4%) of 10 patients (20.8%). All hypersensitivity reactions were grade 1 toxicity, including nine patients with vasodilatation and two patients with pruritus.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The aim of this study was to confirm the efficacy of single-agent docetaxel treatment at a dose of 75 mg/m2 in the first- and second-line treatment of patients with unresectable or metastatic NSCLC. A 3-day dexamethasone administration was given routinely in order to prevent fluid retention. The incidence of fluid retention observed in this study was comparable to that observed with 5-day corticosteroid premedication (17).
Cisplatin-based chemotherapy regimens led to a significant prolongation of survival for NSCLC, achieving a median survival of ~7 months compared with the 4 months seen with the best supportive care in randomized trials from the 1980s (1,18). New drugs, such as vinorelbine, gemcitabine, paclitaxel and docetaxel, have promising activity against NSCLC. For each of these drugs, median survivals in excess of 7 months have been reported in single-agent studies (18).
Most of the previous studies of single-agent docetaxel treatment against NSCLC were performed with a docetaxel dosage of 100 mg/m2 given as a 1 h infusion on day 1 of every 3 weeks (3–5,7–9,14,15,17), except for that from a Japanese cooperative study (60 mg/m2 every 3 weeks) and from Miller et al. (75 mg/m2 every 3 weeks) (6,10). We initially also planned a dosage of docetaxel 100 mg/m2 every 3 weeks. However, we had to reduce it to 75 mg/m2 because of serious adverse events occurring in patients treated with a 100 mg/m2 dose level. The poorer prognostic factors for first-line patients in this trial (91.2% stage IV) probably had an impact on the lower median survival time of 7.1 months (n = 34) in this study, compared with 9 months (n = 20) in Miller et al.’s study in which the docetaxel dosage was the same as ours, but the stage IV patients were fewer (6). The median survival in the Japanese cooperative study (n = 75) of single-agent docetaxel (60 mg/m2 every 3 weeks) in chemo-naive NSCLC was also better than that in the present study (10 versus 7 months) and fewer stage IV patients were also noted in their patient groups (10). The response rate of the present study was better and median survival was poorer than those in the above two studies. However, the 95% CI in both response rate and median survival overlapped in these studies. Hence there was no significant difference. The dose used in Miller et al.’s study was the same as in ours. They suggested that 100 mg/m2 should be used instead of 75 mg/m2 because the toxicities induced at both levels were similar when compared with another group’s data of docetaxel 100 mg/m2 every 3 weeks (6). However, this suggestion did not apply to Chinese patients and it seemed that our patients’ tolerance was more or less the same as that of the Japanese patients (10).
It was found that the objective response rate was significantly correlated with patients’ median survival time in single-agent phase II trials for NSCLC (19). However, this finding did not apply to our patients. Higher response rates do not equal higher survival and this has been well documented repeatedly in clinical trials (20,21). Performance status and staging are still the most important prognostic factors in most studies.
The older generation drugs, such as etoposide, epirubicin and cisplatin, that are active against previously untreated NSCLC, do not achieve a response rate >10% when used in a second-line setting (13). Among the new drugs used for NSCLC, docetaxel was found to be most active in second-line treatment and appeared to prolong survival when compared with the historical control of other salvage chemotherapy methods (12,13,18,22). Randomized trials of docetaxel versus the best supportive care (23) and of docetaxel versus vinorelbine or ifosfamide (24) have been reported recently. It was found that second-line docetaxel treatment improved the patient’s survival significantly, compared with the best supportive care or other single-agent chemotherapy regimens (23–25).
In summary, single-agent docetaxel 75 mg/m2 every 3 weeks, premedicated with dexamethasone for 3 days, is highly effective and reasonably safe in Chinese patients with NSCLC, in both first- and second-line treatment. A confirmatory trial using docetaxel in patients with prior chemotherapy is on-going at our hospital.
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FOOTNOTES |
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+ For reprints and all correspondence: Yuh-Min Chen, Chest Department, Veterans General Hospital – Taipei, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. E-mail: ymchen@vghtpe.gov.tw
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Received May 30, 2000; accepted July 17, 2000.
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