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Weekly combination of non-pegylated liposomal doxorubicin and taxane in first-line breast cancer: wALT trial (phase I–II)
original article
Annals of Oncology 22: 315–320, 2011 doi:10.1093/annonc/mdq392 Published online 6 August 2010
Weekly combination of non-pegylated liposomal doxorubicin and taxane in first-line breast cancer: wALT trial (phase I–II) M. S. Rosati1*, C. Raimondi1, G. Baciarello1, P. Grassi1, S. Giovannoni1, E. Petrelli1, M. L. Basile1, M. Girolami2, M. Di Seri1 & L. Frati1 1
Department of Oncology A; 2IV Surgical Division, Policlinico ‘‘Umberto I’’, ‘‘Sapienza’’ University of Rome, Rome, Italy
Received 11 March 2010; revised 25 May 2010; accepted 1 June 2010
Background: Through different pharmacodynamic–kinetic interactions, weekly administration of proved efficacy
introduction Despite research progress in oncology, metastatic breast cancer (MBC) remains incurable. One of the numerous causes resides on Norton and Simon hypothesis [1] for which tumor regrowth may be particularly rapid when the number of viable cells is at its lowest because of the Gompertzian shape of the growth curve [2]. Dose-dense chemotherapy theoretically offers the advantage, over conventional treatment, of slowing tumor cell regrowth between cycles (by shortening the interval between them). However, the experience with the use of dosedense chemotherapy in advanced disease is rather limited. Conventional anthracyclines are the most widely used agents to treat breast cancer in the adjuvant setting, as well as in metastatic disease. In fact, in a number of studies, doxorubicinbased regimens have demonstrated benefits in terms of response rate, time-to-disease progression (TTP) and overall survival (OS). Despite its excellent antitumor activity, its use is limited by myelosuppression, alopecia, acute nausea and *Correspondence to: Dr M. S. Rosati, Department of Oncology A, Policlinico ‘‘Umberto I’’, ‘‘Sapienza’’ University of Rome, 155 V.le del Policlinico, 00161 Rome, Italy. Tel: +39-06-4441675; Fax: +39-06-4941035; E-mail: [email protected]
vomiting, stomatitis and, above all, cumulative cardiotoxicity [3] that can lead to potentially fatal congestive heart failure. Initially, damage to the heart is subclinical but continued treatment will lead to progressive myocytes damage. The resulting cumulative cardiac dysfunction may become evident during treatment or, subsequently, in months or years after the final doxorubicin dose [4]. In the last years, many issues on anthracyclines use and rechallenge animated contrasting position. Data from meta-analysis suggest that anthracyclinebased chemotherapy would be more efficacious than nonanthracyclines-containing regimens in HER2-positive (HER2+) women [5]. Moreover, recent results from MA5 trial support the hypothesis that adjuvant regimens with anthracycline are inferior to adjuvant combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil in women with basal breast cancer (hormone receptors and HER2 negative and CK5/6 or epidermal growth factor receptor positive) [6]. These data cannot yet be translated into the clinical settings because of the lack of basal-like phenotype definition from common histology feature. Data from TOP trial, the first prospective study to evaluate topoisomerase II a as a predictive marker of response to anthracycline, suggest that
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
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agents can overcome resistance with lower toxicity and greater benefit. Based on this assumption, we designed a phase I–II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients. Patients and methods: We enrolled 56 previously untreated metastatic breast cancer patients; they were randomly assigned to receive paclitaxel (Taxol) (50 mg/mq) or docetaxel (Taxotere) (30 mg/mq) combined with non-pegylated liposomal anthracycline (25 mg/mq) on days 1, 8 and 15 every 4 weeks. The primary end points were the clinical benefit and treatment-related toxic effects assessment. Secondary end points were time-to-disease progression (TTP) and overall survival (OS). Results: The overall clinical benefit was 87.04%. World Health Organization G3–4 toxic effects included neutropenia (45%), anemia (44%), complete alopecia (83%), severe onycholysis and neuropathy. The 24% of patients developed left ventricular ejection fraction reduction but none >10% with recover after treatment completion. The median absolute decrease from baseline was 1%. Median TTP was 11 months and median OS was 23 months. Conclusions: Combined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design. Key words: dose dense, first-line breast cancer, NPLD
original article gene expression profile predicts response/resistance to anthracyclines, both in HER2(+) and HER2(2) patients [7]. Taken together, these data are not sufficient to determine the breast cancer target patient candidate to receive anthracycline in all settings. None of the study mentioned examined the role of liposomal anthracycline to overcome resistance. The present trial is the first study designed to investigate the outcome of a combined dose-dense non-pegylated liposomal anthracycline and taxane regimen in MBC.
patients and methods patients
received paclitaxel (50 mg/mq)/Myocet (25 mg/mq) on days 1, 8, and 15 every 4 weeks. Arm B (n = 24) received docetaxel (30 mg/mq)/Myocet (25 mg/mq) on days 1, 8, 15 every 4 weeks. No granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was used. Filgrastim was prescribed for those patients who developed febrile neutropenia as a s.c. 5 lg/kg daily injection for 3 days after the first event and continued on subsequent cycles. The primary phase II study end points were the rate of clinical benefit after six cycles of chemotherapy and treatment-related toxic effects assessment. The clinical benefit was defined as the rate of complete response (CR), partial response (PR) and stable disease (SD) lasting at least 6 months, evaluated by RECIST criteria and calculated for all patients with measurable disease. Secondary end points were TTP and OS. OS was calculated from the date of study entry to the date of death from any cause. Patients lost to follow-up or those with no date of death recorded were censored on the date of last follow-up. Kaplan–Meier survival curves were generated and median OS calculated for the ITT population with 95% confidence interval (CI). TTP was calculated from the date of study entry to the date of disease progression or death from any cause, whichever occurred first. Patients without a date of progression recorded were censored on the date of last follow-up. Surviving patients without disease progression were censored at the date last known to be progression free.
assessment Baseline evaluation included: physical examination, assessment of medical history, evaluation of PS and blood count. During the treatment, patients were evaluated before each cycle of therapy with the above parameters. All patients carried out an abdominal and thoracic computed tomography scan at baseline and every three cycles to assess tumor response. Tumor response and disease progression were assessed according to RECIST guidelines and confirmed as lasting longer than 4 weeks. After the end of the therapy, HER2(+) patients received trastuzumab until progression and they were followed every 3 months until progression. We defined adverse event (AE), any adverse change in health, or side-effect while the patients were receiving the study treatment or within 3 weeks of time after treatment completion. Toxicity was graded according to the National Cancer Institute (NCI)—Common Toxicity Criteria for AE (version 3.0). LVEF decrease was defined as a level lower than the institutional limit or an absolute 10% decrease from the patient’s baseline.
study design and treatment
statistical methods
We design a phase I–II prospective randomized trial. All the patients received a parenteral premedication regimen with: ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. the day before treatment and at day 1. The maximum tolerated dose (MTD) and dose-limiting toxicity were rapidly assessed through a phase I trial. A number of four consecutive patients was enrolled in paclitaxel (Taxol, Bristol Myers Squibb)/Myocet (Cephalon) arm: first three consecutive patients received paclitaxel (50 mg/mq)/Myocet (25 mg/mq) on days 1, 8 and 15 every 4 weeks for six cycles and no limiting toxic effects were recorded and then one patient (PS 0) received paclitaxel (60 mg/mq)/Myocet (25 mg/mq) on days 1, 8 and 15 every 4 weeks and developed severe febrile neutropenia with sepsis after the completion of the second cycle, so we defined paclitaxel (50 mg/mq)/Myocet (25 mg/mq) as the MTD. A number of five patients were enrolled in phase I docetaxel (Taxotere, Sanofi Aventis)/Myocet trial: the first three consecutive patients received docetaxel (30 mg/mq)/Myocet (25 mg/mq) and no dose-limiting toxic effects were recorded and then two patients received docetaxel (35 mg/mq)/Myocet (25 mg/mq) and the last enrolled patient developed severe febrile neutropenia with sepsis after the completion of the first cycle, so we define docetaxel (30 mg/mq)/Myocet (25 mg/mq) as the MTD. A total of 54 patients (included 7 patients who received full-dose treatment in phase I study) were randomly assigned to receive a combination of weekly paclitaxel/Myocet or docetaxel/Myocet in a 1 : 1 mode. Arm A (n = 30)
The study was planned to test an estimated rate of clinical benefit of 75%, with a type I error (a) of 0.05 and a power of 80% (1-b). This hypothesis required a sample size of 60 patients, taking into account a 10% of drop out. After cessation of treatment, patients without documented progression were followed every 3 months with clinical and radiological evaluation. OS and TTP distributions were plotted using the Kaplan–Meier method. Data were recorded and analyzed in a Medlogs database. All analyses were done on an intention-to-treat population. Comparison of survival curves were made with log-rank test. Because the study was not powered to address therapeutic effect within subsets of patients, comparisons within docetaxel and paclitaxel arms are exploratory only; differences between groups were analyze with v2 test; P value was considered significative for <0.05.
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results patients characteristics A total number of 56 patients were enrolled. Table 1 summarizes patients characteristics by stratification factors [i.e. hormone receptor (HR), HER2 status], demographics (age) and pre-treatment clinical characteristics.
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From January 2002 to June 2005, we enrolled 56 patients. Eligible patients were required to have measurable histologically proven MBC and at least one measurable lesion according to RECIST criteria, World Health Organization performance status (PS) zero to two, age between 18 and 75 years, estimated life expectancy of at least 3 months, adequate hepatic function [serum bilirubin < 1.5 · upper normal limit (UNL), transaminase < 3 · UNL; however, in cases of liver metastases, there were no upper limit for transaminases], adequate renal function (calculated creatinine clearance > 30 ml/min by the Cockroft and Gault formula) and adequate hematological function (neutrophil count > 1.5 · 109/l; platelets > 100 · 109/l). No prior chemotherapy for metastatic disease was allowed. Hormonal treatment of advanced or metastatic disease was allowed. All patients who had received anthracycline-containing regimen in adjuvant setting had to provide that 1 year had transpired from its completion to protocol entry. Median prior doxorubicin received dose was 379 mg/mq; median epirubicin dose was 446 mg/mq. Adequate renal, hepatic and hematologic parameters were required. A normal (50%–70%) baseline left ventricular ejection fraction (LVEF) assessed by echocardiogram within 30 days before the first cycle was required. Patients within class II New York Heart Association Classification cardiac disease were accrual; patients with severe congestive heart failure were excluded. Pregnant or lactating women were not included. The study was conducted according to the principles of the Declaration of Helsinki and all patients provided written informed consent.
Annals of Oncology
original article
Annals of Oncology
efficacy Table 2 summarizes overall clinical benefit from phase II trial. primary end point: clinical benefit. Table 3 summarizes the overall response rate (RR) for both Arms A and B. The overall clinical benefit was 87.04% (CR: 12.96%, PR: 66.67% and SD: Table 1. Demographic and disease characteristics of patients Characteristics
n
(%)
ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; CHT, chemotherapy; PgR, progesterone receptor; PS, performance status.
toxicity. Weekly schedule was very well tolerated. Hematologic toxicity was generally mild and it is summarized in Table 3. Grade 3 or worse granulocytopenia was recorded in 45 patients (83%) but febrile neutropenia was infrequent (n = 6 patients) and none but one patient in phase II trial required hospitalization. Nonhematologic toxic effects occurring with at least 5% incidence are summarized in Table 4. Moderate or severe sensory neuropathy was encountered in 40% and 5% of patients, respectively. Neuropathy was significantly greater in docetaxel arm than in paclitaxel arm (G1–2: 70% versus 16%, P = 0.007; G3–4: 12% versus 0%, P = 0.0001). Dose modification was required in 4% of patients with severe neuropathy. Slightly more patients receiving docetaxel experimented mucositis but differences were not significative. Otherwise, moderate-to-severe onycholysis was greater in docetaxel-treated patients (75% versus 13%, P = 0.0001)(see Table 5). Alopecia was frequent (83%) and generally complete. Other grades 3 and 4 nonhematologic toxic effects were rare, including serious hypersensitivity reactions, as a result of the all-parenteral premedication regimen employed. Limited data are available on the 25/30 HER2(+) patients who received trastuzumab after treatment completion. None of the patients received adjuvant trastuzumab because the study was designed when NCI guidelines did not recommend its use in adjuvant setting. The study was not designed to analyze differences between HER2(+)/HER2(2) groups. Notwithstanding, 2 of 25 (8%) HER2(+) patients developed grade 3 cardiac dysfunction while on trastuzumab treatment. None of the HER2(2) Table 3. Hematologic toxicity Toxicity grade
Patients (n = 54) 1–2 3–4 n (%) n (%)
Administrations (n = 786) 1–2 3–4 n (%) n (%)
Granulocytopenia NFN FN Trombocitopenia Anemia
41 35 – 8 28
257 209 – 104 155
(75) (64) (14) (51)
45 37 6 – 24
(83) (68) (11) (44)
(32) (26) (13) (19)
170 160 36 60 96
(21) (20) (4) (7) (12)
NFN, non-febrile neutropenia; FN, febrile neutropenia.
Table 2. Overall response, time to disease progression (TTP) and overall survival (OS)
CR (%) PR (%) SD (%) PD (%) Clinical benefit (%) TTP (months) OS (months) (%)
Patients (n = 54)
Myocet/paclitaxel (n = 30)
Myocet/docetaxel arm (n = 24)
P
12.96 66.67 7.41 12.96 87.04 11 23 (57.4%)
13.33 66.67 10 10 90 12 24
12.5 66.67 4.17 16.67 83.33 9 18
0.89 ns 0.11 0.3 0.3 0.5 0.3
CR, complete response; OS, overall survival; PR, partial response; TTP, time-to-disease progression.
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Total assessable patients 56 Demographics Median age (range) 56 years (45–67) Pre-menopausal 5 9 Clinicopathological characteristics ECOG PS 0 38 68 1 13 23 2 5 9 Type of cancer Ductal 36 64 Lobular 10 18 Mixed 10 18 Receptor status ER(+) 42 75 PgR(+) 33 59 HER2 (FISH +) 30 54 Prior CHT (neoadjuvant and adjuvant) Anthracycline 51 91 Taxane 13 23 Hormonotherapy 43 77 Adjuvant trastuzumab 6 11 Median cumulative anthracycline exposure in prior treatment (mg/mq) Epirubicin 350 Doxorubicin 381 Metastases (n) 1 18 32 ‡2 37 66 Sites of metastases Soft tissue 7 13 Nodes 12 21 Liver 33 59 Lung 4 7 Brain 2 4 Bone 38 68
7.41%) with a PD: 12.96%. The overall clinical benefit with weekly paclitaxel/Myocet was 90% (CR: 13.3, PR: 66.67 and SD: 10) and 83.33% with weekly docetaxel/Myocet (CR: 12.5%, PR: 66.67% and SD: 4.17%). No significative differences were noted between groups.
original article
Annals of Oncology
drug exposure. The median administration/patient ratio was 14.5 with a median cumulative non-pegylated liposomal doxorubicin exposure of 363 mg/mq/patient.
Table 4. Treatment related toxicity (non hematologic) Grade (WHO)
Patients (n = 54) 1–2 3–4 n (%) n (%)
Administrations (n = 786) 1–2 3–4 n (%) n (%)
Mucositis Neuropathy Astenia Nausea/vomiting Onycholysis Edema Allergic reaction Alopecia LVEF reduction
19 22 32 18 22 19 6 45 13
155 116 156 42 – – – – –
10 (18) 3 (5) 5 (9) –
(19) (14) (19) (5)
69 (8) 157 (19) 43 (5) –
Table 5. Non-hematologic related toxicity: subgroups analysis. Docetaxel Arm (D) versus Paclitaxel Arm (P) WHO grade
Docetaxel arm 1–2, 3–4, n (%) n (%)
Paclitaxel arm 1–2, 3–4, n (%) n (%)
P value
Onycholysis Mucositis
– 10 (41%)
18 (75%) 6 (25%)
– 9 (30%)
4 (13%) 4 (13%)
Neuropathy
17 (70%)
3 (12%)
5 (16%)
0
0.0001 0.2 0.08 0.007 0.0001
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40 20
5
0
10 Time
15
20
Figure 1. Time to progression analysis. In all eligible patients TTP was analyzed with the use of Kaplan-Meier method.
TTP 100
TREAT D P
80 60 40 20 0
0
5
10 Time
15
20
Figure 2. TTP subsets analysis: Paclitaxel Arm (P) versus Docetaxel Arm (D) (12 versus 9 months, HR: 1.4, 95% CI: 0.8–2.4, P = 0.01).
TTP
100
LVEF, left ventricular ejection fraction; WHO, World Health Organization.
WHO, World Health Organization.
60
0
Survival probability (%)
(35) (40) (59) (33) (40) (35) (11) (83) (24)
80
GROUP H NH
80 60 40 20 0
0
5
10 Time
15
20
Figure 3. TTP subsets analysis: HER2+ patients (H) versus HER22 patients (NH) (9 versus 12 months, HR: 0.9, 95% CI: 0.5–1.5, P = 0.64).
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overall survival. To a median follow-up of 29 months (Figure 4), the median OS was 23 months (57.4% of patients). Differences between two groups in terms of OS are not significative [Arm A versus B: 24 versus 18 months (HR: 1.3, 95% CI 0.7–2.4, P = 0.34)] (Figure 5).
Survival probability (%)
time-to-disease progression. Kaplan–Meier estimated TTP curves are represented in Figure 1. The median TTP was 11 months. Subsets analysis did not demonstrate advantage for Arm A over B (12 versus 9 months, HR: 1.4, 95% CI 0.8–2.4, P = 0.1) (Figure 2). TTP was 9 months in HER2(+) and 12 months in HER2(2) (HR: 0.9, 95% CI 0.5–1.5, P = 0.64); thus, the addition of trastuzumab after treatment completion in patients with HER2(+) breast cancer was not associated with significantly longer TTP (Figure 3).
TTP 100
Survival probability (%)
patients developed cardiac heart failure within the 12 months after treatment completion. There were no deaths attributable to cardiac toxicity. After the treatment completion, a LVEF reduction was encountered in the 24% of patients (n = 13) but it was never > 10%. The 24% of patients (n = 13) experimented a LVEF reduction after treatment completion but none of them developed a >10% decreased. The median absolute decrease from baseline was 1%. No treatment-related deaths occurred.
original article
Annals of Oncology OS
Survival probability (%)
100 90 80 70 60 50 40 30 20 0
5
10
15
20 25 Time
30
35
40
Figure 4. Overall survival in all eligible patients was analyzed with the use of the Kaplan-Meier method (median OS was 23 months).
OS 100
Survival probability (%)
80 70 60 50 40 30 20 10
0
5
10
15
20
25
30
35
40
Time Figure 5. Overall survival subset analysis (to be considered exploratory only). Paclitaxell Arm (P) versus Docetaxel Arm (D) (24 versus 18 months, HR 1.3, 95% CI: 0.7–2.4, P = 0.034).
discussion This phase II trial was designed to address the efficacy and safety of a combined weekly schedule of non-pegylated liposomal anthracycline and taxane in MBC. Use of anthracycline in advanced or metastatic disease was deeply debated in the recent years. Since the anthracycline-containing regimens are increasingly used in the adjuvant setting, retreatment, even if effective, is limited to patients exposed to low cumulative anthracycline doses and with a relapse-free survival longer than 12 months after adjuvant chemotherapy. One of the biggest issue in anthracycline rechallenge is the cumulative cardiotoxicity. However, few data are available on the efficacy of anthracycline rechallenge after prior adjuvant exposure. Some reports [8] showed that anthracycline–taxane combinations as first-line treatment of MBC are effective, regardless of previous adjuvant chemotherapy. Our data support the hypothesis that weekly combination of Myocet and taxane, improves the outcome with a modest toxicity profile, which represents the first goal in maintaining quality of life. In 54 assessable patients, the overall clinical benefit was 87.04 % (CR: 12.96%, PR: 66.67% and SD: 7.41%). Subgroups analysis showed a 90% (CR: 13.3%, PR: 66.67% and
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Treatment D P
90
SD: 10%) benefit in the paclitaxel arm and 83.33% (CR: 12.5%, PR: 66.67% and SD: 4.17%) with weekly docetaxel. It is noteworthy that responses were observed in patients with previous anthracycline exposure (94% of patients). Weekly combination of proved efficacy agents combined with different pharmaceutical strategy such as non-pegylated liposomal formulation seems to be able to overcome resistance and to improve treatment outcome. Although comparison between data from different trials has to be considered speculative, our results support the general idea that adding taxane to anthracycline can significantly improve the outcome. The clinical benefit of the combination of weekly Myocet and taxane in MBC is almost the 30% greater than what expected with Myocet alone [9]. Weekly administration of both the drugs resulted in a total of 75 mg/mq per cycle of Myocet with 150 and 90 mg/mq per cycle of paclitaxel or docetaxel, respectively. This intense dose-dense chemotherapy schedule seems to improve the outcome while reducing toxicity. In fact, the wALT study combinations appeared to be very well tolerated. Toxicity profile was generally mild and predominantly hematologic. At least one episode of severe granulocytopenia was recorded in 83% of patients. Primary prophylaxis with G-CSF is kindly recommended from the National Comprehensive Cancer Network (NCCN) guidelines when anthracycline is combined with taxane, especially in dose-dense regimen [10]. We decided not to use primary prophylaxis because we wanted to test if there were differences between conventional and liposomal anthracycline in terms of febrile neutropenia. Although severe granulocytopenia was frequent, febrile neutropenia was recorded in six patients only and none but one patient in phase II trial required hospitalization. The most frequent nonhematologic toxic effects were alopecia (83%), moderate asthenia (59%), peripheral neuropathy (40%) and mucositis (35%). Even the two groups were well balanced in terms of demographic characteristics, subsets analysis have to be considered exploratory only. However, significantly higher incidence of peripheral neuropathy (P = 0.007) and onycholysis (P = 0.0001) were recorded in docetaxel group. Cardiac toxicity was generally modest. None of the patient developed congestive heart failure. A number of 13/56 patients (24%) experimented LVEF reduction. However, the median absolute decrease from baseline was 1% only and LVEF reduction was never >10%, with complete recover after treatment completion. Our data confirm the safety of the cardiac profile of Myocet, which has been already demonstrated in a number of studies [11]. However, the present study has three major limitations: the slow accrual (in part due to patients selection criteria) and it was not powered to investigate differences in HER2 subtypes or to analyze other molecular predictors. To our knowledge, the present work represents the first attempt to combine weekly non-pegylated liposomal anthracycline and taxane. Even if NCCN guidelines recommended the use of trastuzumab [12] or bevacizumab [13] combined with taxane in first-line chemotherapy, our data demonstrated that Myocet/ taxane combination significantly improves the outcomes in unselected patients with MBC who strongly benefit anthracycline rechallenge with non-pegylated liposomal formulation. In the molecular age, anthracyclines still represent a valid therapeutic option. The encouraging results in terms of
original article TTP (11 months) and OS (23 months) deserve larger phase III trial confirmation.
disclosure MSR is a Cephalon consultant since February 2010. MDS received honoraria from Roche, Sanofi-Aventis and AmgenDompe`. No other conflicts of interest have been declared.
references
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6. Cheang M, Chia SK, Tu D et al. Anthracyclines in basal breast cancer: the NCICCTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 2009; 27: 15s (Suppl; Abstr 519). 7. Desmedt C, Azambuja E, Larsimont D et al. Predicting the efficacy of anthracyclines in breast cancer (BC) patients: results of the neoadjuvant TOP trial. J Clin Oncol 2009; 27: 15s (Suppl; Abstr 523). 8. Gennari A, Bruzzi P, Orlandini C et al. Activity of first line epirubicin and paclitaxel in metastatic breast cancer is independent from type of adjuvant therapy. Br J Cancer 2004; 90: 962–967. 9. Batist G, Harris L, Azarnia N et al. Improved anti-tumor response rate with decreased cardiotoxicity of nonpegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs 2006; 17(5): 587–595. 10. Kelly S, Wheatley D. Prevention of febrile neutropenia: use of granulocyte colony-stimulating factors. Br J Cancer 2009; 101 (Suppl 1): S6–S10. 11. Batist G. Cardiac safety of liposomal anthracyclines. Cardiovasc Toxicol 2007; 7(2): 72–74. Review. 12. Dowsett M, Procter M, McCaskill-Stevens W et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol 2009; 27(18): 2962–2969. 13. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357(26): 2666–2676.
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1. Simon R, Norton L. The Norton-Simon hypothesis: designing more effective and less toxic chemotherapeutic regimens. Nat Clin Pract Oncol 2006; 3(8): 406–407. Review. No abstract available. 2. Norton L. Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy. Oncologist 2005; 10(6): 370–381. 3. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 2000; 22: 263–302. 4. Billingham ME, Mason JW, Bristow MR et al. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 1978; 62: 865–872. 5. Gennari A, Sormani MP, Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20.
Annals of Oncology
Annals of Oncology 22: 315–320, 2011 doi:10.1093/annonc/mdq392 Published online 6 August 2010
Weekly combination of non-pegylated liposomal doxorubicin and taxane in first-line breast cancer: wALT trial (phase I–II) M. S. Rosati1*, C. Raimondi1, G. Baciarello1, P. Grassi1, S. Giovannoni1, E. Petrelli1, M. L. Basile1, M. Girolami2, M. Di Seri1 & L. Frati1 1
Department of Oncology A; 2IV Surgical Division, Policlinico ‘‘Umberto I’’, ‘‘Sapienza’’ University of Rome, Rome, Italy
Received 11 March 2010; revised 25 May 2010; accepted 1 June 2010
Background: Through different pharmacodynamic–kinetic interactions, weekly administration of proved efficacy
introduction Despite research progress in oncology, metastatic breast cancer (MBC) remains incurable. One of the numerous causes resides on Norton and Simon hypothesis [1] for which tumor regrowth may be particularly rapid when the number of viable cells is at its lowest because of the Gompertzian shape of the growth curve [2]. Dose-dense chemotherapy theoretically offers the advantage, over conventional treatment, of slowing tumor cell regrowth between cycles (by shortening the interval between them). However, the experience with the use of dosedense chemotherapy in advanced disease is rather limited. Conventional anthracyclines are the most widely used agents to treat breast cancer in the adjuvant setting, as well as in metastatic disease. In fact, in a number of studies, doxorubicinbased regimens have demonstrated benefits in terms of response rate, time-to-disease progression (TTP) and overall survival (OS). Despite its excellent antitumor activity, its use is limited by myelosuppression, alopecia, acute nausea and *Correspondence to: Dr M. S. Rosati, Department of Oncology A, Policlinico ‘‘Umberto I’’, ‘‘Sapienza’’ University of Rome, 155 V.le del Policlinico, 00161 Rome, Italy. Tel: +39-06-4441675; Fax: +39-06-4941035; E-mail: [email protected]
vomiting, stomatitis and, above all, cumulative cardiotoxicity [3] that can lead to potentially fatal congestive heart failure. Initially, damage to the heart is subclinical but continued treatment will lead to progressive myocytes damage. The resulting cumulative cardiac dysfunction may become evident during treatment or, subsequently, in months or years after the final doxorubicin dose [4]. In the last years, many issues on anthracyclines use and rechallenge animated contrasting position. Data from meta-analysis suggest that anthracyclinebased chemotherapy would be more efficacious than nonanthracyclines-containing regimens in HER2-positive (HER2+) women [5]. Moreover, recent results from MA5 trial support the hypothesis that adjuvant regimens with anthracycline are inferior to adjuvant combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil in women with basal breast cancer (hormone receptors and HER2 negative and CK5/6 or epidermal growth factor receptor positive) [6]. These data cannot yet be translated into the clinical settings because of the lack of basal-like phenotype definition from common histology feature. Data from TOP trial, the first prospective study to evaluate topoisomerase II a as a predictive marker of response to anthracycline, suggest that
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
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agents can overcome resistance with lower toxicity and greater benefit. Based on this assumption, we designed a phase I–II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients. Patients and methods: We enrolled 56 previously untreated metastatic breast cancer patients; they were randomly assigned to receive paclitaxel (Taxol) (50 mg/mq) or docetaxel (Taxotere) (30 mg/mq) combined with non-pegylated liposomal anthracycline (25 mg/mq) on days 1, 8 and 15 every 4 weeks. The primary end points were the clinical benefit and treatment-related toxic effects assessment. Secondary end points were time-to-disease progression (TTP) and overall survival (OS). Results: The overall clinical benefit was 87.04%. World Health Organization G3–4 toxic effects included neutropenia (45%), anemia (44%), complete alopecia (83%), severe onycholysis and neuropathy. The 24% of patients developed left ventricular ejection fraction reduction but none >10% with recover after treatment completion. The median absolute decrease from baseline was 1%. Median TTP was 11 months and median OS was 23 months. Conclusions: Combined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design. Key words: dose dense, first-line breast cancer, NPLD
original article gene expression profile predicts response/resistance to anthracyclines, both in HER2(+) and HER2(2) patients [7]. Taken together, these data are not sufficient to determine the breast cancer target patient candidate to receive anthracycline in all settings. None of the study mentioned examined the role of liposomal anthracycline to overcome resistance. The present trial is the first study designed to investigate the outcome of a combined dose-dense non-pegylated liposomal anthracycline and taxane regimen in MBC.
patients and methods patients
received paclitaxel (50 mg/mq)/Myocet (25 mg/mq) on days 1, 8, and 15 every 4 weeks. Arm B (n = 24) received docetaxel (30 mg/mq)/Myocet (25 mg/mq) on days 1, 8, 15 every 4 weeks. No granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was used. Filgrastim was prescribed for those patients who developed febrile neutropenia as a s.c. 5 lg/kg daily injection for 3 days after the first event and continued on subsequent cycles. The primary phase II study end points were the rate of clinical benefit after six cycles of chemotherapy and treatment-related toxic effects assessment. The clinical benefit was defined as the rate of complete response (CR), partial response (PR) and stable disease (SD) lasting at least 6 months, evaluated by RECIST criteria and calculated for all patients with measurable disease. Secondary end points were TTP and OS. OS was calculated from the date of study entry to the date of death from any cause. Patients lost to follow-up or those with no date of death recorded were censored on the date of last follow-up. Kaplan–Meier survival curves were generated and median OS calculated for the ITT population with 95% confidence interval (CI). TTP was calculated from the date of study entry to the date of disease progression or death from any cause, whichever occurred first. Patients without a date of progression recorded were censored on the date of last follow-up. Surviving patients without disease progression were censored at the date last known to be progression free.
assessment Baseline evaluation included: physical examination, assessment of medical history, evaluation of PS and blood count. During the treatment, patients were evaluated before each cycle of therapy with the above parameters. All patients carried out an abdominal and thoracic computed tomography scan at baseline and every three cycles to assess tumor response. Tumor response and disease progression were assessed according to RECIST guidelines and confirmed as lasting longer than 4 weeks. After the end of the therapy, HER2(+) patients received trastuzumab until progression and they were followed every 3 months until progression. We defined adverse event (AE), any adverse change in health, or side-effect while the patients were receiving the study treatment or within 3 weeks of time after treatment completion. Toxicity was graded according to the National Cancer Institute (NCI)—Common Toxicity Criteria for AE (version 3.0). LVEF decrease was defined as a level lower than the institutional limit or an absolute 10% decrease from the patient’s baseline.
study design and treatment
statistical methods
We design a phase I–II prospective randomized trial. All the patients received a parenteral premedication regimen with: ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. the day before treatment and at day 1. The maximum tolerated dose (MTD) and dose-limiting toxicity were rapidly assessed through a phase I trial. A number of four consecutive patients was enrolled in paclitaxel (Taxol, Bristol Myers Squibb)/Myocet (Cephalon) arm: first three consecutive patients received paclitaxel (50 mg/mq)/Myocet (25 mg/mq) on days 1, 8 and 15 every 4 weeks for six cycles and no limiting toxic effects were recorded and then one patient (PS 0) received paclitaxel (60 mg/mq)/Myocet (25 mg/mq) on days 1, 8 and 15 every 4 weeks and developed severe febrile neutropenia with sepsis after the completion of the second cycle, so we defined paclitaxel (50 mg/mq)/Myocet (25 mg/mq) as the MTD. A number of five patients were enrolled in phase I docetaxel (Taxotere, Sanofi Aventis)/Myocet trial: the first three consecutive patients received docetaxel (30 mg/mq)/Myocet (25 mg/mq) and no dose-limiting toxic effects were recorded and then two patients received docetaxel (35 mg/mq)/Myocet (25 mg/mq) and the last enrolled patient developed severe febrile neutropenia with sepsis after the completion of the first cycle, so we define docetaxel (30 mg/mq)/Myocet (25 mg/mq) as the MTD. A total of 54 patients (included 7 patients who received full-dose treatment in phase I study) were randomly assigned to receive a combination of weekly paclitaxel/Myocet or docetaxel/Myocet in a 1 : 1 mode. Arm A (n = 30)
The study was planned to test an estimated rate of clinical benefit of 75%, with a type I error (a) of 0.05 and a power of 80% (1-b). This hypothesis required a sample size of 60 patients, taking into account a 10% of drop out. After cessation of treatment, patients without documented progression were followed every 3 months with clinical and radiological evaluation. OS and TTP distributions were plotted using the Kaplan–Meier method. Data were recorded and analyzed in a Medlogs database. All analyses were done on an intention-to-treat population. Comparison of survival curves were made with log-rank test. Because the study was not powered to address therapeutic effect within subsets of patients, comparisons within docetaxel and paclitaxel arms are exploratory only; differences between groups were analyze with v2 test; P value was considered significative for <0.05.
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results patients characteristics A total number of 56 patients were enrolled. Table 1 summarizes patients characteristics by stratification factors [i.e. hormone receptor (HR), HER2 status], demographics (age) and pre-treatment clinical characteristics.
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From January 2002 to June 2005, we enrolled 56 patients. Eligible patients were required to have measurable histologically proven MBC and at least one measurable lesion according to RECIST criteria, World Health Organization performance status (PS) zero to two, age between 18 and 75 years, estimated life expectancy of at least 3 months, adequate hepatic function [serum bilirubin < 1.5 · upper normal limit (UNL), transaminase < 3 · UNL; however, in cases of liver metastases, there were no upper limit for transaminases], adequate renal function (calculated creatinine clearance > 30 ml/min by the Cockroft and Gault formula) and adequate hematological function (neutrophil count > 1.5 · 109/l; platelets > 100 · 109/l). No prior chemotherapy for metastatic disease was allowed. Hormonal treatment of advanced or metastatic disease was allowed. All patients who had received anthracycline-containing regimen in adjuvant setting had to provide that 1 year had transpired from its completion to protocol entry. Median prior doxorubicin received dose was 379 mg/mq; median epirubicin dose was 446 mg/mq. Adequate renal, hepatic and hematologic parameters were required. A normal (50%–70%) baseline left ventricular ejection fraction (LVEF) assessed by echocardiogram within 30 days before the first cycle was required. Patients within class II New York Heart Association Classification cardiac disease were accrual; patients with severe congestive heart failure were excluded. Pregnant or lactating women were not included. The study was conducted according to the principles of the Declaration of Helsinki and all patients provided written informed consent.
Annals of Oncology
original article
Annals of Oncology
efficacy Table 2 summarizes overall clinical benefit from phase II trial. primary end point: clinical benefit. Table 3 summarizes the overall response rate (RR) for both Arms A and B. The overall clinical benefit was 87.04% (CR: 12.96%, PR: 66.67% and SD: Table 1. Demographic and disease characteristics of patients Characteristics
n
(%)
ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; CHT, chemotherapy; PgR, progesterone receptor; PS, performance status.
toxicity. Weekly schedule was very well tolerated. Hematologic toxicity was generally mild and it is summarized in Table 3. Grade 3 or worse granulocytopenia was recorded in 45 patients (83%) but febrile neutropenia was infrequent (n = 6 patients) and none but one patient in phase II trial required hospitalization. Nonhematologic toxic effects occurring with at least 5% incidence are summarized in Table 4. Moderate or severe sensory neuropathy was encountered in 40% and 5% of patients, respectively. Neuropathy was significantly greater in docetaxel arm than in paclitaxel arm (G1–2: 70% versus 16%, P = 0.007; G3–4: 12% versus 0%, P = 0.0001). Dose modification was required in 4% of patients with severe neuropathy. Slightly more patients receiving docetaxel experimented mucositis but differences were not significative. Otherwise, moderate-to-severe onycholysis was greater in docetaxel-treated patients (75% versus 13%, P = 0.0001)(see Table 5). Alopecia was frequent (83%) and generally complete. Other grades 3 and 4 nonhematologic toxic effects were rare, including serious hypersensitivity reactions, as a result of the all-parenteral premedication regimen employed. Limited data are available on the 25/30 HER2(+) patients who received trastuzumab after treatment completion. None of the patients received adjuvant trastuzumab because the study was designed when NCI guidelines did not recommend its use in adjuvant setting. The study was not designed to analyze differences between HER2(+)/HER2(2) groups. Notwithstanding, 2 of 25 (8%) HER2(+) patients developed grade 3 cardiac dysfunction while on trastuzumab treatment. None of the HER2(2) Table 3. Hematologic toxicity Toxicity grade
Patients (n = 54) 1–2 3–4 n (%) n (%)
Administrations (n = 786) 1–2 3–4 n (%) n (%)
Granulocytopenia NFN FN Trombocitopenia Anemia
41 35 – 8 28
257 209 – 104 155
(75) (64) (14) (51)
45 37 6 – 24
(83) (68) (11) (44)
(32) (26) (13) (19)
170 160 36 60 96
(21) (20) (4) (7) (12)
NFN, non-febrile neutropenia; FN, febrile neutropenia.
Table 2. Overall response, time to disease progression (TTP) and overall survival (OS)
CR (%) PR (%) SD (%) PD (%) Clinical benefit (%) TTP (months) OS (months) (%)
Patients (n = 54)
Myocet/paclitaxel (n = 30)
Myocet/docetaxel arm (n = 24)
P
12.96 66.67 7.41 12.96 87.04 11 23 (57.4%)
13.33 66.67 10 10 90 12 24
12.5 66.67 4.17 16.67 83.33 9 18
0.89 ns 0.11 0.3 0.3 0.5 0.3
CR, complete response; OS, overall survival; PR, partial response; TTP, time-to-disease progression.
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Total assessable patients 56 Demographics Median age (range) 56 years (45–67) Pre-menopausal 5 9 Clinicopathological characteristics ECOG PS 0 38 68 1 13 23 2 5 9 Type of cancer Ductal 36 64 Lobular 10 18 Mixed 10 18 Receptor status ER(+) 42 75 PgR(+) 33 59 HER2 (FISH +) 30 54 Prior CHT (neoadjuvant and adjuvant) Anthracycline 51 91 Taxane 13 23 Hormonotherapy 43 77 Adjuvant trastuzumab 6 11 Median cumulative anthracycline exposure in prior treatment (mg/mq) Epirubicin 350 Doxorubicin 381 Metastases (n) 1 18 32 ‡2 37 66 Sites of metastases Soft tissue 7 13 Nodes 12 21 Liver 33 59 Lung 4 7 Brain 2 4 Bone 38 68
7.41%) with a PD: 12.96%. The overall clinical benefit with weekly paclitaxel/Myocet was 90% (CR: 13.3, PR: 66.67 and SD: 10) and 83.33% with weekly docetaxel/Myocet (CR: 12.5%, PR: 66.67% and SD: 4.17%). No significative differences were noted between groups.
original article
Annals of Oncology
drug exposure. The median administration/patient ratio was 14.5 with a median cumulative non-pegylated liposomal doxorubicin exposure of 363 mg/mq/patient.
Table 4. Treatment related toxicity (non hematologic) Grade (WHO)
Patients (n = 54) 1–2 3–4 n (%) n (%)
Administrations (n = 786) 1–2 3–4 n (%) n (%)
Mucositis Neuropathy Astenia Nausea/vomiting Onycholysis Edema Allergic reaction Alopecia LVEF reduction
19 22 32 18 22 19 6 45 13
155 116 156 42 – – – – –
10 (18) 3 (5) 5 (9) –
(19) (14) (19) (5)
69 (8) 157 (19) 43 (5) –
Table 5. Non-hematologic related toxicity: subgroups analysis. Docetaxel Arm (D) versus Paclitaxel Arm (P) WHO grade
Docetaxel arm 1–2, 3–4, n (%) n (%)
Paclitaxel arm 1–2, 3–4, n (%) n (%)
P value
Onycholysis Mucositis
– 10 (41%)
18 (75%) 6 (25%)
– 9 (30%)
4 (13%) 4 (13%)
Neuropathy
17 (70%)
3 (12%)
5 (16%)
0
0.0001 0.2 0.08 0.007 0.0001
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40 20
5
0
10 Time
15
20
Figure 1. Time to progression analysis. In all eligible patients TTP was analyzed with the use of Kaplan-Meier method.
TTP 100
TREAT D P
80 60 40 20 0
0
5
10 Time
15
20
Figure 2. TTP subsets analysis: Paclitaxel Arm (P) versus Docetaxel Arm (D) (12 versus 9 months, HR: 1.4, 95% CI: 0.8–2.4, P = 0.01).
TTP
100
LVEF, left ventricular ejection fraction; WHO, World Health Organization.
WHO, World Health Organization.
60
0
Survival probability (%)
(35) (40) (59) (33) (40) (35) (11) (83) (24)
80
GROUP H NH
80 60 40 20 0
0
5
10 Time
15
20
Figure 3. TTP subsets analysis: HER2+ patients (H) versus HER22 patients (NH) (9 versus 12 months, HR: 0.9, 95% CI: 0.5–1.5, P = 0.64).
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overall survival. To a median follow-up of 29 months (Figure 4), the median OS was 23 months (57.4% of patients). Differences between two groups in terms of OS are not significative [Arm A versus B: 24 versus 18 months (HR: 1.3, 95% CI 0.7–2.4, P = 0.34)] (Figure 5).
Survival probability (%)
time-to-disease progression. Kaplan–Meier estimated TTP curves are represented in Figure 1. The median TTP was 11 months. Subsets analysis did not demonstrate advantage for Arm A over B (12 versus 9 months, HR: 1.4, 95% CI 0.8–2.4, P = 0.1) (Figure 2). TTP was 9 months in HER2(+) and 12 months in HER2(2) (HR: 0.9, 95% CI 0.5–1.5, P = 0.64); thus, the addition of trastuzumab after treatment completion in patients with HER2(+) breast cancer was not associated with significantly longer TTP (Figure 3).
TTP 100
Survival probability (%)
patients developed cardiac heart failure within the 12 months after treatment completion. There were no deaths attributable to cardiac toxicity. After the treatment completion, a LVEF reduction was encountered in the 24% of patients (n = 13) but it was never > 10%. The 24% of patients (n = 13) experimented a LVEF reduction after treatment completion but none of them developed a >10% decreased. The median absolute decrease from baseline was 1%. No treatment-related deaths occurred.
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Annals of Oncology OS
Survival probability (%)
100 90 80 70 60 50 40 30 20 0
5
10
15
20 25 Time
30
35
40
Figure 4. Overall survival in all eligible patients was analyzed with the use of the Kaplan-Meier method (median OS was 23 months).
OS 100
Survival probability (%)
80 70 60 50 40 30 20 10
0
5
10
15
20
25
30
35
40
Time Figure 5. Overall survival subset analysis (to be considered exploratory only). Paclitaxell Arm (P) versus Docetaxel Arm (D) (24 versus 18 months, HR 1.3, 95% CI: 0.7–2.4, P = 0.034).
discussion This phase II trial was designed to address the efficacy and safety of a combined weekly schedule of non-pegylated liposomal anthracycline and taxane in MBC. Use of anthracycline in advanced or metastatic disease was deeply debated in the recent years. Since the anthracycline-containing regimens are increasingly used in the adjuvant setting, retreatment, even if effective, is limited to patients exposed to low cumulative anthracycline doses and with a relapse-free survival longer than 12 months after adjuvant chemotherapy. One of the biggest issue in anthracycline rechallenge is the cumulative cardiotoxicity. However, few data are available on the efficacy of anthracycline rechallenge after prior adjuvant exposure. Some reports [8] showed that anthracycline–taxane combinations as first-line treatment of MBC are effective, regardless of previous adjuvant chemotherapy. Our data support the hypothesis that weekly combination of Myocet and taxane, improves the outcome with a modest toxicity profile, which represents the first goal in maintaining quality of life. In 54 assessable patients, the overall clinical benefit was 87.04 % (CR: 12.96%, PR: 66.67% and SD: 7.41%). Subgroups analysis showed a 90% (CR: 13.3%, PR: 66.67% and
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Treatment D P
90
SD: 10%) benefit in the paclitaxel arm and 83.33% (CR: 12.5%, PR: 66.67% and SD: 4.17%) with weekly docetaxel. It is noteworthy that responses were observed in patients with previous anthracycline exposure (94% of patients). Weekly combination of proved efficacy agents combined with different pharmaceutical strategy such as non-pegylated liposomal formulation seems to be able to overcome resistance and to improve treatment outcome. Although comparison between data from different trials has to be considered speculative, our results support the general idea that adding taxane to anthracycline can significantly improve the outcome. The clinical benefit of the combination of weekly Myocet and taxane in MBC is almost the 30% greater than what expected with Myocet alone [9]. Weekly administration of both the drugs resulted in a total of 75 mg/mq per cycle of Myocet with 150 and 90 mg/mq per cycle of paclitaxel or docetaxel, respectively. This intense dose-dense chemotherapy schedule seems to improve the outcome while reducing toxicity. In fact, the wALT study combinations appeared to be very well tolerated. Toxicity profile was generally mild and predominantly hematologic. At least one episode of severe granulocytopenia was recorded in 83% of patients. Primary prophylaxis with G-CSF is kindly recommended from the National Comprehensive Cancer Network (NCCN) guidelines when anthracycline is combined with taxane, especially in dose-dense regimen [10]. We decided not to use primary prophylaxis because we wanted to test if there were differences between conventional and liposomal anthracycline in terms of febrile neutropenia. Although severe granulocytopenia was frequent, febrile neutropenia was recorded in six patients only and none but one patient in phase II trial required hospitalization. The most frequent nonhematologic toxic effects were alopecia (83%), moderate asthenia (59%), peripheral neuropathy (40%) and mucositis (35%). Even the two groups were well balanced in terms of demographic characteristics, subsets analysis have to be considered exploratory only. However, significantly higher incidence of peripheral neuropathy (P = 0.007) and onycholysis (P = 0.0001) were recorded in docetaxel group. Cardiac toxicity was generally modest. None of the patient developed congestive heart failure. A number of 13/56 patients (24%) experimented LVEF reduction. However, the median absolute decrease from baseline was 1% only and LVEF reduction was never >10%, with complete recover after treatment completion. Our data confirm the safety of the cardiac profile of Myocet, which has been already demonstrated in a number of studies [11]. However, the present study has three major limitations: the slow accrual (in part due to patients selection criteria) and it was not powered to investigate differences in HER2 subtypes or to analyze other molecular predictors. To our knowledge, the present work represents the first attempt to combine weekly non-pegylated liposomal anthracycline and taxane. Even if NCCN guidelines recommended the use of trastuzumab [12] or bevacizumab [13] combined with taxane in first-line chemotherapy, our data demonstrated that Myocet/ taxane combination significantly improves the outcomes in unselected patients with MBC who strongly benefit anthracycline rechallenge with non-pegylated liposomal formulation. In the molecular age, anthracyclines still represent a valid therapeutic option. The encouraging results in terms of
original article TTP (11 months) and OS (23 months) deserve larger phase III trial confirmation.
disclosure MSR is a Cephalon consultant since February 2010. MDS received honoraria from Roche, Sanofi-Aventis and AmgenDompe`. No other conflicts of interest have been declared.
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