1 Aristotle University of Thessaloniki School of Medicine, Thessaloniki; 2 University of Patras School of Medicine, Patras; 3 Laboratory of Biostatistics, University of Athens School of Nursing, Athens; 4 Department of Clinical Therapeutics, University of Athens School of Medicine, Athens; 5 Metropolitan Hospital, Athens; 6 Ippokration Hospital, Athens; 7 Laikon Hospital, Athens; 8 Agii Anargiri Cancer Hospital, Athens; 9 University Hospital Attikon, Athens; 10 University of Ioannina School of Medicine, Ioannina; 11 Henry Dunant Hospital, Athens; 12 IKA Hospital, Thessaloniki; 13 Theagenion Cancer Hospital, Thessaloniki; 14 Hygeia Hospital, Athens, Greece
* Correspondence to: Dr G. Fountzilas, 1st Department of Internal Medicine, Section of Medical Oncology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece. Tel/Fax: +30-2310-994617; Email: fountzil{at}med.auth.gr
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Abstract |
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Patients and methods: From January 1999 to April 2002, 327 eligible patients with ABC were randomized to receive either paclitaxel 175 mg/m2 in a 3-h infusion followed by epirubicin (EPI) 80 mg/m2 (group A) or paclitaxel, as in group A, followed by Cp at an AUC of 6 mg x min/ml (group B) every 3 weeks for six cycles.
Results: After a median follow-up of 23.5 months, median survival was not significantly different between the two groups (22.4 months versus 27.8 months, P=0.25), whereas median time to treatment failure was significantly longer in patients treated with paclitaxel/Cp (8.1 months in group A versus 10.8 months in group B, P=0.04). Both regimens were well tolerated. In total, 39 patients (24%) in group A and 46 (29%) in group B suffered at least one severe side-effect. Quality-of-life assessment and cost analysis did not reveal any significant differences between the two groups.
Conclusion: Our study suggests that the paclitaxel/Cp combination is an effective therapeutic alternative for patients with ABC in which anthracycline administration has the potential of being harmful.
Key words: anthracyclines, breast cancer, carboplatin, chemotherapy, paclitaxel
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Introduction |
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Cisplatin or carboplatin (Cp) are active in patients with ABC, with an overall (complete plus partial) response rate (ORR) in the range of 2030% [13]. Furthermore, cisplatin is very active as first-line chemotherapy in ABC, with response rates of 50%, whereas Cp appears to be moderately active in patients without prior chemotherapy (ORR around 30%) [14
]. Substitution of Cp for cisplatin is particularly useful especially in patients in whom cisplatin administration is precluded because of other co-morbid diseases. The combination of paclitaxel and Cp has been repetitively shown in phase II studies to demonstrate significant efficacy in ABC [15
17
]. Based on this rationale, we conducted a randomized phase III trial comparing the combination of paclitaxel and EPI with that of paclitaxel and Cp, as first-line chemotherapy, in patients with ABC. The primary end point of the study was survival. Secondary end points were ORR, time to treatment failure (TTF) and severe toxic effects.
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Patients and methods |
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Patients with a history of treatment with adjuvant chemotherapy were allowed to enter the study if the interval between completion of adjuvant chemotherapy and first relapse was 12 months or more. Anthracycline pretreated patients could not have received cumulative doses of more than 360 mg/m2 for doxorubicin, more than 450 mg/m2 for EPI, or 72 mg/m2 for mitoxantrone. Patients with osseous metastases as the only metastatic site and receptor-positive status were eligible only if they progressed after at least one hormonal manipulation. Exclusion criteria were symptomatic brain metastases, history of other malignancy (except curatively resected nonmelanoma skin cancer or in situ cervical cancer), myocardial infarction within the last 6 months, or other serious illness that would impair the ability of the patient to receive protocol treatment. Previous chemotherapy for advanced disease was not allowed. However, patients pretreated with hormona1 therapy or radiation either in the adjuvant setting or for metastatic disease were eligible, provided that any treatment was stopped at least 4 weeks before study entry. The protocol was approved by the HeCOG Protocol Review Committee and Institutional Review Boards in participating institutions. Written informed consent was obtained from all patients.
Treatment plan
Patients were randomized centrally at the HeCOG Data Office in Athens and stratified according to the history of previous adjuvant chemotherapy and risk category in a modified version of that used by Cavalli et al. [18]. Risk categories were based on the following criteria: (i) free interval from initial radical surgery to first recurrence >5 years with only osseous or with only locoregional metastases, (ii) free interval 15 years and absence of visceral metastases, (iii) all others.
Patients randomized to group A were treated with six cycles of EPI at a dose of 80 mg/m2 followed by paclitaxel (Taxol; Bristol-Myers Sqiubb Company, New Jersey, USA) 175 mg/m2 in a 3-h infusion. Patients randomized to group B were treated with six cycles of paclitaxel 175 mg/m2 in a 3-h infusion immediately followed by Cp at an area under the curve (AUC) of 6 mg x min/ml in 500 ml normal saline in a 30-min infusion. Creatinine clearance was calculated using the Jelliffe formula [19] and AUC, the Calvert formula [20
]. Cycles were delivered every 3 weeks. Ondansetron was given as anti-emetic treatment in all cycles.
Postmenopausal patients with positive ER/PgR were treated with letrozole following the completion of chemotherapy, as maintenance treatment if they were previously treated with Tamoxifen. Women who were premenopausal or perimenopausal (last menstrual period within a year) at the time of randomization, received LH/RH analogs as well as letrozole. Patients with unknown hormonal receptor status were treated as hormone receptor-positive.
Treatment with biphosphonates was allowed in all patients with osseous metastases after the completion of chemotherapy.
Dose modification
Complete biochemistry and full blood count (FBC) were measured on the day of treatment. FBC was repeated between cycles only in the case of fever, hemorrhagic manifestations or severe mucositis. In the case of granulocytopenia or thrombocytopenia on the first day of the cycle, treatment was delayed until absolute neutrophil count (ANC) was 1500/µl and platelets
100 000/µl, respectively. In the case of severe toxicity, the dosages of the three drugs were modified as previously described [12
, 13
]. Erythropoietin was recommended to all patients with hemoglobin level
11 g/dl.
Response evaluation and follow-up
Standard ECOG criteria were used to define measurable disease, evaluable disease, response and toxicity [21]. Response was evaluated clinically (whenever it was applicable) in each cycle, and by imaging techniques after the third and sixth cycle of chemotherapy. Thereafter, all patients were followed every 3 months with physical examination, FBC and biochemistry and every 6 months with chest X-rays, bone scan and CT-scans, or as otherwise indicated. All imaging material pertinent for tumor response to chemotherapy was scanned and evaluated after the completion of the study by two of the authors (A.K.-F., L.A.M.) and by an independent Radiological Response Review Committee (RRRC). Imaging scans from a total of 272 patients in the study (83%) were reviewed by the RRRC.
Quality-of-life assessment
Quality of life (QoL) was assessed using the Greek version of the EORTC QLQ-C30 [22].
Cost analysis
The economic evaluation was carried out from the perspective of the National Health Service (NHS) in Greece. Because the results of the trial indicate no significant differences in median survival between the two treatment groups, a cost-minimization analysis was carried out. Data on resource use were obtained from the clinical study and were combined with unit cost data from Greek national sources and the database of the University General Hospital of Patras. The time horizon of the economic analysis is the same as that of the trial and the analysis is according to the intention to treat. The analysis included first-line data only. In particular, total treatment costs included: (i) chemotherapy, concomitant and other medications (e.g. G-CSF, ondansetron) used in case of adverse events, (ii) infusions on the outpatient setting, (iii) hormonotherapy and consolidation radiotherapy after chemotherapy in selected cases, (iv) subsequent hospitalizations and visits to health professionals due to adverse events or follow-ups and (v) all the laboratory and imaging examinations carried out during the chemotherapy period or treatment of adverse events associated with drug toxicity or patient health deterioration. Because economic data are often skewed by small numbers of very costly cases, individual patient cost estimates were bootstrapped [23] 2500 times and the mean of the bootstrapped means and its confidence intervals (CI) were used in the comparisons.
Statistical analysis
The main end point for sample size determination was survival rate. In order to detect a ±15% difference to a survival rate of 50% at 20 months in the paclitaxel/EPI group, 320 patients were needed to enter the study to have 80% power at the 5% significance level. Considering a 2% withdrawal rate, the total number of patients was increased to 327. At the interim analysis (99 deaths, May 2002), based on the O'Brien Fleming boundary values, no significant differences in survival were detected and the study was continued to completion (March 2003, 160 events reported). The post-hoc power to detect a ±15% difference according to the study design, based on the total events observed, was 82%.
According to World Health Organization criteria [24], duration of response was calculated in the case of a CR from the date when the CR was documented until the date of progression and in the case of a PR from the initiation of chemotherapy until the date of progression. Time to treatment failure (TTF) was calculated from the randomization date to the date progression of the disease was documented (patients who discontinued their treatment for any reason or probably died from disease-related causes were considered at that time, as treatment failures), and survival from the randomization date to the date of last contact or to the date of death. Analysis was conducted on an intent-to-treat basis.
Fisher's exact test was used for comparing patients' characteristics, response and toxicity. The KaplanMeier method was used to calculate TTF, survival and duration of response curves, whereas the log rank test was used to compare time to event distributions.
Prognostic factor analyses were carried out with logistic regression for ORR and the Cox proportional hazards model for TTF and survival.
A backward selection procedure with removal criterion P > 0.10, identified the subclass of significant variables among the following: treatment group (P-E versus P-Cp), age, visceral metastasis (no versus yes), number of metastatic sites (1 versus 2 versus 3), PS (0 versus 1 versus 2), adjuvant chemotherapy (no versus yes), adjuvant hormonotherapy (no versus yes), risk category and maintenance HT for advanced disease (no versus yes). CIs were used to determine the 95% upper and lower confidence limits of the response rate.
QoL was assessed at baseline and at the end of study. Differences between the two study groups at baseline and at the end of study as well as changes between baseline and end-of-study within each group were compared using the Wilcoxon test. For ease of interpretation, all scale and item scores were linearly transformed to a 0100 scale. For the five functional scales and the global QoL scale, item responses were recoded so that higher scores represent a better level of functioning. For the symptom-oriented scales and items, a higher score corresponds to a higher level of symptoms.
All statistical tests were two-sided and carried out at significance level of 0.05. Bonferroni adjustment for multiple comparisons was used whenever appropriate.
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Results |
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Major patient and tumor characteristics were equally distributed in the two groups of patients (Table 1) except for the rate of osseous metastases which was significantly higher in group B (44% versus 57%, P=0.02). The vast majority of patients presented with PS 01.
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The median relative dose-intensity (DI) of EPI was 0.96 and that of paclitaxel 0.96 in group A and 0.95 in group B (Table 2).
Both regimens were well tolerated. In total, 39 patients (24%) in group A and 46 (29%) in group B suffered at least one severe (grade 3 or 4) side-effect. These side-effects included anemia (3.5% versus 4.0%), leukopenia (7% versus 9.3%), neutropenia (11.2% versus 12%), thrombocytopenia (1.0% versus 4.5%, P=0.04), nausea/vomiting (1.2% versus 1.0%), peripheral neuropathy (2.5% in both groups), hypersensitivity reactions (0% versus 1.0%) and infection (6% in both groups). Febrile neutropenia developed in nine patients in group A and eight in group B. As previously stated, one patient in group B died of sepsis after the first cycle. Alopecia was universal. One patient in group A and two in group B were hospitalized for a cardiac event, consisting of grade 3 arrhythmia in two patients and myocardial infarction in the third patient.
G-CSF administration was required in 73 patients (45%) in group A and 79 patients (48%) in group B, mainly for maintaining DI, i.e. to administer subsequent cycles on time. Antibiotics were prescribed in 20 (12%) patients in group A and 10 (6%) in group B (P=0.06). Of note, significantly more patients in group B received biphosphonates [group A: 14 (9%) versus group B: 34 (21%); P=0.003], which is probably related to the higher rate of osseous metastases in group B. Furthermore, erythropoietin was administered in 19 (12%) patients in group A and 25 (15%) in group B. Nine patients (5.5%) from group A and 10 in group B (6%) were transfused with packed red blood cells and three in each group with platelets.
Response to treatment and survival
Results of response evaluation by the RRRC reported to the HeCOG Data Office on April 15, 2003 are depicted in Table 3. Fourteen patients in group A and 20 in group B were not assessed for response, because they died before response evaluation (6 versus 4), withdrew consent (2 versus 3), never started chemotherapy (1 versus 4), experienced toxicity (3 versus 2), died early of unrelated causes (0 versus 2), had non-measurable/evaluable disease or their scans were not available for review (2 versus 5).
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After a median follow-up of 23.5 months (range, 0.149.5), 231 patients (71%) had progressed (120 in group A and 111 in group B) and 160 (49%) had died (83 in group A and 77 in group B). The median TTF was 8.1 months (range, 0.142.7+; 95% CI 7.09.2) in group A and 10.8 months (range, 0.140.7+; 95% CI 8.912.6) in group B (P=0.04; when adjusting for maintenance HT P=0.02) (Figure 2). Furthermore, median survival was 22.4 months (range, 0.142.7+; 95% CI 17.827.0) in group A and 27.8 months (range, 0.2649.5+; 95% CI 20.834.9) in group B (P=0.25; when adjusting for maintenance HT P=0.26) (Figure 3).
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Even though assessment of HER-2 status was not required by the protocol, an attempt was made to collect all relevant data from the medical records, retrospectively (Table 1). Overall, survival of patients with HER-2 3+ overexpression did not differ significantly from that of patients with 0, 1+ or 2+.
In multivariate Cox analysis, worse PS, presence of visceral metastases, higher number of metastatic sites and lack of maintenance HT were identified as significant adverse prognostic factors for survival (Table 4). Also, treatment group, visceral metastases, number of metastatic sites and maintenance HT appeared to significantly affect the hazard of treatment failure (Table 4). No interactions with treatment were found to be significant. Finally, PS was the only important prognostic factor for ORR (0 versus 1: OR = 0.57 P=0.03; 0 versus 2: OR = 0.17 P=0.005).
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Discussion |
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On the contrary, paclitaxel administered by a 3-h infusion, as in this study, and EPI (or doxorubicin) has been compared in a number of randomized studies with other commonly used regimens in first-line chemotherapy for ABC, such as the combination of EPI (or doxorubicin) and cyclophosphamide with or without fluorouracil (Table 7). The primary end point in these trials however was different. Time to disease progression was the primary end point in three studies, ORR in two and survival only in three of them, probably because of their relatively small sample size. Moreover, two studies, the AGO study by Luck et al. [10] and the ABO-1 study by Carmichael [11
], in which doxorubicin was substituted by EPI, have been published only in an abstract form and therefore, a thorough analysis of the results is not feasible. Notably, median survival was remarkably similar in the paclitaxel/EPI (or doxorubicin) arm of all these studies, with the exception of the ABO-1 study, and ranged from 20 to 23 months. Even though significant differences in median survival between the treatment groups were found only in the study by Jassem et al. [27
], it is obvious that all these studies were underpowered to detect small but meaningful differences in median survival. Only a meta-analysis of these studies combined will probably determine the impact of taxane/anthracycline combinations on the survival of patients with ABC.
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The ORR, reported in this study, was not significantly different in patients treated with EPI or Cp in combination with paclitaxel. Notably, the ORR of 47% achieved by the paclitaxel/EPI regimen is in the range of response rates reported in the trials depicted in Table 7.
Toxicity among our patients was generally mild. Cardiotoxicity was not a main issue in this study or in the AGO [10] and ABO-1 [11
] studies, in which doxorubicin was substituted by EPI. Additionally, there were no significant differences in the rate of severe toxicity among the two treatment groups. Neutropenia was the most frequently recorded severe side-effect. The rate of severe neutropenia was lower than that reported in the AGO trial, probably because of the more frequent use of G-CSF, which enabled us to maintain a high median RDI of paclitaxel and EPI. However, the potential benefit gained by higher DI in patients with ABC should always be weighted against the higher cost of treatment.
An intriguing finding in our study was that there were no differences in ORR or survival between patients with tumors overexpressing HER-2 (3+ by IHC) and all others. The existing literature on the issue of a possible interaction between taxane efficacy and HER-2 status is surprisingly poor. Some investigators claim, however, that patients with HER-2 overexpressing tumors had higher ORR than those with HER-2 negative tumors [30, 31
], a finding that was not confirmed by others [32
]. Nevertheless, our results on this issue should be interpreted cautiously since the assessment of the HER-2 status was not anticipated by the protocol, tissue blocks were collected only when available and no central review of the stained slides was carried out. In order to overcome possible biases, future prospective randomized studies should contain translational research in an effort to explore potential associations between treatment with taxanes and status of HER-2 or other biomarkers. In an ongoing phase III trial, which compares three non-anthracycline taxane-based regimens in patients with ABC, we are currently investigating the role of circulating HER family receptors.
Concerning the QoL assessment, we observed that paclitaxel/Cp was associated with an improvement both in the emotional functioning scale and in sleep disturbance symptoms compared with paclitaxel/EPI. Additionally, it is important to mention that the small numbers included in the QoL analysis (only 30% of patients had baseline and end of study assessment) might account for the lack of other significant differences between the two groups.
Cost analysis revealed that there were no significant differences between the two groups. Therefore, the choice between the two regimes should be based on other factors, if any exist.
In conclusion, this study did not identify a significant difference in median survival when EPI was substituted by Cp in combination with paclitaxel. Moreover, no significant differences in ORR, QoL and cost were found between the two groups of patients. However, since this study did not have sufficient power to possibly detect small but meaningful differences in survival, the substitution of the paclitaxel/anthracycline (and indirectly AC) regimens by the paclitaxel/Cp combination cannot be recommended as first-line chemotherapy in patients with ABC on the basis of these findings. More data from randomized studies are needed before such a statement could be made. At the present, our study can only suggest that the combination of paclitaxel/Cp could be considered as an effective therapeutic alternative to the anthracycline-containing regimens. This combination can be safely prescribed to patients in which anthracyclines have the potential of being harmful such as those previously exposed to anthracyclines in the adjuvant setting. However, our findings could stimulate additional studies that may eventually pave the way to an era of chemotherapy free of anthracyclines, which have been the most valid therapeutic option for patients with ABC for the past three decades.
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Acknowledgements |
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Received for publication February 25, 2004. Revision received June 1, 2004. Accepted for publication June 7, 2004.
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References |
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