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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
Goldstein L, PASCO ’05 abs 512
E2197: Results II
Goldstein L, PASCO ’05 abs 512
E2197: Toxicity
TOXICITY AC AT
Febrile neutr. 6% 19%
deaths - 3 cases
AML/MDS 7cases 7cases
Cardiac nr nr
Goldstein L, PASCO ’05 abs 512
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
Martin M et al N Engl J Med 352; 22, 2, 2005
Risk Reduction for Disease-free Survival in the Main Subgroups
Martin M et al N Engl J Med 352; 22, 2, 2005
BCIRG001: toxicity
Martin M et al N Engl J Med 352; 22, 2, 2005
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
Roché H et al J Clin Oncol 2006
PACS-01: DFS in different subgroups (Forest plot analysis)
Roché H et al J Clin Oncol 2006
PACS-01: Toxicity
Roché H et al J Clin Oncol 2006
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
ECTO A75(4) >CMF (4)
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%
ECTO A75(4) >CMF (4)
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
Slamon “BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
“BCIRG 006”, SABCS 2006
Slamon “BCIRG 006”, SABCS 2006
Slamon “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
Jones S. et al. JCO 2006
Jones S. et al. JCO 2006
TC vs AC: results II
Jones S. et al. JCO 2006
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.
Jones S. et al. JCO 2006
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)
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