Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi...

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Highlights in the Management of Breast Highlights in the Management of Breast Cancer Cancer Nanoparticles incapsulated drugs Nanoparticles incapsulated drugs Alessandra Fabi Alessandra Fabi Medical Oncology Medical Oncology Rome, 10 May Rome, 10 May 2013 2013 Mediterranean School of Mediterranean School of Oncology Oncology

Transcript of Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi...

Page 1: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Highlights in the Management of Breast Highlights in the Management of Breast CancerCancer

Nanoparticles incapsulated drugs Nanoparticles incapsulated drugs

Alessandra FabiAlessandra Fabi

Medical OncologyMedical Oncology

Rome, 10 May Rome, 10 May 20132013

Mediterranean School of Mediterranean School of OncologyOncology

Page 2: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Trasmission electronic Trasmission electronic Microscopy of nab-Microscopy of nab-

paclitaxel paclitaxel nanoparticlesnanoparticles

Piccart, APJOH 2009 Piccart, APJOH 2009

Page 3: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel

Nab-paclitaxel is Albumin-bound Cremophor-free Paclitaxel

Paclitaxel

Albumin

Mean = 130 nm

cryo-TEM

Concentration dependent dissociation into individual

paclitaxel-bound albumin molecules

Paclitaxel exists in the

albumin particle

in an non-crystalline,

amorphous state

Page 4: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24

Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)

Breast MX-1 tumor modelBreast MX-1 tumor modelequidose paclitaxel comparisonequidose paclitaxel comparison

0 10 20 30 40 50 60 70 80 90 100 1100

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ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

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ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

Days postimplant

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m3 )

Abraxane 30 mg/kg/dose

Taxol 30 mg/kg/dose

0 10 20 30 40 50 60 70 80 90 100 1100

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ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

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m3 )

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Taxol 30 mg/kg/dose

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Tum

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m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

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ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

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Tum

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olum

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m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

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1000

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1750

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ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

Abraxane 30 mg/kg/dose

Taxol 30 mg/kg/dose

Preclinical Finding: Replacing Cremophor with Albumin Enhanced the Efficacy of Paclitaxel in Breast Cancer

Page 5: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Nab-paclitaxel Results in Higher Intra-tumoral Concentration Compared to Taxol

ABI-007 = 1.33 X TaxolABI-007 = 1.33 X Taxol

Desai et al. Clin Can Res, 2006.Desai et al. Clin Can Res, 2006.

Intratumor paclitaxel levels following equal doses ABI-007 and Taxol Intratumor paclitaxel levels following equal doses ABI-007 and Taxol in nude mice bearing MX-1 human breast cancer xenograftsin nude mice bearing MX-1 human breast cancer xenografts

Page 6: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Nab-paclitaxel

✔✔ Clinical dataClinical datamono and combination: efficacy and mono and combination: efficacy and

toxicity in toxicity in breast cancerbreast cancer

Is there the patient Is there the patient who could better benefit??

Future directionsFuture directions

The other clinical fieldsThe other clinical fields

Page 7: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Studies Study Arm Standard Arm End-point

Patients

Gradishar 05

Fase III

NAB-P;260 mg/mq q3W

Paclitaxel175 mg/mq q3w

ORR 1-2+ line;Previous AnthracyclineNo previous taxanes

Gradishar 09

R Fase II

NAB-P300 mg/mq q3w100 mg/mq 3q4w150 mg/mq 3q4w

Docetaxel100mg/mq q3w

ORR 1 line;No previous therapy;Adjuvant 1 year before

clinical data in BC

Nab-paclitaxel as single agent

Page 8: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Phase III Random (1:1)n = 460

nab-paclitaxel 260 mg/m2

Every 3 weeksn = 233

paclitaxel 175 mg/m2 Every 3 weeks

n = 227

Misurable diseaseNo taxanes for metastatic diseaseDFI >1 y from adjuvant taxanes

Gradishar et al. J Clin Oncol 2005; 23:7794-803

Primary end point: ORr, SafetyPrimary end point: ORr, Safety

Secondary end-poit: PFS, OSSecondary end-poit: PFS, OS

Page 9: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Previous Therapies

nab-Paclitaxel

n=229

Paclitaxeln=225

Taxanes Adjuvant or metastatic with taxanes 0% 0%

Adjuvant or metastatic Anthracyclines 77% 78%

Metastatic Anthracycline 50% 58%Previous MBC CT

Nihil1 2 ≥ 3

42%41%10%7%

40%43%16%2%

Gradishar et al. J Clin Oncol 2005; 23:7794-803

Page 10: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Response rateResponse rate

nab-paclitaxel: 229 97 132 176 176paclitaxel: 225 89 136 175 182

ORR, tasso di risposta globale

All patients I line II line anthracyclines visceral disease

P=0,001

0

10

20

30

40

50

60

33,2%

27,0%

42,3%

18,7%

P=0,029

26,5%

13,2%

P=0,006

34,1%

18,3%

33,5%

P=0,002 P=0,002

18,7%

ORR

(± IC

al 9

5%)

Gradishar et al. J Clin Oncol 2005; 23:7794-803

Page 11: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

1.00

0.75

0.50

0.25

0.00

Time To disease Progression

Note: P value log-rank test

NAB-P (n = 229)

Solvent-based paclitaxel (n = 224)

Median = 23.0 wks(19.4–26.1)

Mediana = 16.9 wks(15.1–20.9)

P = 0.006HR = 0.75

Pro

po

rtio

n w

tho

ut

pro

gre

ssio

n

weeks

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120

Gradishar et al. J Clin Oncol 2005; 23:7794-803

Page 12: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Overall SurvivalOverall Survival

Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803

Note: P value log-rank test

Median = 65.0 wks(52.1–76.9)

NAB-P (n = 229)

Solvent-based paclitaxel (n = 225)

1.00

0.75

0.50

0.25

0.00

Pro

bab

ilit

y o

f s

urv

iva

l

weeks

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144

Median = 55.7 wks(48.0–66.4)

P = 0.374HR = 0.90

Page 13: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

1.00

0.75

0.50

0.25

0.00

weeks

0 8 16 24 32 40 48 56 64 72 80 88 96 104112120128136144

Overall Survival in pts ≥ 2a-line

Note: P value log-rank test

Nab-P (n = 131)

Solvent-based paclitaxel (n = 136)

P = 0.024HR = 0.73

Median = 46.7 wks(39.0–55.3)

Median = 56.4 wks(45.1–76.9)

Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803

Pro

bab

ilit

y o

f s

urv

iva

l

Page 14: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

SafetySafetynab-Paclitaxel

n=229Paclitaxel

n=225

AE (%) Grade Grade

3 4 3 4 p

Neutropenia 25 9 32 22 < 0,001

Thrombocytopenia < 1 0 < 1 0 0,290

Anemia < 1 < 1 0 < 1 0,279

Febbrile Neutropenia < 1 < 1 < 1 0 0,491

Death for sepsis 0 0 –

Gradishar et al. J Clin Oncol 2005; 23:7794-803

nab-Paclitaxel

n=229

Paclitaxel n=225

AE (%) Grade Grade p

2 3 4 2 3 4

Ipersensibility† < 1 0 0 0 1 0 0,150

Hot flash < 1 0 0 5 0 0 < 0,001

Sensorial Neuropaty 20 10 0 10 2 0 < 0,001

Fatigue 13 8 < 1 16 3 < 1 0,062

Mialgie 12 7 0 15 2 0 0,567

Emesis 4 3 < 1 4 1 0 0,022

Aedema 2 0 0 < 1 < 1 0 0,851

Page 15: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Neuropaty and nab-paclitaxel : time of Neuropaty and nab-paclitaxel : time of durationduration

1,00

0,75

0,50

0,25

0,00Days from grade 3 to 1

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140

% o

f u

nre

so

lve

d c

as

es

nab-Paclitaxel (n=24)

++

++

++++

● improvement: medain 22 days (95%CI 17-22) vs 79 days of paclitaxel

● 3% of pts (6/233) discontinued therapy with nab-paclitaxel due to sensorial neuropaty. No case of motor neuropaty

Gradishar et al. J Clin Oncol 2005; 23:7794-803

Page 16: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for MBC

302 MBC pts in I line therapy

Braccio A (n = 76): nab-paclitaxel 300 mg/m2 ogni 3 settimane

Braccio B (n = 76): nab-paclitaxel 100 mg/m2 alla settimana

x 3/ogni 4 settimane

Braccio C (n = 74): nab-paclitaxel 150 mg/m2 alla settimana x 3/ogni 4 settimane

Braccio D (n = 74): docetaxel 100 mg/m2 ogni 3 settimane

R

A

N

D

O

M

I

Z

E

nab-paclitaxel versus docetaxel(A,B,C vs D)

nab-paclitaxelqw versus q3w(B,C vs A)nab-paclitaxel bassa vs alta dose qw(B vs C)

Comparing

Endpoint primario: ORR

Arms A, C e D somministrati alla MTD3q4w, ripetuta wkly per 3 wks / 4 Gradishar et al. J Clin Oncol 2009;27:3611–3619

Page 17: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Response RateResponse Rate

Gradishar et al. J Clin Oncol 2009;27:3611–3619

37

4549

35

46

63

74

39

0

10

20

30

40

50

60

70

80

300 mg/m2 q3w 100 mg/m2 qw 150 mg/m2 qw 100 mg/m2 q3w

Independent

Investigator

P=0.024

P<0.001P=0.002

% o

f p

atie

nts

nab-Paclitaxel Docetaxel

n=302

*

° nab-paclitaxel 150 mg/m2 versus docetaxel P = 0,001* nab-paclitaxel 100 mg/m2

versus docetaxel P = 0,002

Page 18: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Progression Free Survival

Gradishar et al. J Clin Oncol 2009;27:3611–3619

Page 19: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Overall Survival

1.00

0.75

0.50

0.25

010 20 30 40 50

Months

0

HR = 0.688

1. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619.

• The 150 mg/m2 qw NAB-paclitaxel arm demonstrated a numerically longer OS versus docetaxel (not statistically significant)

NAB-paclitaxel 300 mg/m2 q3w and 100 mg/m2 qw arms not shownOS calculated when 58% of patients had died.HR, hazard ratio; OS, overall survival; qw 3/4, first 3 of 4 weeks; q3w, every 3 weeks.

NAB-paclitaxel 150 mg/m2 qw 3/4 (n = 74)

Docetaxel 100 mg/m2 q3w (n = 74)

26.6 33.8

For the purpose of clarity, only these 2 (out of 4) patient groups were

included here.

+7.2+7.2

Page 20: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

qw or q3w ABRAXANE® vs q3w docetaxel: toxicity†

Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.

ABRAXANE® Docetaxel

300 mg/m2 q3w (n = 76)

100 mg/m2 qw (n = 76)

150 mg/m2 qw (n = 74)

100 mg/m2 q3w (n = 74)

Neuropatia, n (%)

grade 2 17 (22) 11 (14) 19 (26) 14 (19)

grade 3 13 (17) 6 (8) 10 (14) 9 (12)

grade 4 0 (0) 0 (0) 0 (0) 0 (0)

Fatigue, n (%)

grade 2 17 (22) 5 (7) 15 (20) 12 (16)

grade 3 4 (5) 0 (0) 2 (3) 14 (19)

grade 4 0 (0) 0 (0) 0 (0) 0 (0)

† reported in ≥ 25% of patients

Page 21: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

ASCO Breast Symposium, Abstract # 275

nab-paclitaxel 150 mg/m2 qw ¾ demonstreted the best as I line MBC

Final Overall Survival Analysis of a Randomized Phase 2 Trial

Page 22: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

O’Shaughnessy et al, Poster P1-12-07, San Antonio 2012

Who patients could better benefit

Visceral metastasesVisceral metastasesShort DFIShort DFI

Page 23: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Weekly nab-paclitaxel is safe and effective in 65 years old patientswith metastatic breast cancer:

A post-hoc analysis

Matti Aapro, Sergei Tjulandin, Paul Bhar, William Gradishar

Page 24: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

ORr - DCR

In the phase 2 study

ORR nab-paclitaxel 22% 300 mg/m2 q3w

64% 100 mg/m2 weekly

60% 150 mg/m2 weekly

docetaxel 32% 100 mg/m2 q3w

In the phase 3 study

ORR nab-paclitaxel 27% 260 mg/m2 q3w

paclitaxel 19% 175 mg/m2 q3w

Aapro M et al, The Breast 2011

In the phase 2 study

DCR nab-paclitaxel 56% 300 mg/m2 q3w

86% 100 mg/m2 weekly

90% 150 mg/m2 weekly

docetaxel 79% 100 mg/m2 q3w

In the phase 3 study

DCR nab-paclitaxel 53 % 260 mg/m2 q3w

paclitaxel 41% 175 mg/m2 q3w

Page 25: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

PFS

In the phase 3 study

PFS median nab-paclitaxel 5.6 260 mg/m2 q3w

paclitaxel 3.5 175 mg/m2 q3w

Aapro M et al, The Breast 2011

In the phase 2 studyPFS median nab-paclitaxel 13.8 300 mg/m2 q3w

9.2 100 mg/m2 weekly 18.9 150 mg/m2 weekly

docetaxel 8.5 100 mg/m2 q3w

Page 26: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Combination therapy

Page 27: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Phase II combinationsPhase II combinationsNab-P + gemcitabine

I line ORr 50%PFS 7.9 mos

Roy et al. Ann Oncol 2009;20:449–453

Nab-P + capecitabine

I line ORr 61%PFS 8.2 mos

Somer et al. Presented at ASCO Meeting 2007; Abstract 1053

Nab-P + trastuzumab + carboplatin

I lineHER2+

ORr 63%PFS 16.6 mos

Conlin et al. Clin Breast Cancer 2010; 281-7

Nab-P + lapatinib II lineHER2+

ORr 54%PFS 9.3. mos

Yardley et al. SABCS 2011

Nab-P + Bevacizumab

I line ORr 75.9%PFS 10.7 mos

Lobo et al. Breast Cancer Res Treat 2010

Page 28: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Considerations

• The actual indication of NAB-paclitaxel is at three-weekly

schedule (260 mg/m2), but the evidences justify the weekly

administration (150, 125, 100 mg/m2 )

• Clinical data support the use of NAB-paclitaxel in MBC from the

1- line, also for pts pretreated with taxanes in adjuvant

setting, relapsed or refractory

• The sensorial neuropaty usual occur late in course of

treatment, and it can be manage with dose reduction, short drug

interruption and rapidly improve

• Future marker will be evaluated, such as caveolin and SPARC

Page 29: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Future DirectionsFuture Directions

Targeted therapyTargeted therapy

Piccart, APJOH 2009 Piccart, APJOH 2009

Page 30: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Phase III in first - line Phase III in first - line NSCLC: NSCLC: nabnab-Paclitaxel + -Paclitaxel + carboplatin demonstrated carboplatin demonstrated improved activity vs improved activity vs conventional paclitaxel + conventional paclitaxel + carboplatincarboplatin

ORr: 41% vs 24% (p=.005)ORr: 41% vs 24% (p=.005)

higher in squamous higher in squamous subtypesubtype

Lung Lung Cancer Cancer

Phase III in first-line metastatic Phase III in first-line metastatic melanoma:melanoma:nab-paclitaxel vs dacarbazinenab-paclitaxel vs dacarbazine

PFS: 4.8 vs 2.5 mos (p=.04)PFS: 4.8 vs 2.5 mos (p=.04)

MelanomaMelanomaBreast Breast CancerCancer

First approved in the US in First approved in the US in 2005 and in the EU in 2008 for 2005 and in the EU in 2008 for the treatment of MBC.the treatment of MBC.

nab®-Paclitaxel Improves Clinical Outcomes Across Multiple Tumor Types, Including Historically Non-Taxane Sensitive Tumors1-9

Pancreatic Pancreatic CancerCancer

Phase III trial IMPACT: Phase III trial IMPACT: nabnab--paclitaxel + gemcitabine vs paclitaxel + gemcitabine vs gemcitabine alone. gemcitabine alone.

OS: 14.8 vs 11.5 mosOS: 14.8 vs 11.5 mos

(p=.0000015)(p=.0000015)

nabnab®® is a registered trademark of Celgene Corporation.is a registered trademark of Celgene Corporation.

1.1. Gradishar et al. Gradishar et al. J Clin OncolJ Clin Oncol. 2009;27(22):3611-3618.. 2009;27(22):3611-3618.2.2. Gradishar et al. Gradishar et al. J Clin OncolJ Clin Oncol. 2005;23(31):7794-7803.. 2005;23(31):7794-7803.

3.3. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275].4.4. Von Hoff et al. Published online ahead of print October 3, 2011. Von Hoff et al. Published online ahead of print October 3, 2011.

J Clin OncolJ Clin Oncol. doi: 10.1200/JCO.2011.36.5742.. doi: 10.1200/JCO.2011.36.5742.5.5. Burris et al. Burris et al. J Clin OncolJ Clin Oncol. 1997;15(6):2403-2413.. 1997;15(6):2403-2413.

6.6. Hersh et al. Hersh et al. CancerCancer. 2010;116(1):155-163.. 2010;116(1):155-163.7.7. Boasberg et al. ASCO. 2011 [Abstract 8543].Boasberg et al. ASCO. 2011 [Abstract 8543].

8.8. Kottschade et al. ASCO. 2011 [Abstract 8532].Kottschade et al. ASCO. 2011 [Abstract 8532].9.9. Socinski et al. ASCO. 2010 [Abstract LBA7511].Socinski et al. ASCO. 2010 [Abstract LBA7511].

Page 31: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Comparing views of patients with those of doctors, nurses and general public

Slevin ML, Br Med J 300:1458, 1990

Respondents accepting intensive treatments Respondents accepting intensive treatments with a supposed minimum chance of effectivenesswith a supposed minimum chance of effectiveness

Page 32: Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School.

Thanks for attentionThanks for attention