Highlights in the Management of Breast Cancer CINBO Consorzio Interuniversitario Nazionale per la...

Highlights in the Management ofBreast Cancer

CINBOConsorzio InteruniversitarioNazionale per la Bio-Oncologia

“Taxanes vs Anthra-containing chemotherapy in the treatment of early-BC and the issue of cardiac toxicity”

Vincenzo Adamo

Oncologia Medica e Terapie Integrate A.O.Universitaria, Policlinico “G. Martino” Messina

Rome, May 25-26, 2007

from Lancet ‘98 to Oxford 2000

CMF and node positive Patients

G. Bonadonna, BMJ, Jan 2005

Median Follow up 28.5 yrs

RFSHR 0.71, p.005 OS

HR 0.79, p.04

Crown J. Ed. Book, ASCO 2004

To need of adjuvant chemotherapy for early breast cancer

A superiority of antrhaciclynes based regimens in adjuvant setting

EBCTCG OVERVIEW 2005 AND ISSUE SYSTEMIC CHEMOTHERAPY

TO CONFIRM

The Lancet Vol 365 May 14, 2005

Single-Agent Chemotherapy vs Not and Polychemotherapy vs Not

from the EBCTCG (2005)

Anthravs otherregimens

5 yr of

recurrence

from the EBCTCG (2005)

• Three-drug regimens

• CAF > CMF ± Tam (INT 0102)

• CEF > CMF (NCIC-CTG)

• Sequential regimen

• E CMF > CMF (NEAT-SCTBG BR9601)

• Two-drug regimens

• AC = CMF TAM (NSABP B-15, B-23)

• EC and hEC = CMF (Belgian trial)

Which Anthracycline-based regimen ?

“Taxanes (Paclitaxel and Docetaxel) with significant

antitumoral activity in metastatic disease have been

evaluated in the adjuvant setting, and their inclusion

can further modify the natural history of the disease

by reducing the risk of recurrence and death”

ROLE OF TAXANES IN ADJUVANT SETTING

Buzdar AU, et al. editorial JCO2007

First Generation Trials: 31000 pts– Comparing taxane/anthracycline to

non-taxane/anthracycline• Sequential (anthra followed by taxane)• Combination

Second Generation Trials: 25000 pts– Comparing taxanes in both arms

• Sequential• Combination• With Herceptin

ROLE OF TAXANES IN ADJUVANT SETTING

Nowak AK et al. Lancet Oncol 5: 372–80, 2004

Randomized Trials of Adjuvant Chemotherapy with Taxanes

Trials Treatments N° pts N+/N- (%)

NSABP B28 AC(4) >P225 (4)

AC(4)

3068 100/0

CALGB 9344 AC(4) >P175 (4)

AC(4)

3121 100/0

E2197 A60T60 (4)

A60C600 (4)

2958 35/65

BCIRG 001 TA50C (6)

FA50C (6)

1491 100/0

MDACC

94-002

P250(4) >FA50C (4)

FA50C (8)

524 62/38

PACS01 FE100C (3) >T (3)

FE100C (6)

1999 100/0

ECTO A75(4) >CMF (4)

A60P200 (4) >CMF (4)

PST:A60P200 (4) >CMF (4)

1355

(250 PST)

NA/NA

NSABP B28

N= 3060 N+ pts

NONE A 60 mg/m2

C 600 mg/m2

P 225mg/m2 (3 h)

Mamounas et al JCO 2005

RecommendedTAM if HR(+)with chemoRx

Median follow-up64.8-64.4 months

Main G3 toxicity AC AC PTX

Neurosensory - 15%

Neuromotor - 7%

Arthralgia/myalgia - 12%

granulocytopenia - 3%

Feb. neutropenia - 3%

Thromboembolic -event - 1%

Hypersensitivity reaction

- 1%

Cardiac * 1% 0.9%

AML/MDS° 2 cases 6 cases

Deaths** 5 pts 2pts

*cardiac dysfunction either during or subsequent to therapy°acute myelogenous leukemia ormyelodysplastic syndrome**AC: pulmonary embolism in one, congestive heart failure in two, sepsis in one, and seizure in one; AC and PTX: coronary artery disease in one, pulmonary embolism in one.

NSABP B28: Toxicity

CALGB 9344

N= 3121 N+ pts

NONEA 60= 75= 90 mg/m2

C 600 mg/m2

P 175 mg/m2 (3 h)

RecommendedTAM if HR(+)after chemoRx

Henderson et al JCO 2003

RR:death18%

RR: recurrence 17%

RR: death 18%

Median follow-up69.0 months

CALGB 9344: ToxicityMain toxicity AC(60 mg/mq) AC PTX

Granulocytopenia G4 62% 16%

Infection 17% 11%

Nausea G2-3-4 32% 3%

Vomiting G2-3-4 27% 1%

stomatitis G2-3-4 10% 1%

Sensory neurotoxicity G3 - 3%

Paresthesias G2 - 15%

Hypersensitivity reaction - 6%

AML/MDS° 9 cases 8 cases

Deaths 1 pts 2 pts

There was no difference in incidence of cardiotoxicity between those who did and those

who did not receive paclitaxel. CHF was observed during active protocol

therapy in four (<1%) and six (<1%) pts and during post treatment follow-up in 23 (1%) and 27 (2%) pts randomly assigned to CA alone and CA

plus paclitaxel, respectively.

°including high dose of Doxorubicin

E2197 Trial

Goldstein L, PASCO ’05 abs 512

E2197: Results I


E2197: Results II


E2197: Toxicity

TOXICITY AC AT

Febrile neutr. 6% 19%

deaths - 3 cases

AML/MDS 7cases 7cases

Cardiac nr nr


Adaptated 26° SABCS 2003

BCIRG001

BCIRG001: post Chemotherapy Treatment

Adaptated 26° SABCS 2003

BCIRG001: characteristics of the pts and the tumors

Martin M et al N Engl J Med 352; 22, 2, 2005

Analysis of Survival Rates in the two Study Groups


Risk Reduction for Disease-free Survival in the Main Subgroups


BCIRG001: toxicity


MDACC TRIAL

Buzdar AU, et al. Clinical Cancer Research 2002

MDACC TRIAL: Results

Buzdar AU et al, Clinical Cancer Research 2002

RFS all ptsER- pts

ER+ pts

MDACC TRIAL: toxicity

Buzdar AU, et al. Clinical Cancer Research 2002

PACS-01

SURGERY

R

6 FEC-100: ARM AFluorouracil 500 mg/m² d1Epirubicin 100 mg/m² d1Cyclophosphamide 500 mg/m² d1

6 cycles every 21 days

3 FEC-100/3 Docetaxel: ARM B3 cycles of FEC 100 every 21 days

followed by 3 cycles of Docetaxel 100 mg/m² d1

every 21 days

Radiotherapy delivered within 4 weeks after the last chemotherapy cycle Tamoxifen 20 mg/day for 5 years prescribed in hormone-receptor positive post-menopausal women after chemotherapy

Stratified on: Center Age: < or 50 N: 1-3; 4

PACS-01:characteristics of pts and tumors

Roché H et al J Clin Oncol 2006

PACS-01: RESULTSDFS OS


PACS-01: DFS in different subgroups (Forest plot analysis)


PACS-01: Toxicity


ECTO Study

Gianni L, et al, Clin Cancer Res 2005

Patient characteristics and results

Gianni L, et al. Clin Cancer Res 2005

Main toxicities

Gianni L, et al. Clin Cancer Res 2005

NCIC CTG MA.21

q 3 w

q 2 w

q 3 w

Burnell M et al. Breast Cancer Res Treat. Abs 53, 2006

Primary end point: relapse free survival (RFS)Secondary end-points: overall survival, toxicity and QoL

Pts N+ orN-

HRisk

Regimencourses

Schedule

Anthracycline

Taxane Cyclophosphamide 5-FUx cycle Total

CEF6

q3w 60 mg/m2 iv D1- D8

720 mg N/A 75 mg/m2 by mouth D1-14

500 mg/m2 D1 - D8

AC-T4+4

q3w 60 mg/m2 iv D1

240 mg175

mg/m2 iv D1

600 mg/m2 iv D1

N/A

EC-T(DD)6+4

q2w 120 mg/m2 iv D1

720 mg175

mg/m2 iv D1

830 mg/m2 iv D1

N/A

CEF = oral cyclophosphamide/epirubicin/5-fluorouracil; AC-T =doxorubicin/cyclophosphamide and paclitaxel; EC-T = epirubicin/cyclophosphamide and paclitaxel;

NCIC CTG MA.21: Schedules

from medscape : Update on Adjuvant Chemotherapy in BC H McArthur & C Hudis, 2007

Regimen Hazard Ratio (95% CI) P Value

EC-T to CEF 0.89 (0.64, 1.22) .46

AC-T to CEF 1.49 (1.12, 1.99) .005

AC-T to EC-T 1.68 (1.25, 2.27) .0006

NCIC CTG MA.21: Results

2104 patients enrolled Dec-2000-April 2005

Regimen Recurrence free survival Fw-up

CEF 90.1 % 3 years

AC-T 89.5% 3 years

EC-T 85.0% 3 years

global test of significance

NCIC CTG MA.21

However, both the CEF and dose-dense EC-T regimens were associated with increased rates of febrile neutropenia,TVE, and delayed cardiotoxicity compared with AC-T.

Toxicity Febrile Neutropenia

Cardiac disfunction

CEF 22.9% 36.9%

EC-T 16.7% 28.7%

AC-T 4.8% 21.9%

Randomized Trials of Adjuvant Chemotherapy with Taxanes

Trials Treatments N° pts N+/N- (%) 5Y-DFS(%) 5Y-OS (%)

NSABP B28

AC(4) >P225 (4)

AC(4)

3068 100/0 76/72

p=0.006

85/85

p=0.46

CALGB 9344

AC(4) >P175 (4)

AC(4)

3121 100/0 70/65

P=0.0023

80/77

P=0.0064

E2197 A60T60 (4)

A60C600 (4)

2958 35/65 87/87

p=0.70*

94/93

p=0.49*

BCIRG

001

TA50C (6)

FA50C (6)

1491 100/0 75/68

p=0.001

87/81

p=0.008

MDACC

94-002

P250(4) >FA50C (4)

FA50C (8)

524 62/38 86/83

p=0.09*

NA

PACS01 FE100C (3) >T (3)

FE100C (6)

1999 100/0 78.3/73.2

p=0.041

90.7/86.7

p=0.05


A60P200 (4) >CMF (4)

PST:A60P200(4)>CMF(4)

1355

(250 PST)

NA/NA HR=0.66

p=0.012* NSD

* parameter after 4 years of follow up

Cardiac ToxicityTrials Treatments Cardiac toxicity

NSABP B28 AC(4) >P225 (4)

AC(4)

Cardiac disfunction G3 (during and posttreatment)

0.9%

1%

CALGB 9344 AC(4) >P175 (4)

AC(4)

CHF

<1% (during treat.); 2% (posttreat.)

<1% (during treat.); 1% (posttreat.)

E2197 A60T60 (4) vs A60C600 (4) NR

BCIRG

001 TA50C (6)

FA50C (6)

Mild to severe CHF G3-4

1.6% 0.1%

0.7% 0.1%

MDACC

94-002 P250(4) >FA50C (4)

FA50C (8)

Transient arrhyt. CHF

3% 0%

5% 1%

PACS 01FE100C (3) >T (3)

FE100C (6)

Any events CHF LEVF>20% end CT LEVF>20% \ after 1y

0.4% 0% 6.5% 7.8%

1.3% 0.4% 7.0% 10%


A60P200 (4) >CMF (4)

PST:A60P200(4)>CMF(4)

CTC 1 CTC 2 CTC 3 LEVF<50% LEVF>20%

67.8% 13.6% 0.5% 8.0% 5.6%

70.8% 11.1% 0.4% 5.7% 5.4%

P=0.09 P=1.0

P=.03 P=.63 P=.09

During and posttreat

CommentsCardiac toxicity data are controversial: most of the trials don’t include a careful cardiac monitoring before, during and after the treatments

Many trials demostrate that Anthracyclines and Taxanes are the most active cytotoxic drugs for the treatment of breast cancer also as adjuvant chemotherapy.

However the advantages obtained by this combination must be carefully balanced against potential risks, particularly in the adjuvant setting.

Mechanisms and types of Cardiotoxicity Associated with different therapeutic modalities

by Brian R, et al, Ed Boock ASCO 2007

Who need Adjuvant Chemotherapy ?

Adjuvant Chemotherapy Options

Trastuzumab if HER-2 positive

adapted from Piccart et al. (2005)

Anthracyclines may not be

necessary in adjuvant therapy

of breast cancer ?

Slamon SABCS 2006

Slamon “BCIRG 006”, SABCS 2006

“BCIRG 006”, SABCS 2006

Slamon “BCIRG 006”, SABCS 2006

TC vs AC

Jones S. et al. JCO 2006

TC vs AC

TC vs AC: results I



TC vs AC: results II


TC vs AC: toxicity

Conclusion: Thirty-one years ago, the original AC regimen was reported. Now, there is a superior nonanthracycline regimen, TC. At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.


High Risk Patientprovocative new scenarious

HR negativeNode neg/posHER2 negativeTopo II positive

HR negativeNode neg/posHER2 positiveTopo II negative

HR negativeNode neg/posHER2 positiveTopo II positive

HR negativeNode neg/posHER2 negativeTopo II negative

FECFEC docetaxel

Taxanes(carbo) +Trastuzumab

FC(caelyx)C +Trastustumab

Taxanes +Cyclophosphamide

The End

Stop Here

Anthacyclines Taxanes

Haematologic Haematologic

Gastrointestinal Neurological

Cardiac Hipersensivity reaction

Dermatological Dermatological

Cardiac

MAIN TOXICITY

????????

When should we offer a Taxane-regimen ?

Which Taxane: Paclitaxel ? Docetaxel ?

Which Regimen: Sequential A(C)T,

Combined AT ?

Which Antracycline regimen: (CEF ?)

Which Schedule: 3 Weekly, Weekly ?

Which Patients ?: Role of Predictive Factors

Best Use of Taxanes / Anthracyclines

Adjuvant Taxanes : which data from randomized trials

• Adjuvant taxanes improve DFS (Level 1 evidence ?)2 positive trials (CALGB 9344, BCIRG 001)1 negative trial ( NSABP B-28), but:TAM concomitant to chemotherapyTAM to all pt >50 years old

• Adjuvant Taxanes do not improved OS:longer follow-upwaiting for ongoing trials results

• Adjuvant taxanes increase toxicity

Slamon “BCIRG 006”, SABCS 2006Togliere ???

Slamon “BCIRG 006”, SABCS 2006?????

Adjuvant Chemotherapy Options

Trastuzumab if HER-2 positive

CMF ? TAXANES ?

adapted from Piccart et al. (2005)

Highlights in the Management of Breast Cancer CINBO Consorzio Interuniversitario Nazionale per la...

Documents

Transcript of Highlights in the Management of Breast Cancer CINBO Consorzio Interuniversitario Nazionale per la...