Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer

Figures & data

Figure 1 Mechanism of action of DOX and L-DOX.

Notes: Once L-DOX diffuses across the phospholipid bilayer of malignant cells, free DOX is released and it can be converted into a semiquinone or translocate into the nucleus or mitochondria. Conversion of DOX to a semiquinone causes the formation of ROS. DOX can also translocate to the nucleus where it intercalates between strands of DNA, inhibits topoisomerases I and II and activates PARP-1. In the mitochondria, DOX intercalates between strands of mitochondrial DNA and leads to the release of cytochrome C and the activation of caspases. Ultimately, damage to nuclear and mitochondrial DNA as well as that caused by ROS leads to apoptosis.
Abbreviations: DOX, doxorubicin; L-DOX, liposomal DOX; PARP, poly ADP ribose polymerase; ROS, reactive oxygen species.

Figure 2 PEGylated liposomal DOX (Doxil^®).

Notes: DOX is surrounded by a phospholipid bilayer (liposome) that is coated with methoxypolyethylene glycol. Enclosing DOX in a liposome helps decrease systemic side effects while PEGylation protects the liposomes from recognition by the mononuclear phagocyte system and increases its circulation time.
Abbreviation: DOX, doxorubicin.

Table 1 Pharmacokinetic properties of DOX and L-DOX

Parameter (unit)	Definition	DOX, min–max^Citation35	L-DOX, average ± SD^Citation36
CL (mL/min/m^2)	Plasma clearance	324–809	0.683±0.066
T1/2 (h)	Half-life	20–48	55±4.8
Vd (L/m^2)	Volume of distribution	809–1,214	2.72±0.12
Fb (%)	Fraction bound to plasma proteins	75a	Not determined

Note:

a Data shown as average.

Abbreviations: CL, clearance; DOX, doxorubicin; L-DOX, liposomal DOX; SD, standard deviation.

Table 2 Comparison of use, efficacy, and safety profiles of DOX and L-DOX

Criteria	DOX^Citation16,Citation21,Citation23	L-DOX^Citation16,Citation22,Citation24
Indications	Label: leukemia, bladder cancer, breast cancer, gastric cancer, sarcomas, small cell lung cancer among others	Label: Kaposi’s sarcoma, multiple myeloma, and ovarian cancer
	Off label: biliary tract cancer, endometrial cancer,	Off label: use for breast cancer, cutaneous
	Kaposi’s sarcoma, malignant melanoma	T-cell lymphoma
Maximum dose limits	Lifetime: up to 550 mg/m^2 IV	50 mg IV weekly
	Up to 450 mg IV if previous mediastinal radiation	Safety and efficacy have not been established in children and adolescents
Black box warnings	Bone marrow suppression, cardiotoxicity, extravasation	Cardiotoxicity and infusion-related reactions
Adverse effects	Cardiotoxicity	Palmar–plantar erythrodysesthesia
	Nausea/vomiting	Nausea/vomiting
	Alopecia	Alopecia
	Leukopenia/neutropenia	Cardiotoxicity
	Palmar–plantar erythrodysesthesia	Leukopenia/neutropenia

Abbreviations: DOX, doxorubicin; L-DOX, liposomal DOX; IV, intravenous.

Table 3 Clinical trials with L-DOX in combination with other chemotherapeutics in breast cancer

Drugs	Clinical trial	Main findings	References
PLD and bevacizumab	Phase II	46% of patients had grade three toxicities	^Citation37
- 20 mg/m^2 PLD and 10 mg/kg bevacizumab given days 1 and 15 of 4-week cycle		ORR: 21%
		Median PFS: 5.7 months
		Median OS: 15.9 months
		Severe cardiotoxicity in one patient 4.7 months after treatment
PLD and bortezomib	Phase II	ORR: 8%	^Citation38
- 1.3 mg/m^2 bortezomib days 1, 4, 8, and 11 and 30 mg/m^2 PLD day 4 of 21-day cycle		Median OS: 4.3 months
		Median TTP: 1.3 months
		No cardiotoxicity reported despite prior anthracycline use in 77% of patients
PLD and carboplatin (+ trastuzumab if HER2+)	Phase II	PLD/carboplatin	^Citation39
		1A: taxane naive
30 mg/m^2 PLD and carboplatin AUC = 5 mg^*min/mL day 1 of 21-day cycle		ORR: 31%
		Median PFS: 8 months
If HER2+ also got 8 mg/kg loading dose of trastuzumab and then 4 mg/kg days 1 and 15 of 28-day cycle		1B: taxane pretreated
		ORR: 31%
		Median OS: 13 months
		Median PFS: 5 months
		PLD/carboplatin/trastuzumab
		ORR: 56%
		Median OS: 33 months
		Median PFS: 10 months
		No clinically significant cardiotoxicity. Declines in LVEF of at least
		15% in two patients in arm 1A and one patient in trastuzumab arm
PLD, cisplatin, infusional 5-FU, and trastuzumab	Phase II	Clinical response rate: 94%	^Citation31
		2-year DFS: 94%
25 mg/m^2 PLD, 60 mg/m^2 cisplatin day 1 and 200 mg/m^2 5-FU as a continuous infusion days 1–21 of 21-day cycle 8 mg/kg trastuzumab loading dose then 6 mg/kg on day 2 of cycle		No relevant cardiotoxicity – two patients had asymptomatic, transient declines in LVEF of at least 20%, but absolute LVEF was maintained above 50% in both cases
PLD and cyclophosphamide	Phase II	Objective response: 51%	^Citation40
Cohort I: 50 mg/m^2 PLD day 1 and 100 mg/m^2 cyclophosphamide orally days 1–14 (28-day cycle)		Clinical benefit rate (complete response + partial response + stable disease): 86%
		Median DOR: 35.1 weeks
Cohort II: 30 mg/m^2 PLD and 600 mg/m^2 cyclophosphamide day 1 of 21-day cycle		Median time-to-tumor progression: 34.4 weeks
		No clinical cardiotoxicity or significant declines in median LVEF following treatment
Cohort III: 35 mg/m^2 and 600 mg cyclophosphamide day 1 of 21-day cycle
PLD and cyclophosphamide (in elderly patients between 65–75 years old)	Phase II	Objective response rate: 28.6%	^Citation41
		Median PFS: 8.8 months
- 40 mg/m^2 PLD and 500 mg/m^2 cyclophosphamide day 1 of 4-week cycle		Median OS: 20.3 months
		Mucositis, myelosuppression in the elderly
		No reported cardiac toxicity or significant changes in LVEF
PLD, cyclophosphamide, and 5-FU	Phase II	ORR: 41.9%	^Citation42
- 40 mg/m^2 PLD, 500 mg/m^2 cyclophosphamide, and 500 mg/m^2 5-FU on day 1 of 21-day cycle		Median PFS: 8.2 months
		Median OS: 36.6 months
		No significant changes in LVEF, even after prior anthracycline exposure
PLD, cyclophosphamide, and paclitaxel	Phase II	Overall pCR: 32%	^Citation43
- 35 mg/m^2 PLD, 600 mg/m^2 cyclophosphamide every 4 weeks, and 80 mg/m^2 paclitaxel weekly		Radiological ORR: 26%
		5-year PFS: 58%
		5-year OS: 62%
		No significant declines in LVEF or ECG changes; five cardiac events reported
PLD, cyclophosphamide, and trastuzumab	Phase II	Objective response rate: 68.8%	^Citation27
		Median OS: 34.2 months
50 mg/m^2 PLD and 600 mg cyclophosphamide every 4 weeks		Median TTP: 12 months
		No symptomatic CHF; declines in LVEF observed in eight of the
4 mg/kg trastuzumab loading dose then 2 mg/kg weekly		48 patients and reversed in seven patients (six of them had prior anthracycline exposure)
PLD, cyclophosphamide, docetaxel, and trastuzumab (if HER2+)	Phase II	Objective response rate: 83%	^Citation44
		pCRT: 13%
35 mg/m^2 PLD and 600 mg cyclophosphamide on day 1 of 21-day cycle		Normal LVEF maintained during the study
100 mg/m^2 docetaxel day 1 of 21-day cycle
If HER2+ got 8 mg/kg loading dose of trastuzumab then 6 mg/kg day 1 of 21-day cycles
PLD and docetaxel	Phase II	Overall clinical benefit: 47%	^Citation45
Group A: 35 mg/m^2 PLD on day 1 and 40 mg/m^2 docetaxel days 1 and 15 of 28-day cycle		ORR: 49%
		High rates of toxicity in both groups
		No significant cardiotoxicity
Group B: 30 mg/m^2 PLD day 1 and 75 mg/m^2 docetaxel day 2 (3-week cycle)
PLD and docetaxel (trastuzumab if HER2+)	Phase II	PLD/docetaxel	^Citation46
		ORR: 47.4%
Group A: 30 mg/m^2 PLD and 60 mg/m^2 docetaxel every 3 weeks		Median PFS: 11 months
		Median OS: 24.6 months
Group B: 30 mg/m^2 PLD, 60 mg/m^2 docetaxel every 3 weeks, and 4 mg/kg trastuzumab loading dose then 2 mg/ kg weekly		PLD/docetaxel/trastuzumab
		ORR: 45.7%
		Median PFS: 10.6 months
		Median OS: 31.8 months
		Higher rates of hand foot syndrome
		Incidence of CHF <3% and the addition of trastuzumab did not increase CHF risk
PLD and docetaxel vs docetaxel (in patients who experienced a relapse following adjuvant anthracycline use)	Phase III	PLD/docetaxel	^Citation47
		Objective response rate: 35%
		Median TTP: 9.8 months
- 30 mg/m^2 PLD and 60 mg/m^2 docetaxel (21-day cycle) vs 75 mg/m^2 docetaxel (21-day cycle)		Median OS: 20.5 months
		Docetaxel
		Objective response rate: 26%
		Median TTP: 7 months
		Median OS: 20.6 months
		No significant increase in CHF incidence or LVEF decline with the addition of PLD
PLD and GEM	Phase II	ORR: 47.8%	^Citation48
- 25 mg/m^2 PLD day 1 and 800 mg/m^2		Median TTP: 7 months
GEM on days 1 and 8 of 21-day cycle		Median duration of clinical benefit: 8 months
		Mild cardiac toxicity in 4% patients; it was recovered after the end of the study
PLD and GEM	Phase II	ORR: 52%	^Citation49
- 24 mg/m^2 PLD day 1 and 800 mg/m^2 GEM days 1 and 8 (21-day cycle)		Median OS: 16.1 months
		Median TTP: 4.5 months
		Clinical benefit: 78%
		Minimal cardiotoxicity, with a transient decline in LVEF in one patient, who recovered after the end of the study
PLD and GEM	Phase II	ORR: 39.1%	^Citation50
- 25 mg/m^2 PLD and 800 mg/m^2 GEM days 1 and 8 of 21-day cycle		Median TTP: 11 months
		Overall clinical benefit: 85.9%
		Only one case of cardiac toxicity was observed, despite 41% of patients having undergone prior anthracycline therapy
PLD, GEM and docetaxel	Phase II	ORR: 74%	^Citation51
- 1,000 mg/m^2 GEM on day 1 followed by 800 mg/m^2 GEM, 75 mg/m^2 docetaxel, and 30 mg/m^2 PLD on day 8 (3-week cycles)		No cardiotoxicity was observed as per protocol-defined criteria and all patients maintained LVEF >50%
PLD and lapatinib	Phase II	ORR: 54%	^Citation52
- 1,250 mg lapatinib daily and 40 mg/m^2		Median PFS: 5.8 months
PLD every 4 weeks		Median OS: 23.3 months
		No cardiac events were observed
PLD (low dose) and paclitaxel	Phase II	Objective response rate: 74%	^Citation53
- 15 mg/m^2 PLD every other week and 80 mg/m^2 paclitaxel weekly		9% pathological complete response on breast and axilla
		55% had breast conserving surgery
		No impairment of cardiac function was observed
PLD and paclitaxel	Phase II	Objective response rate: 80%	^Citation54
- 30 mg/m^2 PLD and 175 mg/m^2 paclitaxel (3-week cycles)		Median duration of objective response: 31 weeks
		Median time to treatment failure: 45 weeks
		Decline in LVEF was observed in eight of the 26 patients; however, no clinical signs or symptoms of cardiac toxicity/failure were observed
PLD and trastuzumab	Phase II	Clinical benefit: 50%	^Citation30
- 40 mg/m^2 PLD every 4 weeks and 4 mg/kg trastuzumab loading dose then 2 mg/kg weekly		Median PFS: 9.67 months
		Median OS: 16.23 months
		Three of the 16 patients developed decline in LVEF; a clinically relevant and symptomatic decrease occurred in only one patient
PLD and trastuzumab	Phase II	ORR: 52%	^Citation28
- 50 mg/m^2 PLD every 4 weeks and 4 mg/kg trastuzumab loading dose then 2 mg/kg weekly		Median DOR: 11.1 months
		Median PFS: 12 months
		10% of the patients developed protocol-defined cardiotoxicity, albeit without any symptoms of CHF
PLD and trastuzumab	Phase II	ORR: 22%	^Citation55
- 30 mg/m^2 PLD and 8 mg/kg trastuzumab loading dose then 6 mg/kg (3-week cycles)		Median PFS: 6.5 months
		Median OS: 18.7 months
		Severe cardiotoxicity as per protocol-defined criteria was not recorded. Median LVEF was maintained at 62% throughout the study
PLD and VNB	Phase II	Objective response rate: 36%	^Citation56
- 30 mg/m^2 PLD day 1 and 20 mg/m^2		Median PFS: 6.7 months
VNB on days 1 and 8 (3-week cycles)		Median OS: 13.2 months
		No cardiotoxicity was observed
PLD and VNB	Phase II	ORR: 39%	^Citation29
- 40 mg/m^2 PLD day 2 and 25 mg/m^2		Median TTP: 6.5 months
VNB on days 1 and 15 (4-week cycles)		Median OS: 14.5 months
		Four of the 36 patients developed a decline in LVEF (>15%); all four had received prior anthracycline treatment. There were no clinical symptoms of cardiac failure
PLD and VNB	Phase II	ORR: 35%	^Citation57
- 35 mg/m^2 PLD day 1 and 30 mg/m^2		Median TTP: 7 months
VNB day 1 (4-week cycles)		Median OS: 13 months
		Three of the 33 patients had a significant decline in LVEF (<50%); none had clinical cardiac symptoms and cardiac function recovered for two patients after cessation of treatment
EPI/VNB vs PLD/VNB	Phase II	EPI/VNB:	^Citation58
- 90 mg/m^2 EPI day 1 and 25 mg/m^2		ORR: 42.6%
VNB days 1 and 5 (21-day cycle)		Median PFS: 10.7 months
40 mg/m^2 PLD day 1 and 30 mg/m^2		Median OS: 34.6 months
VNB days 1 and 15 (4-week cycles)		PLD/VNB:
		ORR: 52%
		Median PFS: 8.8 months
		Median OS: 24.8 months
		No cases of CHF, two transient LVEF decreases in arm EPI/VNB that resolved in 2 months

Abbreviations: 5-FU, 5-fluorouracil; AUC, area under the concentration curve; CHF, congestive heart failure; DFS, disease-free survival; DOR, duration of response; ECG, electrocardiogram; EPI, epirubicin; GEM, gemcitabine; HER2, human epidermal growth factor receptor 2; L-DOX, liposomal doxorubicin; LVEF, left ventricular ejection fraction; ORR, overall response rate; OS, overall survival; pCR, pathological complete response; pCRT, total pathological complete response; PFS, progression-free survival; PLD, PEGylated L-DOX; TTP, time to progression; VNB, vinorelbine.

Doxorubicin full prescribing information [webpage on the internet]DAILYMED Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1fd148fb-0fbc-4b6f-b790-23546fb46a71#section-11.2Accessed August 20, 2018

 Google Scholar

Doxil full prescribing information [webpage on the internet]DAILYMED Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21d9c619-7e94-49e2-ac41-31e9ea96554a#section-11.2Accessed August 20, 2018

 Google Scholar

O’BrienMEWiglerNInbarMCAELYX Breast Cancer Study GroupReduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancerAnn Oncol200415344044914998846

 PubMed Web of Science ®Google Scholar

FribergLEKarlssonMOMechanistic models for myelosuppressionInvest New Drugs200321218319412889739

 PubMed Web of Science ®Google Scholar

MinamiHSasakiYSaijoNIndirect-response model for the time course of leukopenia with anticancer drugsClin Pharmacol Ther19986455115219834043

 PubMed Web of Science ®Google Scholar

FribergLEHassanSBLindhagenELarssonRKarlssonMOPhar-macokinetic-pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre modelEur J Pharm Sci200525116317315854812

 PubMed Web of Science ®Google Scholar

FribergLEBrindleyCJKarlssonMODevlinAJModels of schedule dependent haematological toxicity of 2’-deoxy-2’-methylidenecytidine (DMDC)Eur J Clin Pharmacol200056856757411151746

 PubMed Web of Science ®Google Scholar

RochlitzCRuhstallerTLerchSSwiss Group for Clinical Cancer Research (SAKK)Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)Ann Oncol2011221808520595448

 PubMed Web of Science ®Google Scholar

IrvinWJOrlowskiRZChiuWKPhase II study of bortezomib and pegylated liposomal doxorubicin in the treatment of metastatic breast cancerClin Breast Cancer201010646547021147690

 PubMed Web of Science ®Google Scholar

ColleaRPKruterFWCantrellJEPegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II studyAnn Oncol201223102599260522431702

 PubMed Web of Science ®Google Scholar

TorrisiRCardilloACancelloGPhase II trial of combination of pegylated liposomal doxorubicin, cisplatin, and infusional 5-fluorouracil (CCF) plus trastuzumab as preoperative treatment for locally advanced and inflammatory breast cancerClin Breast Cancer201010648348821147693

 PubMed Web of Science ®Google Scholar

OvermoyerBSilvermanPHolderLWTripathyDHendersonICPegylated liposomal doxorubicin and cyclophosphamide as first-line therapy for patients with metastatic or recurrent breast cancerClin Breast Cancer20056215015716001993

 PubMedGoogle Scholar

KurtzJERousseauFMeyerNPhase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in older metastatic breast cancer patientsOncology2007733–421021418424884

 PubMed Web of Science ®Google Scholar

RauKMLinYCChenYYPegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II studyBMC Cancer20151542325994543

 PubMed Web of Science ®Google Scholar

Gil-GilMJBelletMMoralesSPegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE studyBreast Cancer Res Treat2015151359760625981896

 PubMed Web of Science ®Google Scholar

MartínMSánchez-RoviraPMuñozMGEICAMPegylated liposomal doxorubicin in combination with cyclophosphamide and trastuzumab in HER2-positive metastatic breast cancer patients: efficacy and cardiac safety from the GEICAM/2004-05 studyAnn Oncol201122122591259621421542

 PubMed Web of Science ®Google Scholar

TuxenMKColdSTangeUBBalslevENielsenDLPhase II study of neoadjuvant pegylated liposomal doxorubicin and cyclophosphamide ± trastuzumab followed by docetaxel in locally advanced breast cancerActa Oncol201453101440144524991893

 PubMed Web of Science ®Google Scholar

de La FouchardièreCLargillierRGoubelyYDocetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLEAnn Oncol200920121959196319556321

 PubMed Web of Science ®Google Scholar

WolffACWangMLiHPhase II trial of pegylated liposomal doxorubicin plus docetaxel with and without trastuzumab in metastatic breast cancer: Eastern Cooperative Oncology Group trial E3198Breast Cancer Res Treat2010121111112020333545

 PubMed Web of Science ®Google Scholar

SparanoJAMakhsonANSemiglazovVFPegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III studyJ Clin Oncol200927274522452919687336

 PubMed Web of Science ®Google Scholar

FabiAFerrettiGPapaldoPPegylated liposomal doxorubicin in combination with gemcitabine: a phase II study in anthracycline-naïve and anthracycline pretreated metastatic breast cancer patientsCancer Chemother Pharmacol200657561562316163541

 PubMed Web of Science ®Google Scholar

RiveraEValeroVArunBPhase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancerJ Clin Oncol200321173249325412947059

 PubMed Web of Science ®Google Scholar

AdamoVLorussoVRosselloRPegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II studyBr J Cancer200898121916192118493232

 PubMed Web of Science ®Google Scholar

ArtioliGGraziaAMocellinSPhase II study of neoadjuvant gemcitabine, pegylated liposomal doxorubicin, and docetaxel in locally advanced breast cancerAnticancer Res20103093817382120944176

 PubMed Web of Science ®Google Scholar

PircherMMlineritschBFridrikMALapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trialAnticancer Res201535151752125550597

 PubMed Web of Science ®Google Scholar

RossiDBaldelliAMCasadeiVNeoadjuvant chemotherapy with low dose of pegylated liposomal doxorubicin plus weekly paclitaxel in operable and locally advanced breast cancerAnticancer Drugs200819773373718594216

 PubMed Web of Science ®Google Scholar

VorobiofDARapoportBLChasenMRFirst line therapy with paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) in patients with metastatic breast cancer: a multicentre phase II studyBreast200413321922615177425

 PubMed Web of Science ®Google Scholar

StickelerEKlarMWatermannDPegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trialBreast Cancer Res Treat2009117359159819156515

 PubMed Web of Science ®Google Scholar

ChiaSClemonsMMartinLAPegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trialJ Clin Oncol200624182773277816682726

 PubMed Web of Science ®Google Scholar

ChristodoulouCKostopoulosIKalofonosHPStudy of the Hellenic Cooperative Oncology GroupTrastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer. Phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluationOncology200976427528519262067

 PubMed Web of Science ®Google Scholar

ChowLWYipAYLangBHA phase II trial of vinorelbine and pegylated liposomal doxorubicin in patients with pretreated metastatic breast cancerAm J Clin Oncol200730213313817414461

 PubMed Web of Science ®Google Scholar

ArdavanisAMavroudisDKalbakisKPegylated liposomal doxorubicin in combination with vinorelbine as salvage treatment in pretreated patients with advanced breast cancer: a multicentre phase II studyCancer Chemother Pharmacol200658674274816718470

 PubMed Web of Science ®Google Scholar

MartinMGarcía-DonasJCasadoAPhase II study of pegylated liposomal doxorubicin plus vinorelbine in breast cancer with previous anthracycline exposureClin Breast Cancer20045535335715585072

 PubMedGoogle Scholar

ViciPColucciGGiottaFA multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM studyJ Exp Clin Cancer Res2011303921481280

 PubMed Web of Science ®Google Scholar