Breast Cancer Res Treat DOI 10.1007/s10549-013-2589-8
CLINICAL TRIAL
Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group Hans-Joachim Lu¨ck • Andreas Du Bois • Sibylle Loibl • Iris Schrader • Jens Huober • Volker Heilmann • Matthias Beckmann • Ann Sta¨hler • Christian Jackisch • Michael Hubalek • Barbara Richter • Elmar Stickeler • Holger Eidtmann • Christoph Thomssen • Michael Untch • Kerstin Wollschla¨ger Tibor Schuster • Gunter von Minckwitz
•
Received: 15 May 2013 / Accepted: 29 May 2013 Ó Springer Science+Business Media New York 2013
Abstract Capecitabine/taxane combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, noninferiority trial comparing capecitabine plus paclitaxel (XP) with epirubicin plus paclitaxel (EP) as first-line therapy for MBC, regarding progression-free survival (PFS) as primary efficacy endpoint. Females who had received no prior chemotherapy for MBC were randomized to six 3-weekly cycles of XP This study was presented at the American Society of Clinical Oncology Annual Meeting 2006, abstract 517.
Electronic supplementary material The online version of this article (doi:10.1007/s10549-013-2589-8) contains supplementary material, which is available to authorized users.
(capecitabine 1000 mg/m2 b.i.d., days 1–14; paclitaxel 175 mg/m2 3-h infusion, day 1) or EP (epirubicin 60 mg/m2 1-h infusion, day 1; paclitaxel as above). Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Each arm included 170 patients, most of whom received all six cycles as planned. The difference in means of (logarithmic) PFS times (-0.205) did not meet the pre-defined level for noninferiority (-0.186). However, PFS was similar in the two arms [HR: XP vs. EP: 1.012 (95 % CI 0.785–1.304); median 10.4 months XP vs. 9.2 months EP]. Overall survival was also similar [HR 1.027 (95 % CI 0.740–1.424); median 22.0 vs. 26.1 months], and response rate was 47 % versus 42 %. Both regimens were tolerable: there were
H.-J. Lu¨ck A. Du Bois Dr. Horst Schmidt Klinik, Wiesbaden, Germany
C. Jackisch University Women’s Hospital, Marburg, Germany
S. Loibl G. von Minckwitz (&) German Breast Group, Martin-Behaim-Str. 12, 63263 Neu-Isenburg, Germany e-mail:
[email protected]
M. Hubalek University Women’s Hospital, Innsbruck, Austria
I. Schrader Henriettenstiftung, Hannover, Germany J. Huober University Women’s Hospital, Tubingen, Germany V. Heilmann University Women’s Hospital, Ulm, Germany M. Beckmann University Women’s Hospital, Erlangen, Germany
B. Richter University Women’s Hospital, Dresden, Germany E. Stickeler University Womens’Hospital, Freiburg, Germany H. Eidtmann University Womens’ Hospital, Kiel, Germany C. Thomssen University Women’s Hospital, Hamburg/Halle, Germany M. Untch Helios Klinikum, Berlin Buch, Germany
A. Sta¨hler St. Vincentius-Kliniken, Karlsruhe, Germany
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more grade 3/4 diarrhea and grade 3 hand–foot syndromes with XP and more grade 3/4 hematologic toxicities with EP. There were no major differences in QoL. Although, noninferiority of XP to EP was formally not proven, firstline XP was active and feasible. XP is a valid first-line alternative to anthracycline/taxane regimens, especially in patients previously treated with adjuvant anthracyclines. Keywords Capecitabine Combination therapy Paclitaxel Epirubicin Metastatic breast cancer
Capecitabine and paclitaxel show no overlap of key toxicities and avoid anthracycline-related risks for cardiotoxicity and leukemia. Since synergy between capecitabine and docetaxel (XT) translates into a survival benefit when compared to docetaxel alone in the clinical setting, it seems reasonable to anticipate similar clinical efficacy with XP [18]. Indeed, phase II studies suggest that XP is a valid alternative to XT, whether paclitaxel is administered using a 3-weekly or a weekly schedule [19, 20]. In a randomized, phase III trial, XT and XP demonstrated very similar efficacy [21]. Therefore, we decided to compare XP with EP in this randomized, phase III trial MAMMA-3.
Introduction Combination chemotherapy is still one option as first-line treatment for high-risk metastatic breast cancer (MBC). It significantly improves the response rate and time to disease progression compared with single-agent therapy in this setting [1, 2]. The choice of anthracycline and the preference of an anthracycline/taxane combination vary according to geographic region, patient characteristics, and safety profile. In the USA, doxorubicin is most widely used, whereas in many European countries epirubicin is often preferred [3, 4]. First-line epirubicin plus paclitaxel (EP) is still as one regimen supported by the results of several randomized phase III trials investigating EP with epirubicin plus cyclophosphamide [5–8]. One of the difficulties with first-line anthracycline/taxane therapy for MBC is the established inclusion of anthracyclines (with or without a taxane) in standard neoadjuvant chemotherapy regimens [9, 10]. In patients who received an adjuvant anthracycline-containing regimen, the risk of cumulative cardiotoxicity often prevents anthracycline therapy in the first-line setting. Furthermore, data supporting re-exposure to nonliposomal anthracyclines are limited and sometimes conflicting [11]. However, re-exposure to taxanes has been shown to be effective [12]. Therefore, a nonanthracycline combination partner for taxanes in the first-line setting is clinically interesting. There is a strong rationale for evaluating the combination of capecitabine plus paclitaxel (XP). Both agents have demonstrated high-single-agent activity in breast cancer, both in pretreated disease and earlier in the disease course [13–17].
K. Wollschla¨ger University Womens’Hospital, Magdeburg, Germany T. Schuster Technische Universitaet, Munich, Germany G. von Minckwitz University Women’s Hospital, Frankfurt, Germany
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Patients and methods Trial design This was a multicenter, prospective, randomized, phase III, noninferiority trial comparing XP and EP as first-line treatment for MBC. Randomization was stratified by study center and prior anthracycline-containing therapy. The primary endpoint was progression-free survival (PFS), defined as the time interval between the day of randomization and the day of diagnosis of disease progression, secondary malignant disease, or death from any cause. Secondary endpoints were overall survival (defined as the time interval between randomization and death), response rate according to RECIST criteria, tolerability [incidence and severity of adverse events graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0], and quality of life (QoL; EORTC-QLQ-C30 and BR23). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation (ICH) Guideline on Good Clinical Practice, and the rules and regulations of the Federal Republic of Germany. Patients Inclusion criteria: women 18–75 years of age with histologically confirmed, measurable breast cancer with metastasis; ECOG performance status \2; life expectancy C3 months; left ventricular ejection fraction (LVEF) within the hospital’s normal range; and adequate hematologic, hepatic, and renal function. Patients may have received several prior endocrine therapies in the adjuvant and/or metastatic setting. At least 4 weeks must have elapsed since any radiotherapy. Exclusion criteria: prior chemotherapy for MBC; primary and/or adjuvant chemotherapy within the previous 12 months; primary and/or adjuvant chemotherapy with total doses of epirubicin 600 mg/m2, doxorubicin 300 mg/m2, mitoxantrone 80 mg/m2, or docetaxel 600 mg/m2 (prior adjuvant paclitaxel was permitted); prior
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high-dose chemotherapy with peripheral stem cell transplant; metastases limited to the bone; symptomatic brain metastases; secondary carcinomas except for curatively treated basal cell carcinomas of the skin or cervical carcinoma in situ; pre-existing peripheral neuropathy of grade C1; known hypersensitivity to any of the drugs or components to be administered; myocardial infarction within previous 6 months; uncompensated cardiac insufficiency or other severe cardiovascular conditions; psychiatric disorders; and participation in another clinical trial within the previous 4 weeks. All the patients provided written informed consent before any study-specific procedures were performed. Drug administration Patients randomized to XP received oral capecitabine 1000 mg/m2 twice daily on days 1–14 plus i.v. paclitaxel 175 mg/m2 as a 3-h infusion on day 1 of a 3-week cycle. Patients randomized to EP received epirubicin 60 mg/m2 as a 1-h infusion plus i.v. paclitaxel 175 mg/m2 as a 3-h infusion both on day 1 every 3 weeks. Premedication 30 min prior to paclitaxel administration consisted of i.v. dexamethasone 20 mg, i.v. clemastine 2 mg, and i.v. ranitidine 50 mg (or i.v. cimetidine 300 mg). Prophylactic growth factor support was not permitted. Patients in both treatment arms received a maximum of six cycles of therapy. Maintenance therapy consisted of endocrine therapy in patients with hormone receptor-positive disease (if endocrine options were still available) and trastuzumab in patients with HER2-positive disease with appropriate cardiovascular monitoring. In patients with disease progression, second-line chemotherapy consisted of anthracycline-containing treatment in patients initially randomized to XP and capecitabine in patients initially randomized to EP. Dose modification If patients experienced febrile neutropenia, grade 4 leukopenia, or grade 3 thrombocytopenia, treatment was interrupted until recovery of neutrophil count to C 1.5 9 109/l and platelet count to C 100 9 109/l. Treatment was then continued at reduced doses (paclitaxel 150 mg/m2; epirubicin 45 mg/m2; and capecitabine 750 mg/m2 twice daily). If grade 3 or 4 hematologic toxicity recurred, treatment was interrupted, and then continued at a resolution with hematopoietic growth factor support. Doses of paclitaxel and epirubicin were reduced if patients experienced grade 2 or neurologic toxicity, and treatment was discontinued in case of grade 3 or 4 sensory neuropathy. If patients experienced grade 3 gastrointestinal toxicities and/or grade 2 hand–foot syndrome (HFS), capecitabine was interrupted until the
resolution to grade 1 or 0, and then continued at the reduced dose. If these toxicities recurred, capecitabine was interrupted again until recovery, and when resumed at the reduced dosage, the treatment-free interval in each cycle was extended from 7 to 14 days. Doses of all the drugs were reduced if patients experienced grade 3 or 4 mucositis. Treatment was discontinued if any toxicity had not resolved after 42 days. Study assessments Before study treatment, each patient underwent clinical examination, standard laboratory tests, electrocardiogram, and tumor assessment (tumor-specific radiology, ultrasonography, computed tomography, and/or magnetic resonance imaging, according to indication and clinic standard). Prior medical history was recorded. An EORTC QoL questionnaire was completed at baseline, prior to each cycle and after completion of therapy. During the treatment, hematologic tests were carried out every week. Before each cycle of therapy, patients underwent physical examination. ECOG performance status, clinical chemistry, and toxicities were recorded. Tumors were assessed every three cycles according to RECIST criteria 1.0. A final assessment was performed 3–6 weeks after completing the study therapy, and included clinical examination, assessment of toxicities, laboratory tests, and tumor assessment. Patients were followed up every 3 months for the first 2 years after the last cycle, and every 6 months thereafter. Statistical methods The primary aim of the study was to demonstrate the noninferiority of XP to EP, defined as a lower limit of the 95 % CI for the difference in the means of the logarithmic PFS times (XP - EP) exceeding -0.1863. This critical value, assuming constant hazard rates within the treatment arms, corresponds to an upper limit of the 95 % CI for the PFS hazard ratio (XP vs. EP) of 1.205 which must not be exceeded. According to Monte Carlo experiments, taking into account drop-out and therapy failure rates in a recent study [4], 165 patients per treatment arm (randomization 1:1) would be sufficient to demonstrate the noninferiority of XP to EP using the parameters described below, if patients were recruited within a period of 2 years and all patients were followed until the last patient had been followed up for 2 years. As estimation of sample size was based on a previous study, data were examined at each interim analysis to determine whether there were considerable deviations in the patient characteristics (age, pTNM classification, recurrence location, time from initial diagnosis of breast cancer to randomization, histology, grading, and hormone receptor status), pretreatment characteristics (surgery, chemotherapy,
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and hormone therapy), and drop-out rates (exclusion after randomization, withdrawal of consent, on-therapy death or progression, toxicity, and loss to follow-up) compared with the earlier MAMMA-1 study. In the event of relevant deviations, the sample size was to be adjusted[6 months prior to the planned end of recruitment. The primary endpoint (PFS) and other time-related endpoints were analyzed using the intent-to-treat population, which included all the patients as randomized [22]. Estimation and illustration of event-free probabilities were performed using the Kaplan–Meier method. Analyses of other secondary endpoints were descriptive and exploratory. The safety population included all the patients who received at least one cycle of therapy according to the protocol. QoL data in the two treatment arms were compared using the Wilcoxon test.
Results Patient population Between December 2002 and June 2005, 340 patients were enrolled from 63 centers in Germany and Austria, 170 of whom were randomized to XP and 170 to EP (Fig. 1). Baseline characteristics were relatively well-balanced in the two treatment arms (Table 1). Notably, 59 % of patients in each treatment arm were chemotherapy-naive, and more than 80 % had not previously been exposed to anthracyclines. Treatment exposure Overall, in the XP arm 850 cycles of capecitabine and 854 cycles of paclitaxel were applied, in the EP arm 896 epirubicin and 898 paclitaxel cycles were given. The majority of patients in both the treatment arms completed all the six
planned treatment cycles (124/165, 77 % in the XP arm and 134/165, 81 % in the EP arm). The most common reason for discontinuing the treatment prematurely was disease progression (9 % with XP; 11 % with EP). Patients in both the arms received therapy at or near to the full intended doses. The median dose per cycle was 860 (833) mg/m2 capecitabine twice daily and 172 (167) mg/m2 paclitaxel in the XP arm and 60 (58) mg/m2 epirubicin and 175 (169) mg/m2 paclitaxel in the EP arm. Efficacy Median follow-up at the time of this final analysis was 24.9 months. The primary endpoint, to demonstrate the noninferiority of XP to EP, was not met. The difference in means of the logarithmic PFS times (XP - EP) was -0.205, which exceeded the predefined value of-0.1863 [this critical value corresponds to an upper limit of the 95 % CI for the hazard ratio (XP vs. EP) of 1.205, which must not be exceeded]. Figure 1 shows PFS, which was very similar between the two arms (hazard ratio XP vs. EP: 1.012; 95 % CI 0.785–1.304). Median PFS was 10.4 months (95 % CI 9.0–11.8) with XP and 9.2 months (95 % CI 7.2–11.2; Fig. 2) with EP. There was no significant difference between the two treatment arms in response rate (47 % vs. 42 %, respectively; Table 2) and overall survival was very similar (hazard ratio 1.027; 95 % CI 0.740–1.424; Fig. 3). After completing the study therapy, a large proportion of HER2-positive patients did not receive trastuzumab as this was not standard of care at the time of the study design. Sixty-one percent of endocrine responsive patients (n = 143 of 236) received an endocrine treatment after finishing chemotherapy. In the XP arm, 26 patients had documented chemotherapy as second-line treatment, mostly (n = 22/26) consisting of an anthracycline-containing regimen. In the standard arm, seven patients continued with the EP regimen for up to ten cycles.
Randomized (n=340) Received no treatment (n=1) XP (n=169) Withdrawn before completing 6 cycles (n=46) Disease progression (n=15) Toxicity (n=10) Death (n=3) Protocol violation (n=2) Patient’s wish (n=7) Physician’s decision (n=2) Other (n=5) Missing (n=2)
Fig. 1 Patient disposition throughout the study
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Completed planned treatment (n=123)
EP (n=170)
Completed planned treatment (n=129)
Withdrawn before completing 6 cycles (n=41) Disease progression (n=18) Toxicity (n=5) Death (n=5) Protocol violation (n=3) Patient’s wish (n=1) Physician’s decision (n=5) Other (n=1) Missing (n=3)
Breast Cancer Res Treat Table 1 Baseline patient characteristics
Characteristic
Capecitabine ? paclitaxel (XP) (n = 170)
Epirubicin ? paclitaxel (EP) (n = 170)
Median age, years (range)
57 (29–75)
58 (21–76)
ECOG performance status B1
100 %
99 %
Node positive at first diagnosis
56 %
58 %
ER/PR-positive
70 %
68 %
HER2-positivea
11 %
18 %
C2
45 %
56 %
Visceral
56 %
47 %
Lymph
25 %
24 %
Lobular Ductal
17 % 72 %
16 % 75 %
Other
11 %
10 % 41 %
Metastatic sites
ECOG Eastern Cooperative Oncology Group, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor
Histology
Adjuvant chemotherapy
41 %
a
Anthracycline-containing
18 %
19 %
CMF
18 %
19 %
Unknown/missing in 16 % of the XP arm and 17 % of the EP arm
(28.1 %) and cycle 6 of EP (26.7 %). Febrile neutropenia occurred typically in the second or third cycle of EP.
1.0
XP EP
estimated probability
0.8
Quality of life
0.6
0.4
0.2
0 0
6
12
18
24
30
36
8 5
6 2
42
48
months
There were no considerable differences between the treatment arms in ECOG status No significant differences between treatment arms were observed for results of the BR23 questionnaire. For the QLQ-C30 questionnaire statistically significant differences between treatment arms were found for difficulties taking a long walk (p = 0.016), physical condition or medical treatment interfering with social activities (p = 0.011), limitations in hobbies or leisure activities (p = 0.003), worries over the last week (p = 0.032), and all in favor for EP. (Supplemental figure 1).
patients at risk: XP 168 EP 165
121 117
52 59
28 37
13 17
1 1
0 0
Fig. 2 Median PFS was 10.4 months (95 % CI 9.0–11.8) with XP, and 9.2 months (95 % CI 7.2–11.2) with EP. Hazard ratio progression-free survival: XP versus EP: 1.012 (95 % CI 0.785–1.304)
Safety The safety profile of both the regimens was relatively acceptable (Table 3). There was more grades 3–4 diarrhea and grade 3 HFS with XP and more grades 3–4 hematologic toxicity with EP. The incidence of HFS increased steadily until cycle 6, and grade 3 HFS peaked in cycle 6 of XP. Muscositis grades 1–2 was highest in cycle 2 of XP
Discussion The MAMMA-3 trial investigating the combination of paclitaxel plus either capecitabine or epirubicin could not confirm that XP is noninferior to EP. The lower limit of the 95 % CI for the difference in means of the PFS distribution -0.205 was below the predefined limit of -0.1863. Whereas the hazard ratio for XP of 1.01 is lower than the assumed HR of 1.2 to show noninferiority. In both the treatment arms, the duration of PFS was considerably longer than the anticipated when the study was designed: at this final analysis, 28 % of patients in each arm remained progression free. The actual number of events was
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Breast Cancer Res Treat Table 2 Response rates
Overall response rate Complete response
XP (%)
EP (%)
Difference (XP - EP) 95 % CI
p value
47
42
-6 to ?16 %
0.351
9
6
-3 to ?8 %
0.237
Partial response
38
36
-8 to ?13 %
Stable disease
31
36
-15 to ?6 %
Disease progression
4
9
-10 to ?1 %
Not evaluable
18
14
1.0 XP EP
estimated probability
0.8
0.6
0.4
0.2
0 0
6
12
18
24
30
36
21 21
8 8
42
48
months patients at risk: XP 168 EP 165
141 132
106 109
77 74
41 47
1 1
0 0
Fig. 3 Median overall survival was 22.0 months (95 % CI 17.8–26.2) for XP, and 26.1 months (95 % CI 20.6–31.7) for EP (hazard ratio XP vs. EP: 1.027; 95 % CI 0.740–1.424)
markedly lower than the estimated number used when designing the trial, leading to difficulties in estimating the PFS distribution. XP demonstrated high activity, showing similar response rate, PFS, and overall survival to EP. Therefore, we consider XP to be an active first-line treatment option for MBC, which can be administered on an outpatient basis. As expected, XP was associated with less hematologic toxicity than EP, while manageable diarrhea and hand–foot syndrome were more common than with EP. The efficacy of XP in this trial is supported by findings of a Mexican, randomized, phase III trial in which patients received XT, XP, or sequential capecitabine followed at disease progression by either docetaxel or paclitaxel [21]. In the XP arm, the planned capecitabine dose was 825 mg/m2 twice daily in combination with the paclitaxel
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dose used in our trial. The actual dose delivered was slightly higher than this (median 949 mg/m2 in cycle 1, 902 mg/m2 in cycle 8), and thus, very similar to the regimen administered in our trial. The Mexican investigators reported median PFS of approximately 7 months with XP and median overall survival [24 months. The findings from the present trial are in line with the preliminary results of a randomized phase III trial comparing 3-weekly cycles of epirubicin 75 mg/m2 plus docetaxel 75 mg/m2 (ET; n = 98) on day 1 versus capecitabine 950 mg/m2 twice daily on days 1–14 plus docetaxel 75 mg/ m2 on day 1 (XT; n = 98) as first-line therapy [23]. Efficacy was similar within the two regimens, suggesting the potential for capecitabine as an alternative to epirubicin in combination with a taxane in the first-line setting. XT was associated with less severe toxicities and there were no toxicity-related deaths, whereas two patients died from sepsis in the ET treatment arm. The good tolerability observed with the XP combination in the present trial is noteworthy. Our results show that at appropriate doses, capecitabine/paclitaxel combinations are relatively well tolerated. Hand–foot syndrome and gastrointestinal toxicities were considerably less frequent in our trial than in the phase III trial of XT reported by O’Shaughnessy et al. [18], in which rates of grades 3–4 diarrhea and grade 3 HFS were 14 and 24 %, respectively, with capecitabine given at 1,250 mg/m2 twice daily. However, the rates we observed are similar to those observed by Soto et al. [21] in patients receiving first-line capecitabine 825 mg/m2 with paclitaxel (grades 3–4 diarrhea in 7 %; grade 3 HFS in 8 %). One limitation of the trial is that EP is no longer considered to be an option in pretreated metastatic breast cancer patients. Epirubicin is widely used in Europe and Japan and is as effective as doxorubicin at equitoxic doses, justifying its use as a comparator [24]. Second, the epirubicin dose may be considered to be too low, based on the reports of a dose-response effect of epirubicin in the adjuvant setting [25, 26]. However, there is no evidence to confirm whether the dose relationship seen in the adjuvant setting can be extrapolated to the metastatic setting. Importantly, median overall survival with our EP regimen was slightly longer than the range of 20–23 months reported in previous randomized trials of paclitaxel plus an anthracycline in the first-line setting, suggesting that the lower dose of epirubicin in our trial did not adversely affect the outcome [27–29]. In phase III trials of epirubicin in the metastatic setting, administration of a high dose of epirubicin is frequently not feasible because of toxicity and pretreatment with an anthracycline in the adjuvant setting [30]. Furthermore, two randomized trials comparing different doses of epirubicin in the metastatic setting demonstrated similar efficacy with lower and higher doses
Breast Cancer Res Treat Table 3 Summary of adverse events per patient; p-values are given overall Capecitabine ? paclitaxel (XP) (n = 165a)
Epirubicin ? paclitaxel (EP) (n = 167b)
Grades 1–4
Grades 1–2
Grades 3–4
Grades 1–4
Grades 1–2
Grades 3–4
Neutropenia
61.3
34.5
26.8
74.7
19.6
54.8
\0.001
Leukopenia
77.4
63.7
13.7
91.8
51.2
40.6
\0.001
Anemia
76.8
72.6
4.2
89.5
87.7
1.8
0.011
Thrombocytopenia
36.3
33.3
3.0
33.8
30.8
Lymphocytopenia
75.5
68.3
7.2
74.9
54.5
Febrile neutropenia
3.0 % 20.4
p value*
n.s. \0.001
0.6
0
0.6
3.6
0
3.6
n.s.
Infection with Neutropenia Infection without Neutropenia
2.4 15.7
0 13.9
2.4 1.8
2.4 18.0
0 16.2
2.4 1.8
n.s. n.s.
Vomiting
21.2
18.8
2.4
33.0
31.8
1.2
0.011
Nausea
50.9
49.7
1.2
67.7
65.9
1.8
0.009
Mucositis/stomatitis
51.5
51.5
0
46.1
46.1
0
n.s.
Alopecia
95.7
95.7
0
97.6
97.6
0
n.s.
Diarrhea
44.2
39.4
4.8
28.8
28.2
0.6
0.014
Hand–foot syndrome
70.9
60.0
10.9
23.4
23.4
0
Cardiotoxicity
11.6
10.4
1.2
16.2
14.4
1.8
n.s.
Hypersensitivity reaction
11.5
11.5
0
11.4
11.4
0
n.s.
\0.001
Motor neurotoxicity
21.8
20.6
1.2
17.4
16.2
1.2
n.s.
Sensory neurotoxicity
78.2
77.0
1.2
69.4
67.0
2.4
n.s.
Arthralgia
58.8
54.6
4.2
55.7
49.7
6.0
n.s.
Myalgia
52.1
48.5
3.6
52.7
48.5
4.2
n.s.
Fatigue
72.0
69.7
3.0
70.0
65.8
4.2
n.s.
* overall p-values for the comparison of grades 1–4 are given n.s. indicates p [ 0.05 a
n = 168 for hematologic toxicity
b
n = 170 for hematologic toxicity
[31, 32]. Third, the patients did not receive trastuzumab in case of HER2-positivity. The effect of chemotherapy is not strongly related to the HER2 status. The relatively infrequent exposure to adjuvant chemotherapy, particularly anthracycline-containing chemotherapy, in the MAMMA-3 trial population was typical of patients presenting in Germany between 2000 and 2002. This is certainly not the case any more. The good performance status of these patients enabled delivery of treatment at the planned dose and schedule in the large majority of patients. The appeal of nonanthracycline-containing first-line therapy is particularly strong as the majority of the patients receive an anthracycline as part of the adjuvant therapy. Recent trials have demonstrated that XT can be effectively and safely combined with trastuzumab in the first-line metastatic and neoadjuvant setting [33, 34]. The results of our trial suggest that XP is a reasonable, nonanthracycline-containing treatment option in the firstline treatment of patients with high-risk MBC. In addition, ongoing trials are evaluating capecitabine in combination
with taxanes in the adjuvant setting, where nonanthracycline regimens may be particularly beneficial as they avoid the increased risk of cardiotoxicity and secondary acute myeloid leukemia, and myelodysplastic syndrome associated with anthracyclines [35, 36]. In conclusion, we demonstrated that XP is active, with median overall survival of 22 months. The regimen we used was well tolerated and was associated with maintained QoL. Consequently, we consider that capecitabine is a valid combination partner for paclitaxel in the first-line setting, providing an active and well tolerated alternative to anthracycline/taxane regimens. Acknowledgments The authors would like to acknowledge the work of our advisory board, consisting of the following persons: Prof Dr G Emons, Prof Dr F Ja¨nicke, Prof Dr M Kaufmann, Prof Dr H Ku¨hnle, Prof Dr H-G Meerpohl (advisory board), and AGO principal investigators Dr B. Bru¨ckner, Dr H. Eidtmann, Prof Dr V Mo¨bus, Prof Dr W Schro¨der, Prof Dr C Thomssen, Prof. Dr M Untch, Dr T Volm. This study is sponsored by the Arbeitsgemeinschaft Gyna¨kologische Onkologie (AGO) metastatic breast cancer study group. Financial support is provided by F. Hoffmann-La Roche and Bristol-Myers Squibb.
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References 1. Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, Tinazzi A, Liberati A (1998) Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16(10):3439–3460 2. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P (2003) TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 21(6):968–75. Erratum in: J Clin Oncol 21(10):2048 3. French Epirubicin Study Group (1988) A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6(4):679–688 4. Hortobagyi GN, Yap HY, Kau SW, Fraschini G, Ewer MS, Chawla SP, Benjamin RS (1989) A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer. Am J Clin Oncol 12(1):57–62 5. Lu¨ck HJ, Thomssen C, Untch M et al (2000) Multicentric Phase III study in first line treatment of advanced metastatic breast cancer (ABC). Epirubicin/Paclitaxel (ET) Vs Epirubicin/Cyclophosphamide (EC). A study of the ago breast cancer Group. Proc ASCO 19:280 6. Jassem J, Pien´kowski T, Płuzan´ska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group (2001) Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as firstline therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19(6):1707–1715 7. Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M (2005) Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol 23(33):8322–8330 8. Piccart-Gebhart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Lu¨ck HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P (2008) Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol 26(12):1980–1986. doi: 10.1200/JCO.2007.10.8399 9. National Cancer Comprehensive Network (2013) Clinical practice guidelines in oncology: breast cancer, version 2 http://www. nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed on 04 April 2013 10. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thu¨rlimann B, Senn HJ; 10th St. Gallen conference (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 8(7):1133–1144. Erratum in: Ann Oncol. 18(11):1917 11. Gennari A, Bruzzi P, Orlandini C, Salvadori B, Donati S, Landucci E, Guarneri V, Rondini M, Ricci S, Conte P (2004) Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy. Br J Cancer 90(5):962–967 12. Guo X, Loibl S, Untch M, Mo¨bus V, Schwedler K, Fasching PA, Barinoff J, Holms F, Thomssen C, Zahm DM, Kreienberg R,
123
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Hauschild M, Eidtmann H, Tauchert S, Mehta K, von Minckwitz G (2011) Re-challenging taxanes in recurrent breast cancer in patients treated with (neo-)adjuvant taxane-based therapy. Breast Care (Basel) 6(4):279–283 Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17(2):485–493 Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Ko¨lbl H, Ja¨nicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lu¨ck HJ (2003) Multicenter phase II study of oral capecitabine (Xeloda(‘‘)) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 14(8):1227–1233 Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J (1995) Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 13(10):2575–2581 Smith RE, Brown AM, Mamounas EP, Anderson SJ, Lembersky BC, Atkins JH, Shibata HR, Baez L, DeFusco PA, Davila E, Tipping SJ, Bearden JD, Thirlwell MP (1999) Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17(11):3403–3411 Stockler M, Sourjina T, Grimison P, Gebski V, Byrne M, Harvey V, Francis P, Nowak AK, Van Hazel G; J. Forbes ANZ Breast Cancer Trials Group (2007) A randomized trial of capecitabine (C) given intermittently (IC) rather than continuously (CC) compared to classical CMF as first-line chemotherapy for advanced breast cancer (ABC). ASCO Annu Meet Proc (PostMeeting Edition) J Clin Onco 25(18S):1031 O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20(12):2812–2823 Gradishar WJ, Meza LA, Amin B, Samid D, Hill T, Chen YM, Lower EE, Marcom PK (2004) Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study. J Clin Oncol 22(12):2321–2327 Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O’Shaughnessy JA (2006) Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 24(27):4384–4390 Soto C, Torrecillas L, Reyes S, Ramirez M, Perez L, Cervantes G, Gonzalez F, Tellez E, Cortes P, Benitez H (2006) Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized phase III trial. ASCO Annu Meet Proc (Post-Meeting Edition) J Clin Oncol 24(18S):570 Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Lu¨ck HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P (2008) Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 26(12):1987–1992. doi:10.1200/JCO.2007.10.8407 Mavroudis D, Boukovinas I, Ardavanis A, et al. (2005) A multicenter phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first line treatment in patients with locally advanced and metastatic breast cancer. Preliminary report. Proc SABCS 2005 (abstract 6089)
Breast Cancer Res Treat 24. Findlay BP, Walker-Dilks C (1998) Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group. Cancer Prev Control 2(3):140–146 25. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM (2001) Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19(12):3103–3110 26. Bonneterre J, Roche´ H, Kerbrat P, Bre´mond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I (2005) Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23(12):2686–2693 27. Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ (2002) Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 20(14):3114–3121 28. Jassem J, Pien´kowski T, Płuzan´ska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group (2001) Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as firstline therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19(6):1707–1715 29. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as
30.
31.
32.
33.
34.
35.
36.
front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21(4):588–592 Pacilio C, Morabito A, Nuzzo F, Gravina A, Labonia V, Landi G, Rossi E, De Maio E, Di Maio M, D’Aiuto G, Botti G, Normanno N, Chiodini P, Gallo C, Perrone F, de Matteis A; NCI-Naples Breast Cancer Group (2006) Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br J Cancer 94(9):1233–1236 Habeshaw T, Paul J, Jones R, Stallard S, Stewart M, Kaye SB, Soukop M, Symonds RP, Reed NS, Rankin EM (1991) Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial. J Clin Oncol 9(2):295–304 Lu¨ck HJ, Thomssen C, du Bois A, Untch M, Lisboa B, Ko¨hler G, Diergarten K (1997) Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. Semin Oncol 24(5 Suppl 17):S17-35–S17-39 Lybaert W, Wildiers H, Neven P, et al (2006) Multicenter phase II study of neoadjuvant capecitabine (X), docetaxel (T) ± trastuzumab (H) for patients (pts) with locally advanced breast cancer (LABC): preliminary safety and efficacy data. Breast Cancer Res Treat. 100(Suppl. 1):S147 (abstract 3070) Wardley A, Anto´n-Torres A, Pivot X, et al (2006) Trastuzumab plus docetaxel with or without capecitabine in patients with HER2-postiive advanced/metastatic breast cancer: first efficacy results from the Phase II MO16419 (CHAT) study. Breast Cancer Res Treat. 100(Suppl. 1):S101 (abstract 2063) Praga C, Bergh J, Bliss J, Bonneterre J, Cesana B, Coombes RC, Fargeot P, Folin A, Fumoleau P, Giuliani R, Kerbrat P, Hery M, Nilsson J, Onida F, Piccart M, Shepherd L, Therasse P, Wils J, Rogers D (2005) Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23(18):4179–4191 Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905
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