Japanese Journal of Clinical Oncology Advance Access originally published online on December 15, 2006
Japanese Journal of Clinical Oncology 2007 37(1):23-29; doi:10.1093/jjco/hyl124
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© 2006 Foundation for Promotion of Cancer Research
A Phase II Randomized Study of Two Taxanes and Cisplatin for Metastatic Breast Cancer after Anthracycline: A Final Analysis
Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, LinKuo, College of Medicine, Chang Gung University, Taipei, Taiwan
For reprints and all correspondence: Yung-Chang Lin, Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, LinKuo, College of Medicine, Chang Gung University, 199 Tung-Hwa North Road, Taipei, Taiwan, 105. E-mail: yclinof{at}adm.cgmh.org.tw
Received April 28, 2006; accepted September 18, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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OBJECTIVE: The purpose of the study is to compare two taxanes/cisplatin combinations for metastatic breast cancer in terms of time to disease progression, response rates and toxicity.
METHODS: Between April 2000 and December 2002, 101 patients with advanced breast carcinoma, previously treated with an anthracycline but not with a taxane, were enrolled. Fifty patients were treated with docetaxel 60 mg/m2 and cisplatin 50 mg/m2, and 51 patients were treated with paclitaxel 175 mg/m2 and cisplatin 50 mg/m2. Each cycle repeated every 3 weeks.
RESULTS: The overall response rate was 62.5 and 42.6% in the docetaxel and palcitaxel groups respectively (P = 0.06). Median time to disease progression was 9.8 and 6.5 months in docetaxel and paclitaxel groups respectively (P = 0.15). The median overall survival time was 22.7 months in the docetaxel arm and 22.4 months in the paclitaxel arm. Grade 3/4 arthralgia/myalgia, sensory neuropathy and anemia occurred more frequently in the paclitaxel arm, while more mucositis, fatigue and neutropenia occurred in the docetaxel arm.
CONCLUSION: Taxane/cisplatin combinations were active for advanced breast cancer, while there appeared to be evidence in favor of a docetaxel/cisplatin combination. The toxicity in favor of docetaxel/cisplatin warrants future first-line clinical trials.
Key Words: metastatic breast cancer • taxanes • platinum • hemotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Women with metastatic breast cancer (MBC) are essentially incurable and have a median survival of about 2–3 years, urging for the need of new strategies or agents, among which the taxanes (docetaxel and paclitaxel), alone or in combination with others, appear to be the most promising (1).
In patients with MBC who have been exposed to anthracyclines, taxanes are the first choices when the disease recurred or progressed. A number of taxane-based regimens were reported for this purpose; however, single taxane chemotherapy was the most common remedy in clinical practice (2, 3). Taxanes with their unique mechanism of action should offer a chance to develop a more effective combination therapy against breast cancer. However, a number of problems have hindered their rapid development. One of the crucial problems has been the demonstration of unexpected interactions between paclitaxel and the other components of the combination, often resulting in unusual and serious toxic effects (4). It may account for the existence of significant toxicity in most taxane-based regimens. Another is the lack of a randomized trial to confirm the superiority of the combination regimen over a single agent. The randomized docetaxel/capecitabine versus docetaxel alone trial provided solid evidence for the latter (5). However, there still exists, the need to explore taxane/non-anthracycline combinations in addition, because they very common in anathracycline-based regimens in an adjuvant setting.
Platinum is an active first-line regimen against breast cancer, but is not as effective as salvage treatment. A platinum-combining regimen was more successful as the second line chemotherapy (6). The rationale for the combination of taxanes and platinum is their different mechanisms of action, a lack of cross-resistance in vitro (7, 8) and reported efficacy in certain solid tumors, such as non-small cell lung cancer (9). Several phase I and II trials have investigated combinations of taxanes/platinum (cisplatin or carboplatin) in MBC. In general, efficacy of this combination was significant with major response rates in the range of 40–70% (8, 10–13). Unfortunately, most of the trials have documented significant toxicities, especially neuropathy and myelosuppresion that hindered the further development of this promising combination (14).
Since both taxanes are active agents against MBC, and both appear to have a synergistic effect with cisplatin, there has never been a head-to-head comparison between these two taxanes. Therefore, the choice of a feasible regimen according to the clinical efficacy and the toxic profile promoted us to initiate a randomized study. The main objective of this study was to compare efficacy, in terms of, response rate and, time to progression, and toxicity of a docetaxel/cisplatin combination against those of a paclitaxel/cisplatin combination in order to select the better.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Selection
The study group comprised patients either with recurrent or metastaic breast cancer. The tumors were required to be measurable or evaluable. Patients with only bone metastasis were excluded. Patients should have received and failed from at least one kind of anthracyclines, either as an adjuvant or palliative chemotherapy. Other eligibility criteria included a World Health Organization (WHO) performance status
2, age 
18 years, absolute granulocyte count 1.5 x 109/l, platelet count 100 x 109/l, serum creatinine concentration 2 mg/dl, less than five times the upper limit level of transaminase and serum bilirubin 3.0 mg/dl. The patients should have no concurrent major systemic disease and no history of other malignant diseases. If patients had received an operation or radiotherapy, they should have at least 4 weeks rest between the therapies. The study was approved by the Institute Review Board of Chang Gung Memorial Hospital. The informed consent was obtained before treatment.
Study Design
Patients were randomized into two arms. Patients were stratified according to their previous response (chemo-resistant versus chemo-refractory) to anthracyclines. The definition of chemo-resistance to a regimen was: (i) in patients who receive adjuvant chemotherapy, the recurrence occurred after 12 months from the last dose of chemotherapy; and (ii) in patients receiving chemotherapy for metastatic disease, the patients had an initial response but subsequently developed recurrent disease. The definition of chemo-refractory to a regimen was: (i) in patients who received adjuvant chemotherapy, the recurrence occurred within 12 months of the last dose of chemotherapy; and (ii) progressive disease during induction chemotherapy for a metastatic disease. The docetaxel arm consisted of docetaxel 60 mg/m2 intravenous infusion over 1 h on day 1 with a 3-day oral dexamethasone premedication started on day 0, and cisplatin 50 mg/m2 intravenous infusion over 3 h on day 2. The paclitaxel arm consisted of paclitaxel 175 mg/m2 intravenous infusion over 3 h with three dosed pre-medication with intravenous dexamethasone every 6 h as well as cimetidine and diphenylhydramine 30 min before chemotherapy on day 1, and cisplatin 50 mg/m2 intravenous infusion 3 h on day 2. There was no dose reduction if patients developed grade 3/4 toxicity; however, in case of prolonged neutropenia over 3 days or febrile neutropenia, prophylactic granulocyte-colony stimulation factor was given during the following cycles of treatment. If patients had not recovered from grade 3/4 toxicity within 2 weeks, they would be removed from treatment. The course of chemotherapy was repeated every 3 weeks until there was a maximal response judged by a physician, disease progression, unacceptable toxicity, or patient refusal.
Response and Safety Evaluation
Prior to the therapy, all patients were evaluated by a complete history review, physical examination, complete blood counts, biochemistry profile, chest roentgenogram, abdominal computerized tomography scan (CT scan) or ultrasound and bone scan. Before each cycle, a toxicity assessment, physical examination, complete blood counts and biochemical profile were evaluated. The WHO toxicity grading was adapted to record toxicity. Patients were re-assessed with image studies after four cycles of chemotherapy. In instances of clinical suspicion of progressive disease (PD) during treatment, the evaluation was performed immediately. The evaluation was reassessed every three to four cycles thereafter. Patients who discontinued treatment owing to toxicity before response assessment, were considered to have progressive disease.
The primary end point was to compare the response rate of evaluable patients of the arms, while the secondary end points were time to progression, overall survival and toxicities of all patients. The study was designed to select the better regimen from two as reflected by the response rate under the assumption that the better one would show the difference of at least 15%. It was estimated that at least 37 patients of each arm were selected to correctly select best treatment at a probability of 0.9 (15). To analyze the differences of the two arms, continuous variables were analyzed with repeated measures of analysis of variance (ANOVA) between groups; categorical variables were analyzed by 
2 or Fisher exactness test. The time to progression was measured from the date of randomization to the date of progression. The survival time was calculated from the date of randomization to the date of death. Both time to progression (TTP) and survival curves were established by the Kaplan–Meier method. The differences of TTP and survival were analyzed by a log-rank test. A P value of less than 0.05 was considered significant.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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From April 2000 to December 2002, 101 patients were enrolled to the study. Fifty patients were in the docetaxel arm, and 51 patients were in the paclitaxel arm. Both arms were well balanced (Table 1). As a whole, the average age was 48-years old (range from 25 to 70-years old). The performance status was grade 0–1 in 88% of patients in the docetaxel arm and 76.5% in the paclitaxel arm. All patients were treated with anthracycline, and 32% of patients in the docetaxel arm and 15.6% in the paclitaxel arm received anthracycline as adjuvant chemotherapy, while the rest received anthracyclines as first-line chemotherapy for their metastatic cancer. Seventy-two per cent of patients in the docetaxel arm and 64.7% in the paclitaxel arm had visceral metastases.
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A total of 325 cycles and 327 cycles were administered to the docetaxel and paclitaxel arms, respectively. The median cycles were 6.5 and 6.4 respectively. Either there was no dose reduction, or chemotherapy was delayed up to 2 weeks owing to the patients' inability of recovery as a result of toxicity from the preceding chemotherapy.
There were more patients in the docetaxel (42% versus 17.6%, P = 0.01) arm who finished chemotherapy because of the achievement of maximal response. More patients in the paclitaxel arm (72.5% versus 40%, P = 0.001) stopped their chemotherapy owing to progression of disease. There was no difference between arms in the number of patients who refused to continue chemotherapy, mostly as a result of intolerance to the chemotherapy.
Two patients and four patients in the docetaxel and paclitaxel arms, respectively, having only bone metastases, were excluded from response assessment. Forty-eight and 47 patients were assessed for response in the docetaxel and paclitaxel arms, respectively. There were six cases with complete response (12.5%), 24 (50%) partial response, seven (14.6%) stable disease and 11 (22.9%) with progressed disease in the docetaxel arm. There were two (4.3%) complete responses, 18 (38.3%) partial responses, 12 (25.5%) stable disease and 15 (31.9%) with progressive disease in the paclitaxel arm. The overall response rate for docetaxel and paclitaxel arms was 62.5% (95% confident interval [C.I.]: 48–77%) and 42.6% (95% C.I.: 28–57%), respectively (P = 0.06) (Table 2).
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All patients were included for survival analysis. Up to the latest analysis, all patients have progressed. The time to disease progression in the docetaxel arm was 9.8 months (95% C.I, 7–12.5 months), and in paclitaxel arm was 6.5 months (95% C.I., 5.4–7 months) (P = 0.07) (Fig. 1). The 1-year progression free survivals for the docetaxel and paclitaxel arms were 32.3 and 9.8% respectively (P = 0.15). Twenty-six patients in the docetaxel and 21 in the paclitaxel arm were alive; the overall median survivals were 22.7 months (95% C.I., 19–26.4 months) and 22.4 months (95% C.I.>, 16.1–28.7 months), respectively (P = 0.63) (Fig. 2). The 1-year survival rates for the docetaxel and paclitaxel arms were 77.2 and 63.9% respectively. The 2-year survival rates for the two arms were 31.7 and 34% respectively.
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The most severe event per patient was summarized in Table 3. For non-hematologic toxicity, patients in the docetaxel arm experienced more frequent oral mucositis and diarrhea than those receiving paclitaxel. Patients in the paclitaxel arm experienced more frequent sensory neuropathy and myalgia/arthralgia than those in the docetaxel arm. Although patients in the docetaxel arm appeared to have more frequent fatigue events than those in the paclitaxel arm, there was no statistical difference. Nausea and vomiting which were related to cisplatin occurred equally in both arms. One patient from the paclitaxel arm had transient, reversible renal function impairment. Two patients had symptomatic edema in the docetaxel arm that led to discontinuation of chemotherapy. One patient in the paclitaxel arm discontinued treatment owing to symptomatic myocardial failure after three cycles of the therapy. In hematologic toxicity, grade 3/4 neutropenia was more common in thedocetaxel arm, but it was not statistically significant. Febrile neutropenia occurred in five patients in the docetaxel arm, and only one patient in the paclitaxel arm, but it was not significant (P = 0.08). However, anemia was significantly more common in the paclitaxel arm (P = 0.003). No patients experienced grade 3/4 thrombocytopenia.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Our study revealed that taxanes combined with a low-dose cisplatin were active for MBC patients previously treated with anthracyclines; the response rate and TTP were among the highest of second line chemotherapy ever reported (4). The results were also comparable to those of docetaxel/capecitabine combination (5). Second, there appeared a trend towards higher response rates and TTP in the docetaxel arm, though the difference was statistically not significant. Third, both regimens were equal in tolerance so that neither of them required dose modifications. Fourth, there was no difference in overall survival. The latter might be attributed to the allowance of subsequent salvage chemotherapy, or even cross-over to other taxanes. Finally, the higher response rate for taxane/cisplatin combination provides a good rationale as a non-anthracycline-based regimen for future first-line clinical trial in MBC.
There have been certain perceptions from indirect comparisons and pre-clinical studies (16) that docetaxel is a more effective regimen than paclitaxel in MBC. A recent report of a randomized study revealed that single docetaxel at the dose of 100 mg/m2 is superior to paclitaxel at the dose of 175 mg/m2 in terms of response rate and TTP (17). In our opinion, if the dose-responsive correlation of docetaxel is linear and the synergistic effect is equal to both taxanes/cisplatin combinations, the present study echoes the result of this randomized study.
Some pilot studies have suggested prominent activities of taxanes/cisplatin combination against MBC. Synergy between paclitaxel and cisplatin has been demonstrated both in vivo and in clinical phase II or III studies. The studies of paclitaxel/platinum combination were reported in a heterogeneous group of patients with variable dose-schedule. In summary, the response rates ranged from 22 to 81%, but with a high frequency of toxicity, including neutropenia and peripheral neuropathy (8, 10–12). Some of the studies even required granulocyte-colony stimulating factor (G-CSF) support (8, 10). Weekly or biweekly low-dose paclitaxel/cisplatin have been reported to reduce the toxicity, however, the former required G-CSF support (8) and the latter was not effective (12). Sensory neuropathy was one of the major toxicities that became an obstacle to putting this regimen up front. In order to minimize the severity of neurotoxicity from cisplatin, we tried to reduce the dose of cisplatin down to 50 mg/m2. Although there were still a substantial number of patients (60.8%) in the paclitaxel arm who experienced grade 1or 2 neurotoxicity, only 9.8% experienced grade 3/4 toxicity. Carboplatin was an interesting regimen because of its favorable toxicity and tolerance profile. Studies of carboplatin and paclitaxel also yielded encouraging results: Perez reported a 54% response rate as first-line chemotherapy (18). This would be more attractive if the activity can be further confirmed.
Phase II data of single docetaxel have also shown a significant efficacy for patients with MBC. In patients previously-treated with anthracycline, the response rate was reported around 40% (3). Various docetaxel/cisplatin combinations have been studied as well. Most used a full dose of docetaxel/cisplatin combination, where the response rates were approaching 60%. However, grade 3/4 neutropenia, cutaneous and neurologic toxicities were observed in over 50% of patients (13). In contrast to these studies, we observed a rather lower frequency of myelosuppression and neurotoxicty from docetaxel/cisplatin after reduction of the doses of cisplatin and docetaxel. We suggest that the low-dose cisplatin would not compromise the efficacy against MBC, but would significantly reduce the severity of neuropathy and possible myelosuppression.
The comparison of the anti-tumor activity between docetaxel/cisplatin and paclitaxel/cisplatin in anthracycline pre-treated MBC suggests that there was tendency in favor of the docetaxel/cisplatin arm. With these dose schedules, both arms exhibited equal tolerance, but the toxicity profiles were slightly different. Taxanes have been reported to induce apoptosis and inhibit angiogenesis (19, 20). In vitro analyses demonstrate docetaxel to be 100-fold more potent than paclitaxel in bcl-2 phosphorylation and apoptotic cell death (21). Therefore, there have grown certain perceptions among researchers that docetaxel might be more effective than paclitaxel for MBC. A report of single docetaxel (100 mg/m2) versus paclitaxel (175 mg/m2) as second line chemotherapy for MBC has confirmed this point (17). Our study used a relatively low-dose docetaxel, for which the selection of this dose was based on some clinical and pre-clinical studies in the Asian population. Goh et al. reported that peoples of the Chinese ethic group have lower clearance ability for docetaxel (22). In addition, the clinical experience from Japan showed that the optimal dosage for the Japanese patients started from 55 to 60 mg/m2 (23). Our previous experience with single docetaxel at dose of 75 mg/m2 every 3 weeks also revealed a 25% grade 3–4 neutropenia in patients with anthracyclin and paclitaxel pre-treated MBC (24). Therefore, we decided to use docetaxel at the dose of 60 mg/m2. Although the statistical significance was lacking in the study, the trend in favor of docetaxel arm in response rate and TTP suggests that a higher dose of docetaxel might be able to show a significant difference. Furthermore, the difference in toxicity profile, especially that in the dose-limiting toxicity, might have a significant impact on its dose schedule of administration, and consequently, their effect against MBC. Within the dose range of 75–100 mg/m2 as a 1-h infusion, the dose-limiting toxicity of docetaxel is transient neutropenia; while the dose-limiting of a 3-h infusion of paclitaxel at 175 mg/m2 is accumulated neuropathy (3), which is a durable problem with no effective method of management. From this point of view, it might be more manageable and effective to escalate the dose of docetaxel in combination with platinum for future trials. Nevertheless, Seidman et al. recently presented an important study indicating that a weekly schedule of single P aclitaxel was superior to tri-weekly schedule in terms of response rate and time to progression in metastatic breast cancer (25). Therefore, it is interesting to explore whether the weekly paclitaxel/platinum combination can improve the response rate and decrease the neuropathy compared to the tri-weekly schedule of docetaxel/platinum.
In conclusion, this phase II randomized study revealed that the two taxane/cisplatin combination regimens examined were both active for MBC after anthracyclines. The taxane/cisplatin combination can thus become a good alternative to the docetaxel/capecitabine combination. There appeared to be a trend toward higher RR and longer TTP in favor of docetaxel/cisplatin combination, and toxicity profile in favor of docetaxel. The study suggested that docetaxel/cisplatin might have some advantages over paclitaxel/cisplatin, which warrants future clinical trials as the first-line regimen for metastatic MBC.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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