A phase II study of cisplatin and docetaxel administered as three consecutive weekly infusions for advanced non-small-cell lung cancer in elderly patients

Y. Ohe1,*, S. Niho2, R. Kakinuma2, K. Kubota2, H. Ohmatsu2, K. Goto2, H. Nokihara1, H. Kunitoh1, N. Saijo1, H. Aono3, K. Watanabe3, M. Tango4, A. Yokoyama4 and Y. Nishiwaki2

1 Department of Internal Medicine, National Cancer Center Hospital, Tokyo; 2 Division of Thoracic Oncology, National Cancer Center Hospital, Kashiwa City; 3 Division of Respiratory Medicine, Yokohama Municipal Citizen’s Hospital, Yokohama; 4 Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan

Received 20 April 2003; revised 17 August 2003; accepted 28 August 2003


    ABSTRACT
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 REFERENCES
 
Background:

To evaluate the efficacy and safety of treatments for advanced non-small-cell lung cancer in elderly patients aged 75 years or older, we conducted a phase II study of cisplatin and docetaxel administered in three consecutive weekly infusions.

Patients and methods:

The eligibility criteria for the study included the presence of chemotherapy-naive advanced non-small-cell lung cancer, age ≥75 years, Eastern Cooperative Oncology Group performance status of 0 or 1, a measurable lesion, adequate organ functions and signed informed consent. The chemotherapy regimen consisted of cisplatin (25 mg/m2) and docetaxel (20 mg/m2) on days 1, 8 and 15 every 4 weeks.

Results:

Between February 2000 and March 2002, 34 elderly patients with non-small-cell lung cancer were enrolled in the study and 33 patients were treated. Two complete responses and 15 partial responses were obtained for an objective response rate of 52% in 33 treated patients. The median survival period was 15.8 months, and the 1-year survival rate was 64%. Toxicities were mild with no grade 4 toxicities. Only grade 3 leukopenia (6%), neutropenia (12%), anemia (3%), hyponatremia (3%) and nausea/vomiting (3%) were observed.

Conclusion:

Cisplatin and docetaxel administered in three consecutive weekly infusions was safe and effective for the treatment of elderly patients with chemotherapy-naive non-small-cell lung cancer.

Key words: cisplatin, docetaxel, elderly patients, non-small-cell lung cancer, weekly administration


    Introduction
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 Introduction
 Patients and methods
 Results
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Lung cancer is one of the most common carcinomas not only in Japan, but also in the United States and Europe. More than 55 000 patients die from lung cancer each year, and the mortality rate is still increasing in Japan [1, 2]. In particular, the number of elderly lung cancer patients is increasing in Japan [1, 2]. Surgery is the most effective curative treatment for early stage non-small-cell lung cancer (NSCLC); however, only 30% of patients with NSCLC receive a curative resection [3]. Cisplatin-based chemotherapy offers a survival benefit and symptom relief for patients with inoperable NSCLC [4]. However, we have demonstrated that classic standard cisplatin-based chemotherapy regimens such as cisplatin (80 mg/m2) on day 1 with etoposide (100 mg/m2) on days 1–3 or cisplatin (80 mg/m2) on day 1 with vindesine (3 mg/m2) on days 1 and 8 cause severe myelotoxicity in elderly NSCLC patients aged ≥75 years [5]. We used a very restricted eligibility criteria to select patients who could tolerate the cisplatin-based standard chemotherapy. Among 34 elderly patients, only 10 fitted the eligibility criteria. In spite of granulocyte colony-stimulating factor (G-CSF) support, nine of the 10 eligible patients experienced grade 4 neutropenia and six had infectious episodes [5]. Thus, we hypothesized that the recommended dose for elderly patients aged ≥75 years should be determined in a specific phase I study only for elderly patients.

Docetaxel has demonstrated antitumor activity in NSCLC patients with chemotherapy-naive lesions and tumor progression after receiving cisplatin-based regimens [610]. Docetaxel with cisplatin is one of the most promising chemotherapy regimens for NSCLC [11]. The commonly used dose and schedule of docetaxel is 60–100 mg/m2 every 3 weeks; however, moderate to severe neutropenia is frequently observed [611]. Recent studies have shown that weekly administration of docetaxel produces a higher dose intensity and less myelotoxicity [1214]. Thus, we conducted two independent phase I studies for elderly and non-elderly patients with NSCLC to determine the recommended dose for phase II studies and to evaluate the safety and efficacy of cisplatin and docetaxel administered as three consecutive weekly infusions in both non-elderly (≤74 years) and elderly (≥75 years) patients [15]. Different recommended doses of docetaxel were obtained for non-elderly and elderly patients [15]. The recommended doses were 25 mg/m2 cisplatin and 35 mg/m2 docetaxel on days 1, 8 and 15 for non-elderly patients, and 25 mg/m2 cisplatin and 20 mg/m2 docetaxel on days 1, 8 and 15 for elderly patients.

Two phase II studies of cisplatin and docetaxel administered as three consecutive weekly infusions for non-elderly and elderly patients were conducted. The results of the phase II study for non-elderly patients with NSCLC have been reported elsewhere; the objective tumor response was 30% [95% confidence interval (CI) 15% to 46%] and the median survival time was 12.8 months [16]. Here, we report the promising results of a phase II study for elderly patients with NSCLC.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
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Patient selection
Patients with histologically and/or cytologically documented NSCLC were eligible for the study. Each patient was required to meet the following criteria: clinical stage IV or IIIB (including only patients with no indications for curative radiotherapy), an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1, age ≥75 years, no prior chemotherapy, measurable lesions, adequate hematological function [white blood cell count (WBC) 4000–12 000/mm3; neutrophils ≥2000/mm3; platelets ≥100 000/mm3; hemaglobin ≥9.0 g/dl], adequate hepatic function (total bilirubin <1.1 mg/dl, aspartate aminotransferase and alanine aminotransferase <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 and pleural and/or pericardial effusion requiring drainage were excluded. The study was approved by the Institutional Review Board at the National Cancer Center, Yokohama Municipal Citizen’s Hospital and Niigata Cancer Center. Written informed consent was obtained from each patient.

Patient evaluation
The pretreatment evaluation consisted of complete blood cell count, differential count, routine chemistry measurements, a chest radiograph, a chest computed tomography (CT) scan, abdominal ultrasound or CT scan, whole-brain magnetic resonance imaging or CT scan, and an isotope bone scan. Complete blood cell count, differential, count and routine chemistry measurements were carried out 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 docetaxel (20 mg/m2) on days 1, 8 and 15 every 4 weeks. Docetaxel was infused over 30 min with 16 mg dexamethasone and 3 mg granisetron administered just before the docetaxel infusion. Ninety minutes after the completion of the docetaxel infusion, 25 mg/m2 cisplatin were administered over 15 min with 1500 ml normal saline over 3.5 h. The prophylactic administration of G-CSF was not permitted. Administration of G-CSF was permitted in patients with grade 4 neutropenia and/or leukopenia or grade 3 febrile neutropenia. The administration of both cisplatin and docetaxel were skipped on day 8 and/or day 15 if the patients met the following criteria: WBC <2000/mm3 and/or platelets <50 000/mm3. No dose modifications were carried out on days 8 and/or day 15 of the cisplatin and docetaxel administrations. Treatment was carried out for at least two courses, unless unacceptable toxicity or disease progression occurred.

Response and toxicity evaluation
The patients’ responses were evaluated according to the World Health Organization criteria [17]. A complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A partial response (PR) was defined as a reduction of ≥50% 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 >4 weeks with no new areas of malignant disease. No change included: the regression of indicator lesions that were insufficient to meet the criteria for PR, <25% increase in any measurable lesion and no new lesions of malignant disease. Progressive disease was defined as an increase in any measurable lesion by >25% or a new lesion of malignant disease. Survival times from the start of treatment were calculated using the Kaplan–Meier method. The toxicity grading criteria of the Japan Clinical Oncology Group (JCOG) were used to evaluate toxicity [18]. Most detailed gradings for individual organ toxicity in the JCOG Toxicity Criteria are identical to those of the National Cancer Institute Common Toxicity Criteria proposed in 1988. The only differences in the definitions used in the present study were that neutrophils were used instead of granulocytes and the definitions for nausea and vomiting were combined.

Statistical analysis
According to the minimax two-stage phase II study design by Simon [19], the treatment program was designed to refuse response rates of 20% and to provide a significance level of 0.05 with a statistical power of 80% in assessing the activity of the regimen as a 40% response rate. The upper limit for first-stage drug rejection was four responses among 18 evaluable patients; the upper limit of second-stage rejection was 10 responses among 33 evaluable patients. Overall survival was defined as the interval between enrolment in this study and death or the last follow-up visit. Median overall survival was estimated using the Kaplan–Meier analysis method [20].


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
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Patient characteristics
Between February 2000 and March 2002, 34 elderly patients with NSCLC were enrolled and 33 were treated in this study (Table 1). One patient did not receive the protocol treatment because the PS of the patient decreased before the start of the treatment and the patient no longer met the eligibility criteria. All treated patients were assessed for response, survival and toxicity. The median age of the patients was 77 years (range 75–86). The gender, PS and histology of the patients were as follows: 26 males, seven females; seven patients with PS 0, 26 patients with PS 1; 20 patients with adenocarcinoma, nine patients with squamous cell carcinoma, three patients with large cell carcinoma and one patient with NSCLC. Twenty-four patients had no prior treatment, five patients had undergone surgery, three patients had received radiotherapy for brain and/or bone metastases, and one patient had undergone both surgery and radiotherapy as prior treatments.


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Table 1. Characteristics of treated patients
 
Treatment received and dose intensity
The total number of treatment cycles was 101 and the median was 3 (range 1–15). Two patients received only one course because of a decrease in their PS. Of the 33 treated patients, 12 patients received two courses, 13 received three and six received four or more. One patient received 15 courses; however, he received treatments on only days 1 and 15 of the fifth to fifteenth courses. Between the first and fourth cycles, 77–100% of the patients received treatments on days 8 and 15 treatment (Table 2). Of the 303 planned administrations, 272 (90%) were carried out.


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Table 2. Treatment received
 
The median actual dose intensities of docetaxel and cisplatin were 13.4 mg/m2 (range 8.9–16.4) and 16.7 mg/m2 (range 11.1–20.4) per week, whereas the projected dose intensities were 15.0 and 18.8 mg/m2 per week for docetaxel and cisplatin, respectively.

Objective tumor response and overall survival
The objective tumor response is shown in Table 3. Two CRs and 15 PRs occurred for an objective response rate of 52% (95% CI 31% to 67%) in 33 treated patients. The overall survival periods of all treated patients are shown in Figure 1. The median survival time of the 33 treated patients was 15.8 months with a median follow-up time for 11 censored patients of 18.1 (15.2–35.5) months. The 1-year and 2-year survival rates were 64% and 26%, respectively.


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Table 3. Response rate
 


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Figure 1. Overall survival time. The median survival time of the 33 treated patients was 15.8 months, and the median follow-up time for 11 censored patients was 18.1 (15.2–35.5) months. The 1-year and 2-year survival rates were 64% and 26%, respectively.

 
Toxicity
The worst grades of hematological and non-hematological toxicities experienced by each patient are listed in Table 4. Both hematological and non-hematological toxicities were relatively mild. No grade 4 hematological or non-hematological toxicities were observed. Only grade 3 leukopenia (6%), neutropenia (12%), anemia (3%), hyponatremia (3%) and nausea/vomiting (3%) were observed. None of the patients received G-CSF. Renal toxicity was also relatively mild: grade 2 renal toxicity was observed in only one of 33 patients.


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Table 4. Maximum toxicity grades associated with weekly docetaxel and cisplatin in 33 treated patients
 
Discussion

We previously reported that classic standard cisplatin-based chemotherapy regimens cause severe myelotoxicity in elderly patients aged ≥75 years [5]. Based on that previous study of elderly patients with NSCLC, we conducted phase I studies in which cisplatin and docetaxel were administered as three consecutive weekly infusions in both non-elderly and elderly patients with NSCLC using the same eligibility criteria, except for age, and the same definitions of dose-limiting toxicity and maximum-tolerated dose [15]. Our hypothesis was that the recommended dose for elderly patients aged ≥75 years would differ from that for non-elderly patients. In the previous phase I studies, we demonstrated a difference in the recommended dose of docetaxel combined with cisplatin between non-elderly and elderly patients [15]. The recommended doses of docetaxel with 25 mg/m2 cisplatin were 35 and 20 mg/m2 on days 1, 8 and 15 for non-elderly and elderly patients, respectively. We also conducted phase II studies for non-elderly and elderly patients with NSCLC using each recommended dose and the same eligibility criteria, except for age. The results of the phase II study for non-elderly patients with NSCLC have been reported elsewhere [16]. Among the 33 evaluable patients, an objective tumor response of 30% (95% CI 15% to 46%) and a median survival time of 12.8 months were observed [16]. In the current study, we observed an objective tumor response of 52% (95% CI 31% to 67%) and a median survival time of 15.8 months for elderly patients with NSCLC. In spite of the lower dose of docetaxel, the efficacy of the treatment did not seem to be diminished.

Italian oncology groups have conducted randomized trials for elderly patients aged ≥70 years [2123]. In these studies, non-platinum-based single or double chemotherapy regimens, such as vinorelbine alone or vinorelbine plus gemcitabine were used for elderly patients with NSCLC [2123]. These chemotherapy regimens might not be adequate for non-elderly patients with a good PS because the cisplatin plus vinorelbine regimen was significantly superior to vinorelbine alone with regard to both the response rate and the survival [24, 25]. Kubota et al. [26] reported that the frequency of grade 4 leukocytopenia in the elderly (≥70 years of age) group was significantly greater than in the non-elderly group and that no difference in overall survival was observed between the two groups. Langer et al. [27] reported that advanced age alone should not preclude appropriate NSCLC treatment, although elderly patients aged ≥70 years have more co-morbidities and can expect a higher incidence of leukopenia and neuropsychiatric toxicity. In the United States, upper age limits are not included in eligibility criteria to avoid age discrimination. In contrast, most Japanese studies have upper age limits because Japanese government guidelines recommend that elderly patients, >75 years, should not be accrued in common clinical trials [28]. This recommendation was made in concern for the safety of elderly patients. In Japan, most clinical trials include patients aged ≤74 years, and the full-dose chemotherapy is administered. Clinical trials for elderly patients have generally been conducted as specific trials focusing on the treatment of elderly patients in Japan. However, the definition of ‘elderly’ is still unclear. Thus, the use of platinum-based chemotherapy in elderly patients with NSCLC remains controversial because no randomized phase III studies have been conducted to resolve this question.

Several chemotherapy trials for elderly patients with NSCLC have been reported [2123, 29] (Table 5). Of the subjects in these trials, 18–41% were PS 2 patients. Eligible patients were 70 or 65 years or older. The response rates of the non-platinum-based single or double chemotherapy regimens ranged from 15% to 22%, and the median survival times ranged from 18 to 36 weeks [2123, 29]. In the current study, however, PS 2 patients were excluded and only patients aged ≥75 years were included. The objective response rate of 52% (95% CI 31% to 67%) and the median survival time of 15.8 months (69 weeks) in our trial were extremely better than those of previous trials. We considered that the main reason for the better results was the exclusion of PS 2 patients. However, cisplatin chemotherapy might be important not only for non-elderly, but also for elderly patients with NSCLC.


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Table 5. Chemotherapy for elderly patients with non-small-cell lung cancer
 
We divided the cisplatin and docetaxel dosages on days 1, 8 and 15 because full-dose cisplatin is too toxic for elderly patients. The weekly administration of docetaxel produces a higher dose intensity and less myelotoxicity [1214]. Moreover, a weekly schedule may be safer than a 3-weekly schedule because treatment on day 8 and/or day 15 can be omitted if severe toxicity is observed. In the current study, the toxicity, including nausea/vomiting and renal toxicity, was relatively mild, and 90% of the planned administrations were carried out. The dose-limiting toxicities of docetaxel administered in six consecutive weekly infusions were reported to be fatigue and asthenia [1214]. In the previous phase I study, two out of six patients refused chemotherapy on day 15 because of fatigue and asthenia at level 2: 25 mg/m2 cisplatin and 25 mg/m2 docetaxel [15]. However, fatigue and asthenia were relatively mild in the current study because of the relatively low-dose of docetaxel (20 mg/m2).

We conclude that cisplatin and docetaxel administered as three consecutive weekly infusions is very effective and safe for elderly patients with chemotherapy-naive NSCLC. The JCOG is conducting a phase III study of cisplatin and docetaxel versus docetaxel alone, administered as three consecutive weekly infusions, for elderly patients with NSCLC to examine the role of cisplatin in the treatment of elderly patients with NSCLC.


    Acknowledgements
 
This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, a grant from the Ministry of Health, Labor and Welfare for 2nd Term Comprehensive Strategy for Cancer Control, Japan and a Bristol Myers Squibb Unrestricted Grant.


    FOOTNOTES
 
* Correspondence to: Dr Y. Ohe, Department of Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3542-7006; E-mail: yohe{at}ncc.go.jp Back


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