Docetaxel and carboplatin is an active regimen in advanced non-small-cell lung cancer: a phase II study in Caucasian and Asian patients

M. J. Millward1,3,+, M. J. Boyer1, M. Lehnert2, S. Clarke1, D. Rischin3, B.-C. Goh2, J. Wong2, E. McNeil1 and J. F. Bishop1

1 Cancer Therapeutics Research Group, Sydney Cancer Centre, Sydney, Australia; 2 Cancer Therapeutics Research Group, National University Hospital, Singapore; 3 Peter MacCallum Cancer Institute, Melbourne, Australia

Received 21 May 2002; revised 12 November 2002; accepted 21 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The purpose of this study was to report response rates, survival and toxicity in advanced non-small-cell lung cancer (NSCLC) following docetaxel and carboplatin, and to explore potential differences in these end points between Caucasian and Asian patients.

Patients and methods:

Sixty-eight patients of good performance status with Stage IIIB or IV NSCLC were entered on a phase II study at three sites in Australia and Singapore. Docetaxel 75 mg/m2 and carboplatin AUC 6 were given every 3 weeks. Response to treatment and toxicity were graded by standard criteria. The Kaplan–Meier method was used to estimate survival rates, and subgroups compared by the log-rank test. Cox’s proportional hazards regression was used to determine which potentially explanatory variables independently affected the outcome.

Results:

The response rate was 39% (95% confidence interval 27% to 52%), and 42% in evaluable patients. Response occurred in 65% of Asian and 31% of Caucasian patients (P = 0.01). Ethnicity was the only significant predictor of response in multivariate analysis. The 1-year survival rate was 53%. Performance status (P = 0.021), ethnicity (P = 0.035) and presence of bone or liver metastases (P = 0.011) were independent predictors of overall survival. Neutropenia (grade IV in 73% of patients), febrile neutropenia (26% patients) and diarrhea (grade III/IV in 11% of patients) were the major treatment related toxicities. A high rate (three of six) of febrile neutropenia in Singapore, including one treatment-related death in the initial patients treated, resulted in a reduction in the carboplatin dose to AUC 4.5 at that site.

Conclusions:

This regimen is active in advanced NSCLC. The potential impact of ethnicity on efficacy and toxicity of treatment requires further investigation.

Key words: docetaxel, ethnicity, non-small-cell lung cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Despite the introduction of several new active cytotoxic agents for advanced or metastatic non-small-cell lung cancer (NSCLC), there is no universally agreed standard drug combination for this disease. A meta-analysis of trials, most of which were performed prior to the 1990s, showed a significant survival advantage for cisplatin containing chemotherapy regimens compared to supportive care [1]. The combination of cisplatin with paclitaxel has shown superiority over cisplatin–etoposide or cisplatin–teniposide combinations [2, 3]. The combination of cisplatin and vinorelbine has shown superiority over older cisplatin combinations [4]. Docetaxel has shown activity against previously untreated advanced NSCLC in phase II clinical trials [5, 6] and we have previously reported the results of phase I and phase II trials of the docetaxel–cisplatin combination in this setting [7, 8]. Although this combination showed definite activity at doses of docetaxel 75 mg/m2 plus cisplatin 75 mg/m2 including a response rate of 30% in the phase II trial, it produced significant non-hematological toxicity including renal and electrolyte disturbances, nausea/emesis and diarrhea [8]. Results from a large phase III trial did not show any significant benefits of the docetaxel–cisplatin combination compared with the reference regimen of paclitaxel and cisplatin [9].

Carboplatin has shown broad equivalence to cisplatin in combination chemotherapy for advanced NSCLC [1012]. The combination of carboplatin and paclitaxel has a more acceptable safety profile than cisplatin and paclitaxel, although no advantage in antitumor efficacy has been demonstrated [9]. The combination of carboplatin plus docetaxel was therefore a regimen worthy of further exploration in NSCLC. Here we report the results of this regimen in a large phase II study performed in Australia and Singapore. The study sites treated predominantly Caucasian and Asian patients, respectively, allowing an initial comparison of the efficacy and toxicity of this regimen in different ethnic populations.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Eligibility criteria for this study included pathologically proven NSCLC, stage IV or stage IIIB disease, age >=18 and <75 years, ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1 and at least one bidimensionally measurable site of disease outside any prior radiation fields. No prior systemic chemotherapy was permitted and no prior radiation therapy was permitted for patients with stage IIIB disease. Patients were required to have prestudy hemoglobin >=10 g/dl, absolute neutrophil count >=2 x 109/l, platelets >=100 x 109/l, bilirubin <1.25x the upper limit of normal for the institution, aspartate aminotransferase <2x the upper limit of normal for the institution, and creatinine <120 µmol/l. Patients with known brain or leptomeningeal involvement were excluded, as were patients with symptomatic peripheral neuropathy >= grade 1, pregnant or lactating women and patients with coincident serious medical conditions, including unstable cardiac disease and active uncontrolled infection. Patients were not permitted to receive concomitant treatment with corticosteroids except as prophylaxis for docetaxel-related fluid retention or prophylactic antiemesis. Written informed consent was obtained from all patients, and the protocol was reviewed and approved by the Human Subject Ethics Committees of the participating institutions.

Study treatment
Patients received docetaxel 75 mg/m2 as a 1-hour i.v. infusion immediately followed by carboplatin calculated to give an AUC of 6 mg·min/ml according to the Calvert formula [13]. Either a direct radionuclide measurement glomerular filtration rate, or a calculated creatinine clearance using the Cockroft–Gault formula could be used to calculate the carboplatin dose. The docetaxel and carboplatin doses were chosen based on a phase I study performed by Belani et al. [14]. In that study, the recommended phase II dose was carboplatin AUC 6 plus docetaxel 80 mg/m2. The docetaxel dose was reduced slightly to 75 mg/m2 in this trial to allow more direct comparison with our previous cisplatin–docetaxel trials, where that docetaxel dose was recommended for phase II study in combination with cisplatin 75 mg/m2.

All patients received dexamethasone 8 mg twice daily for 3 days commencing the day prior to chemotherapy. A 5HT3 antagonist was given on the day of chemotherapy as antiemesis prophylaxis. Cycles of chemotherapy were repeated every 3 weeks. Treatment was discontinued for progressive disease. Patients with stable disease could cease treatment after four cycles. A maximum of six cycles of chemotherapy were given to responding patients. Patients with stage IIIB disease could receive radical radiation therapy to the chest after four cycles of protocol chemotherapy if this was considered appropriate by their treating physician.

Dose reductions were defined in advance for hematological and non-hematological toxicities. Prophylactic use of granulocyte colony-stimulating factor (G-CSF) was not permitted. The dose of both drugs was reduced by 20% for febrile neutropenia, grade 4 neutropenia of >=7 days duration, or thrombocytopenia grade 4. Following the first cycle, subsequent cycles were delayed if the pretreatment neutrophil count was <1.5 x 109/l or the platelet count <100 x 109/l. For grade 2 peripheral neuropathy, the dose of both drugs was reduced by 20%. Patients with grade 3 peripheral neuropathy were taken off the study. Other grade 3 non-haematological toxicities were managed by withholding treatment until resolution to grade <1, followed by retreatment with a 20% dose reduction of both drugs.

At one site (National University Hospital, Singapore), a protocol amendment was introduced because of significant toxicity in the first six patients treated at that site. The subsequent 15 patients treated at that site received carboplatin AUC 4.5; the docetaxel dose was not modified. The other two sites did not modify the protocol doses.

While on the study, patients underwent physical examination, including performance status and recording of toxicity, prior to every cycle of treatment. Complete blood counts were performed weekly and biochemistry and liver function tests every 3 weeks. Computed tomography (CT) scanning or other imaging required to assess disease extent was performed prior to study treatment and every two cycles on study. After completion of study treatment, patients were followed-up at least every 8 weeks and tumor imaging performed at least every 4 months.

Response to treatment was graded by standard WHO criteria. The development of brain metastases was considered to be progressive disease, even if response outside the brain was present. Toxicity from treatment was graded according to the NCI-CTC (National Cancer Institute common toxicity criteria).

Statistics
The primary end points of this trial were response and toxicity. It was assumed that a true response rate of <20% would not be of interest, and an initial sample size of 25 patients evaluable for response was planned. If fewer than five responses occurred in this cohort, the study would be stopped, with a <10% chance of rejecting a true response rate of 20%. Otherwise, up to 70 patients were to be entered to define a response rate, with a standard error of <7% for a response rate of 40%.

Progression-free and overall survival were measured from the date of study entry to the date of documentation of disease progression and death, respectively. The Kaplan–Meier product limit method was used to estimate survival rates, and the survival times of two or more subgroups were compared by the log-rank test. Cox’s proportional hazards regression was used to determine which potentially explanatory variables independently affected survival duration.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between February 1998 and September 1999, 68 patients were entered on to the trial from three institutions. Two patients were considered ineligible. One patient had cerebral metastases, and the other had performance status 2 and died without receiving any study treatment. A third patient, aged 79 years, was entered despite an upper age limit of 75 years. As he fulfilled all other eligibility criteria, he was included in the analyses. The characteristics of the 66 eligible patients are shown in Table 1. Forty-nine patients (73%) had no prior anticancer treatment, the others had previously undergone surgical resection and/or radiation therapy. All the patients treated in Singapore were Asian. Two patients treated in Australia were Asian, all others were Caucasian.


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Table 1. Patient characteristics
 
Response
Four patients did not undergo assessment for response. Three patients were withdrawn from the study after receiving one cycle of treatment because of toxicity. A fourth patient died from treatment-related causes after two cycles. Thus, 62 patients were evaluable for response. For all evaluable patients, response was determined by CT scanning. There were no complete responders. Twenty-six patients had a partial response. Twenty patients (32%) had stable disease, while 16 patients (26%) progressed during treatment. On an intention-to-treat basis the overall response rate in the 66 patients was 39% [95% confidence interval (CI) 27% to 52%]. The overall response rate was 42% (95% CI 30% to 54%) in the evaluable patients. The response rate was significantly higher for patients with performance status 0 than patients with performance status 1 (53% versus 27%, P = 0.04). In the patients with stage IV disease, the response rate was 43%. Interestingly, the response rate was significantly related to ethnicity, being 65% in Asian patients and 31% in Caucasian patients (P = 0.01). Logistic regression analysis was used to determine independent predictors for response to treatment. The determinants were age, gender, ethnicity, performance status, weight loss, stage, histology, number of metastatic sites, and presence of bone or liver metastases. Ethnicity was the only significant variable, with an odds ratio of 4.5 (95% CI 1.2–17.6) for Asian patients. Of the two Asian patients treated in Australia, one had a partial response.

Survival
For survival analysis, a close out date of 31 August 2000 was used. Only two (3%) patients had <12 months follow-up. For all 66 eligible patients, the median time to progression was 24 weeks, and the median overall survival was 12.9 months. The 1-year overall survival rate was 53% (Figure 1). The following potential determinants of progression-free and overall survival were tested individually in univariate analysis using the log-rank test: gender, stage, histology, performance status, weight loss >10%, ethnicity, number of disease sites, and presence of bone or liver metastases. For progression-free survival, only performance status (P = 0.008) and presence of bone or liver metastases (P = 0.04) were significant predictors. Cox’s proportional hazards regression was used to determine independent predictors for time to disease progression. Performance status was the only significant independent predictor (P = 0.03). For overall survival, only performance status (P = 0.001) and presence of bone or liver metastases (P = 0.002) were significant predictors on univariate analysis. However, using Cox’s proportional hazards regression, in addition to performance status (P = 0.021) both ethnicity (P = 0.035) and presence of bone or liver metastases (P = 0.011) were significant predictors of overall survival. The 1-year survival was 54% in Asians and 52% in Caucasians.



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Figure 1. Overall survival for the 66 eligible patients.

 
Toxicity
A total of 281 cycles of treatment were given; the median number received was four (range 1–6). Twenty-five patients (38%) received six cycles. Seven patients with stage IIIB disease discontinued chemotherapy to receive radical radiotherapy to the chest after four (six patients) or five (one patient) cycles of protocol chemotherapy. One other patient underwent surgical resection after four cycles of protocol chemotherapy followed by radical radiotherapy to pathologically involved mediastinal nodes.

Hematological toxicity
Neutropenia was the predominant toxicity. Grade III or IV neutropenia occurred in 70% of treatment cycles (Table 2). Seventy-three per cent of patients experienced at least one episode of grade 4 neutropenia. Thrombocytopenia was rare. Minor levels of anemia were seen, and may have reflected underlying disease rather than being directly related to study treatment. Severe anemia was also rare.


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Table 2. Hematological toxicity (worst grade, % treatment cycles)
 
Seventeen patients (26%) experienced a total of 21 episodes of febrile neutropenia. Febrile neutropenia occurred in 7% of treatment cycles. Of the 21 episodes, 11 were in the first cycle and five in the second. Eleven of the 17 (65%) patients who developed febrile neutropenia did so in their first cycle. One patient died, following the second cycle of chemotherapy, of neutropenic sepsis with pneumonia and respiratory failure despite aggressive supportive care. This patient had also experienced febrile neutropenia after cycle 1, and the second cycle was given with protocol-specified dose reductions.

The mean cycle 1 neutrophil nadir was 0.98 x 109/l with 43% of patients experiencing grade 4 neutropenia in cycle 1. At the National University Hospital, Singapore, the mean cycle 1 neutrophil nadir in the first six patients was 0.67 x 109/l, with three of the six experiencing febrile neutropenia. Following the reduction of the carboplatin dose to AUC 4.5, the mean cycle 1 neutrophil nadir in the following 15 patients was 0.99 x 109/l, with six of the patients developing febrile neutropenia. Review of the clinical characteristics of these initial six patients showed no major differences from the subsequent patients treated in Singapore. Both Asian patients treated in Australia developed grade 4 neutropenia, although not in cycle 1. Neither patient had febrile neutropenia, although one had grade 3 diarrhea.

There was no evidence of cumulative myelosuppression, and no patients experienced prolonged (>7 days) grade 4 neutropenia. Only one patient required delay of a subsequent cycle because of neutropenia.

Non-hematological toxicity
Treatment-related diarrhea was a prominent non-hematological toxicity. Seven patients (11%) had grade 3 (n = 6) or grade 4 (n = 1) diarrhea. The patient with grade 4 diarrhea had hypotension requiring inotrope support. This patient, together with two others with grade 3 diarrhea also had febrile neutropenia. Six of the seven patients with grade 3 or 4 diarrhea developed it in cycle 1. No other grade 4 non-hematological toxicity occurred. Other grade 3 non-hematological toxicity was rare, and consisted of mucositis (three patients, 4%), peripheral neuropathy (two patients, 3%), nausea/vomiting (two patients, 3%), arthralgia/myalgia (two patients, 3%), skin/nail changes (one patient, 2%), and fatigue (one patient, 2%). Three patients had minor hypersensitivity reactions requiring temporary cessation of the docetaxel infusion. No major hypersensitivity reactions occurred.

Forty-six patients (70%) completed therapy as per protocol. Fifteen patients (23%) stopped treatment for progressive disease. As well as the one toxic death, four other patients (6%) discontinued treatment because of toxicity: combination of febrile neutropenia with grade 3/4 diarrhea (two patients); grade 3 peripheral neuropathy (one patient); and in one patient a general deterioration in performance status. Fourteen patients (21%) had protocol-specified dose reductions; in 11 this was because of febrile neutropenia.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is one of the largest phase II studies of the combination of docetaxel and carboplatin in NSCLC reported to date. The regimen is active with a response rate of 42% and a 1-year survival of 53%. These results are consistent with other reports of this two-drug combination (Table 3). The activity is very similar to our previous study of docetaxel and cisplatin in 47 patients [8], which had almost identical eligibility criteria and study population. In that study, the median survival was 9.6 months and the 1-year survival was 33% [8]. The response rate was 39% in the evaluable patients, but fell to 30% on an intention-to-treat basis, reflecting the high number of early treatment discontinuations due to toxicity [8]. Patient tolerance of treatment was better in the current study, with less than half the incidence of toxicity-related treatment discontinuations (8%) than we reported with cisplatin and docetaxel (17%).


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Table 3. Phase II studies of docetaxel and carboplatin in NSCLC
 
Hematological toxicity was common with the majority of patients developing grade 4 neutropenia. Febrile neutropenia complicated only 10% of the cycles with grade 4 neutropenia, but still developed in 26% of patients particularly in the first cycle. The use of prophylactic antibiotics or G-CSF was not permitted on this protocol, but should be considered in patients at particular risk, such as those with obstructive atelectasis or coincident chronic obstructive pulmonary disease.

Diarrhea was the most significant non-hematological toxicity. It has been previously reported by us and others as a limiting toxicity in phase I and phase II trials of docetaxel–platinum combinations [7, 8, 24]. The incidence of grade 3/4 diarrhea in this trial (11%) is very similar to that which we reported in our docetaxel–cisplatin phase II trial, where the incidence was 13% [8]. Severe bowel toxicity including typhlitis has also been reported with docetaxel and paclitaxel combinations in patients with breast cancer [25, 26]. Other non-hematological toxicity was infrequent in this trial reflecting the low incidence of toxicity associated with carboplatin. In particular, the incidence of severe nausea and vomiting (3%) was much lower than we reported with cisplatin–docetaxel (26%) [8]. Renal/electrolyte problems and cardiac events that were problematic with the cisplatin–docetaxel combination did not occur.

We found that the response rate to docetaxel–carboplatin chemotherapy was significantly higher in Asian patients than Caucasian patients. This difference in response had not been previously reported, but few lung cancer trials have been jointly performed in Asian and Western countries. However, ethnicity was not a prespecified prognostic factor for analysis, so this finding requires prospective evaluation and confirmation in other trials. The unexpectedly high rate of toxicity seen in the first group of patients treated at the National University Hospital, Singapore, resulted in a reduction of the carboplatin dose to AUC 4.5. Although this did result in a reduction in cycle 1 neutropenia, there was still quite a high rate of febrile neutropenia (six of 15) in subsequent patients at that site. Further studies conducted on the pharmacology of docetaxel in Asian patients indicated a slower plasma clearance than in Caucasians [27], suggesting this was the main determinant of the higher toxicity seen.

Studies such as this, which compare outcomes in different ethnic groups require the cooperation of centres from differing countries. It is therefore possible that the observed difference in response rate reflects differences in response assessment between different centres. Although responses were not independently reviewed, it is unlikely that the large difference in response rates found is due to this. All responses were determined by experienced clinicians and radiologists. Other studies performed by our group have not shown a difference in response rate between centres [28].

This phase II study, together with our previous phase II study of docetaxel with cisplatin, shows that both combinations are active, with the carboplatin regimen producing less toxicity and better tolerability. These two regimens are being compared to a reference regimen of vinorelbine and cisplatin in a large multinational phase III trial in NSCLC. Initial results show a reduction in nausea/vomiting with carboplatin–docetaxel compared with the cisplatin combinations [29]. Final results from this trial will determine the place of docetaxel–platinum combinations in this disease. Our trial has suggested potentially important differences between Caucasian and Asian patients with advanced NSCLC in the efficacy and tolerability of treatment, and this should be considered in future studies of novel therapies for this disease. Interestingly, initial results of a large phase II study of Iressa in NSCLC showed a higher response rate in Japanese patients than patients treated outside Japan [30].


    Acknowledgements
 
This work was supported by a grant from Aventis Pharmaceuticals.


    Footnotes
 
+ Correspondence to: Dr M. J. Millward, Sydney Cancer Centre, Gloucester House Level 6, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney 2050, Australia. Tel: +61-2-95157680; Fax: +61-2-95191546; E-mail: michaelm{at}canc.rpa.cs.nsw.gov.au Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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