La chemioterapia adiuvante

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La chemioterapia adiuvante

• Lucia Del Mastro
• Istituto Naz. per la Ricerca sul Cancro - Genova
• Roma 18 Febbraio 2005

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Adjuvant chemotherapy

• The present
• Anthracyclines
• Taxanes
• Herceptin?
• Dose-density
• The future
• Treatment individualization
• Molecular markers to estimate prognosis and to
  predict response to treatment

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St Gallen Consensus, JCO Sept 03Recommended
Adjuvant Chemotherapy Regimens

• Standard efficacy
• Six cycles of classical CMF (oral)4 cycles of AC
• Superior efficacy vs. standard
• Canadian CEF x 6
• CAF x 6
• Tailored FEC x 6
• AC x 4 followed by paclitaxel x 4 better than AC
  x 4 (CALGB 9344 and NSABP-B28)
• T(docetaxel)AC x 6 better than FAC x 6 (BCIRG
  001)

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Are Anthracyclines Standard ?
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Optimal Anthracyclines Regimens

• Impact of drug number
• Three-drug regimens
• CAFos gt CMFos Tam (INT 0102)
• CEFos gt CMFos (NCIC-CTG)
• FEC1/21 gt CMF1/21 (Danish)
• FAC1/21 gt CMF1/21 (GEICAM)
• Two-drug regimens
• AC CMFos (NSABP B-15 e B-23)
• EC CMFos (Belgian Study)

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Optimal Anthracyclines Regimens

• Impact of cycle number
• Six cycles
• 6 CAFos/CEFos gt CMFos (INT 0102, NCIC)
• 6 FAC1/21/FEC1/21 gt CMF1/21 (GEICAM)
• 6 /FEC1/21 gt CMF1/21 (Danish)
• Four cycles
• 4 AC 6 CMFos (NSABP B-15 and B-23)
• Impact of sequence
• EPI?CMF gt CMF (NEAT)
• EPI?CMF gt CMF (GOCSI)

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Optimal Anthracyclines Regimens

• Impact of dose
• Dose reductions below the standard are harmful
  (CAF vs. ½ CAF)
• No dose-response for doxorubicin
• 60 75 90 mg/m2 (CALGB 9344)
• There is a threshold dose for epirubicin
• FE100C gt FE50C x 6 (French Study)
• E100C830 gt E60C500 x 8 (Belgian Study)

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Are Anthracyclines Standard ?

• Yes. Indicated in all patients in whom adjuvant
  chemotherapy is indicated, in the absence of
  specific contraindication, e.g. cardiac disease
• but not all anthracyclines regimens are the same

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Adjuvant chemotherapy

• The present
• Anthracyclines
• Taxanes
• Herceptin?
• Dose-density
• The future
• Treatment individualization
• Molecular markers to estimate prognosis and to
  predict response to treatment

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Taxanes vs no taxanes as adjuvant therapy
CALGB 9344 NSABP B-28 PACS 01 BCIRG 001
AC vs AC-gtT AC vs AC-gtT FEC vs FEC-gtTx FAC vs TAC
5y DFS Abs diff. 5 4 5 7
5y OS Abs diff. 3 0 4 6
RR for recurrence 0.83 P.0023 0.83 P.008 0.83 P.041 0.72 P.001
RR for mortality 0.82 P.0064 0.94 P.46 0.77 P.05 0.70 P.008
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Adjuvant Studies with PaclitaxelCALGB 9344 and
NSABP B-28Confounding Factors

• Different duration of therapy between no
  paclitaxel and paclitaxel containing arm (3 vs. 6
  months)
• Optimal comparator would have been 6 cycles of an
  anthracycline containing regimen instead of 4.
• Unlike CALGB 9344, NSABP-28 did not show a
  survival advantage in favor of paclitaxel
  containing arm

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Adjuvant trials with docetaxel
Study No. Pts FU yrs DFS OS
TAC vs FAC (BCRIG 01 SABCS 2003) 1491 4.6 Improved Improved
FEC100 x 6 vs FEC100 x3 -gtTaxotere x 3 (PACS 01 SABCS2004) 1999 5.0 Improved Improved
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BCIRG 001 Hematological Toxicity
Treated (n1,480) TAC n744 FACn736

ANC lt1000? 65.1 49.0
Febrile Neutropenia 23.9 2.4
Infection (Gr 3/4) 3.1 1.5
Septic Death 0 0
Anemia (Gr 3/4) 4.8 2.2
Thrombocytopenia (Gr 3/4) 2.4 1.8
? Protocol required blood counts every 3 weeks
Gr 4 neutropenia at time of grade gt 2 fever and
i.v. antibiotics p?0.05
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GEICAM 9805Adjuvant High Risk Node Negative

• 1064 pts randomized, safety results reported for
  448 pts who completed therapy

MMartin et al. 27th Annual Symposium of the Am.
Soc. of Breast Disease, April 11-13, 2003.
Abstract 8.
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GEICAM 9805 Toxicity (TAC arm)
Gr 3/4 toxicity per patient (NCI-CTC version 2)
Toxicity TAC-control (n112) TAC-prophylactic (n112) p-value
Febrile Neutropenia 25.9 2.7 lt0.001
Neutropenia 94.6 39.3 lt0.001
Leukopenia 90.2 35.7 lt0.001
Mucositis 6.3 2.7 NS
MMartin et al. 27th Annual Symposium of the Am.
Soc. of Breast Disease, April 11-13, 2003.
Abstract 8.
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Treatment Protocol
Stratified on ? Center ? Age lt or ? 50 ? N
1-3 ? 4
6FEC100 ARM A Fluorouracil 500
mg/m² d1 Epirubicin 100 mg/m²
d1 Cyclophosphamide 500 mg/m² d1 6 cycles
every 21 days
S U R G E R Y
R
3FEC100-3 Docetaxel ARM B 3 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
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Hematologic Toxicity
Per Patient 6FEC100 3FEC100-3D ?² test
Neutropenia gr 3-4 (d21)
Cycle 1 to 3, 21.0 21.5 0.79
Cycle 4 to 6, 20.2 10.9 lt 0.001
Febrile neutropenia,cy.4 1 4.6 0.001
Infection gr 3-4, 1.6 1.6 0.98
Anemia gr 3-4, 1.4 0.7 0.12
Thrombocytopenia gr 3-4, 0.3 0.4 0.71
G-CSF/cycle, per cycle 14.7 8.9 lt 0.001
Cycle 1 to 3, 8.1 10.3 0.004
Cycle 4 to 6, 21.0 7.5 lt 0.001
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Non Hematologic Toxicity
Per Patient 6FEC100 3FEC100-3D ?² test
Nausea-vomiting gr 3-4
Cycle 1 to 3, 13.2 10.1 0.031
Cycle 4 to 6, 11.0 1.6 lt 0.001
Stomatitis gr 3-4, 4.0 5.9 0.05
Edema mod-sev, (cy 4-6) 0.3 4.8 lt 0.001
Nail disorders mod-sev, (cy 4-6) 1.0 10.3 lt 0.001
Chemo- induced-amenorrhea, 72.4 68.4 0.13
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Cardiac Toxicity
6FEC100 3FEC100-3D ?² test
Patients, n () 13 (1.3) 4 (0.4) 0.027
Events, n
CHF 4 0
LVEF 4 1
Arrhythmia 2 0
Others 2 2
Cardiac death 1 1
myocardial infarct, dyspnea /
pericarditis, menace syndrome
cardiogenic shock / sudden death
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Taxanes as adjuvant therapy conclusions

• Paclitaxel
• Paclitaxel-containing regimens (AC-gtPaclitaxel)
  superior to standard (suboptimal?) AC regimen
• No comparison with highly effective regimens
• Longer duration higher toxicity
• Absolute difference
• 5-year DFS 4-5
• 5-year OS 0-3
• Taxotere
• Taxotere-containing regimens superior to highly
  effective regimens (ie FAC? FEC100)
• Equal duration higher toxicity with TAC lower
  toxicity with FECx3 -gtTaxoterex3
• Absolute difference
• 5-year DFS 5-7
• 5-year OS 4-6

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Adjuvant chemotherapy

• The present
• Anthracyclines
• Taxanes
• Herceptin?
• Dose-density
• The future
• Treatment individualization
• Molecular markers to estimate prognosis and to
  predict response to treatment

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CALGB, MIG1, and AGO Studies
C9741 MIG1 AGO
No. of pts. 2005 1214 1284
Selection Nodepos (100) Nodepos (64) Nodepos (100)
Treatment arms AC?T or A?T?C FEC q21 or FEC q14 EC?T or E?T?C
Median F/U 3.0 years 10.4 years 2.3 years
No. of relapses 305 (15) 359 (30) 221 (17)
HR relapse 0.74 (p.01) 0.88 (p.22) 0.64 (p.0009)
HR death 0.69 (p.013) 0.87 (p.29) 0.65 (p.03)
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Age lt 50 years
EFS
Survival
95
84
83
68
90
76
79
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FEC14 (Pts 250) N Events 55 FEC21 (Pts 220) N
Events 69 p0.02
FEC14 (Pts 250) N Events 33 FEC21 (Pts 220)
N Events 41 p0.09
____ FEC14 . FEC21
____ FEC14 . FEC21
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High Proliferative activity
EFS
Survival
93
83
80
69
88
78
76
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FEC14 (Pts 223) N Events 33 FEC21 (Pts 209)
N Events 43 p0.14
FEC14 (Pts 223) N Events 55 FEC21 (Pts 209) N
Events 69 p0.06
____ FEC14 . FEC21
____ FEC14 . FEC21
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Planned subgroup analyses
10-y EFS 10-y EFS 10-y EFS 10y-OS 10y-OS 10y-OS
FEC21 FEC14 Abs. Diff p value FEC21 FEC14 Abs. Diff p value
ER-/PgR- 46 67 21 0.03 71 76 5 0.25
HER2 positive 44 72 28 0.03 60 79 19 0.09
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9741 Reported At SABCS 2002/2004
9741 SA Dec 02 9741 SA Dec 04
CA4T4 q3w v q2w CA4T4 q3w v q2w
ALL ER and PR 26 7-41 Not given
DFS ER and PR Negative 32 Not given 23 0-42
ER or PR Positive 19 Not given 10 -19-33
ALL ER and PR 31 7-50 Not given
OS ER and PR Negative Not given 22 -5-42
ER or PR Positive Not given 1 -44-32
Courtesy of P. Ravdin
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Adjuvant chemotherapy

• The present
• Anthracyclines
• Taxanes
• Herceptin?
• Dose-density
• The future
• Treatment individualization
• Molecular markers to estimate prognosis and to
  predict response to treatment

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Pure Prognostic factor (Unfavorable)

• Factor 1 Neg

100 cure
Plt0.05
Factor 2 Neg
50 cure
Factor 2 Pos
Prognosis
Factor 1 Pos
10 cure
No Therapy
Therapy
Pure Predictive factor (For Sensitivity to
Therapy)
Factor 1 Pos
100 cure
Plt0.05
50 cure
Prognosis
Factor 2 Pos
Factor 2 Neg
10 cure
Factor 1 Neg
No Therapy
Therapy
Modify from D.F. Hayes The Breast 2002
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Gene expression profile recent advances

• Selection of limited number of genes vs very
  large number of genes
• Ready application in the community
• RT-PCR on paraffin embedded tissue vs microarrays
  on fresh tissue

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Soonmyung Paik et al. 3512817-2826, 2004
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Panel of 21 Genes and the Recurrence-Score
Algorithm

• S. Paik, NEMJ 2004

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KaplanMeier Estimates of the Rate of Distant
Recurrence at 10 Years, According to
Recurrence-Score Risk Categories.

• S. Paik, NEMJ 2004

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Rate of Distant Recurrence as a Continuous
Function of the Recurrence Score.

• S. Paik, NEMJ 2004

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Expression of the 21 genes in the Recurrence
Score assay and prediction of clinical benefit
from chemotherapy

• NSABP-B20 Tam (227 pts) vs Tam CMF or MF (434
  pts)
• High recurrence score absolute increase in
  10-year DRFS 27.6 8.0
• Low recurrence score absolute increase in
  10-year DRFS -1 2.2

Paik S, SABCS 2004, abs 24
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MINDACT study (6,000 pts)
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Multigene expression assay Amsterdam 70-gene
signature

• Power prognostic tool
• Outperforms clinical/pathologic criteria
• Can avoid overtreatment. Potential CT sparing
  20-28 of patients
• Validation study (Piccart SABCS 2004) less
  powerful than initial study

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US Intergroup PACCT trial