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![Page 1: Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul Cancro Genova Roma, 19 Febbraio 2005.](https://reader033.fdocuments.net/reader033/viewer/2022061305/55143062550346ec488b5f4b/html5/thumbnails/1.jpg)
Strategia terapeutica nella malattia avanzata
Claudia BighinIstituto Nazionale per la Ricerca sul
CancroGenova
Roma, 19 Febbraio 2005
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Metastatic Breast Cancer. The Big Picture
11,000 new cases/year of metastatic breast cancer in Italy
1,700 (15%) are ‘ab initio’ metastatic patients
Remaining patients are previously treated for early breast cancer
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General Criteria to Select Patients for Endocrine or Chemo-therapy
Endocrine Therapy Chemotherapy
Slow-growing disease(soft tissue, skeleton)
Rapidly growing disease(visceral involvement, skin
limpang.)
Long Disease Free Interval(>2 years)
Short Disease Free Interval(< 2 years)
Positive steroid hormone receptors
Negative steroid hormone receptors
Response to prior endocrine therapy
Failure to first endocrine therapy
Age >35 years Any age group
Modified from Henderson, 1990 Cancer
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General Criteria to Select Patients for Systemic Therapy
Trastuzumab +Endocrinetherapy
Trastuzumab +Chemotherapy
Trastuzumab Alone
3+ by IHCPos. by FISH
(15%)
All the Others(85%)
HER 2 Status
Endocrinetherapy
Long DFS
Age >35 years
Response to prior endocrine therapy
ER Positive/Ukn
Slow-growing disease(soft tissue, skeleton)
Chemotherapy
Short DFS
Any age group
Failure to first endocrine therapy
ER Negative
Rapidly growing disease
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Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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Hormonal Agents for Breast Cancer SERMS
Tamoxifen Toremifene
LHRH analogs Aromatase
Inhibitors Anastrozole Letrozole Exemestane
Estrogens Estradiol DES
Androgens Fluoxymesterone
Progestins Megestrol Acetate MPA
ER-Down Regulator Fulvestrant
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Selective Estrogen Receptor Modulators
First generation Toremifene, Droloxifene, Idoxifene
Second /Third generation Raloxifene, Arzoxifene, EM-800, etc.
Status: Advantage over Tam not shown
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Third Generation Aromatase Inhibitors Trials vs. Tamoxifen
Metastatic SettingStatus: Advantage over Tam
Neoadjuvant SettingStatus: Advantage over Tam
Adjuvant SettingStatus: Advantage over Tam
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Selected Second-line Randomized Phase III Trials with AI
Regimens Number of pts
Outcome
ANA v MA 513 Better OS
LET v MA 363 Better ORR, TTF, QoL
EXE v MA 766 Better TTP, OS, QoL
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Aromatase Inhibitors Versus Tamoxifen as First-Line Therapy in Metastatic Breast Cancer
Anastrozole
Anastrozole
Letrozole Exemestane
Patients, No. 170 vs 182 340 vs 328 453 vs 454 182 vs 189
OR, % 21 vs 17 33 vs 33 30 vs 20 46 vs 31
Clin. Benefit, %
59 vs 46 56 vs 56 49 vs 38 66 vs 49
TTP/PFS, mo 11 vs 6 8 vs 8 9 vs 6 10 vs 6
ER unknown, %
11 vs 11 56 vs 54 34 vs 33 15 vs 11
Nabholtz et al. J Clin Oncol 18:3758, 2000; Bonneterre et al. J Clin Oncol 18:3748, 2000Mouridsen et al. J Clin Oncol 19: 2596, 2001; Mouridsen et al. J Clin Oncol 21:2101, 2003;Paridaens et al. Proc ASCO 2004 Abs. 515
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Neoadjuvant Randomized Phase III Trials with AI
Regimens Number of pts
Outcome
LET v Tam 250 Better ORR Better ORR in
EGF/HER2 positive More Breast-
conserving surgery
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1° lineaABC
Adiuvante
2° lineaABC
Neoadiuvante
DCISPrevenzione
Inibitori dell’ aromatasi
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Fulvestrant vs Anastrozole: 2nd line, after Tamoxifen
Study N° pts
Median FU (mo)
TTP(mo)
OR(%)
Osborne, JCO 02Howell, JCO 02
Robertson, Cancer 03
400
451
425+423
16.8
14.4
15.1
5.4 vs 3.4
5.5 vs 5.1
5.5 vs 4.1
17.5 vs 17.5
20.7 vs 15.7
19.2 vs 16.5
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Fulvestrant vs Tamoxifen: 1st line
Study N° pts
Median FU (mo)
TTP(mo)
OR(%)
Howell, JCO 04
587 14.5 8.2 vs 8.3
31.6 vs 33.9
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Endocrine therapy in advanced pre-menopausal breast cancer
Ovarian Ablation OA vs Tamoxifen Monotherapy vs Combination AI
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Goserelin alone
Meta-analysis of phase II studies: 200 pts Median survival: 26.5 months Overall RR: 36% (44% in ER+)
Phase III study: Goserelin vs Oophorectomy: no
difference in failure-free and overall survival
Blamey, Eur J Cancer 1992Taylor, JCO 1998
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Randomized trials of OA vs Tamoxifen
Study Pts n Treatment Outcome
Ingle, JCO 86
Buchanan, JCO 86
Sawka, BCRT 97
HR+ or HR?
Any HR
HR+ or HR?
53
122
39
OA (surg) vs T
OA (surg) vs T
OA (XRT/surg)
vs T
No diff
No diff
No diff
Meta-analysis on 200 pts: no difference in RR, DFP or mortality
Crump, BCRT 1997
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Randomized trials of Monotherapy vs Combination
Study Pts n Treatment OutcomeBoccardo, Ann Oncol 94
Jonat, EJC 95
Klijn, JNCI 00
HR+ or HR?
Any HR
HR+ or HR?
48
318
161
OA (XRT/surg) vsOA+T vs Z vs
Z+T
Z+T vs T
B vs T vs B+T
No diff
No diff in OSPFS > with
Z+T
PFS and OS > with B+T
Meta-analysis : combination > monotherapy for all end points
Klijn, JCO 2001
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AI in pre-menopausal breast cancer/1 Goserelin + Anastrozole in 16
advanced breast cancer as second line ET 75% objective response or SD Median duration of remission of 17
months (range 6-47)Estradiol FSH
Forward, BJC 2004
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AI in pre-menopausal breast cancer/2
Phase II study of Goserelin + Anastrozole 22 pre-menopausal recurrent or metastatic
BC Objectives:
ORR, CB, TTP, OS Toxicity Efficacy in suppression of plasma estradiol
Preliminary resuts: PR: 22% (4); CR: 6% (1); SD: 44% (8); CB 72%
Carlson, SABCS 2004
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Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
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Metastatic Breast Cancer.Single Agents Grouped by Activity
VERY ACTIVE (> 50% ORR) Docetaxel Doxorubicin Epirubicin Paclitaxel Vinorelbine
MODERATELY ACTIVE ( 20 - 50% RR) Cisplatin Cyclophosphamide Estramustine 5-Fluorouracil Ifosfamide Losoxantrone Methotrexate Mitomycin-C Mitoxantrone Prednimustine Thiotepa Vinblastine Vincristine
WEAKLY ACTIVE (20% RR) Actinomycin-D Amonafide Amsacrine Bisantrene Carboplatin BCNU Chlorambucil CPT-11 Cytarabine Dacarbazine Elliptnium Etoposide Fenretinide Floxuridine Gemcitabine HexaMethyl. Hy.Urea Idarubicin CCNU Lonidamine Melphalan Menogaril Miltefosine 6-MPP Mithramycin
Modified from Chapter 36.2, 1996 De Vita et al.
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Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
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PolyCT with anthracycline vs no anthracycline
Study No. trials
No. pts
Rx RR OS HR
Meta-analysis (Fossati,
JCO’98)
30
5,241
Anthrac
Vs No
anthrac
51%
45%
OR 1.30 95%CI:1.16-1.46
0.97
95%CI:0.90-1.03
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High vs low dose-intensive CT
Study No. trials
No. pts
Rx RR OS HR
Meta-analysis (Fossati,
JCO’98)
20
3,611
High Vs
low DI
44%
33%
OR 1.67 95%CI:1.43-1.95
0.90
95%CI:0.83-0-97
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Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer?
Valero and HortobagyiJCO 15 March 2003
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Anthracycline-paclitaxel: phase III studies
Study No.pts
Random
OR%
CR%
TTP OS
JassemJCO 01
267 A50P220/3h
F500A50C50
0
6855*
198
8.36.2*
23.318.3*
BiganzoliJCO 02
275 A60P175/3h
A60C600
5854
73
66
20.620.5
CarmichaelASCO 01
705 E75P200/3h
E75C600
6756
NrNr
6.76.5
13.813.7
LuckASCO 00
560 E60P175/3h
E60C600
4641
96
9.78.2
NrNr * Statistical significant
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Anthracycline-taxotere: phase III studies
Study No.pts
Random
OR%
CR%
TTP OS
NabholtzJCO 03
429 A50T75
A50C600
5947*
107
9.37.9*
22.521.7
MackeyASCO 02
484 T75A50C600
F600A50C50
0
5544*
73
No diff
No diff
BonneterreBJC 04
142 E75T75
F500E75C50
0
5932*
21
7.85.9*
34 28*
BontenbalECCO 03
216 A50T75
F500A50C50
0
6441*
NrNr
8.16.6*
22.616.1*
* Statistical significant
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PolyCT vs single agent
Study No. trials
No. pts
Rx RR OS HR
Meta-analysis (Fossati,
JCO’98)
15
2,442
polyCT
Vs Single agent
48%
34%
OR 1.79 95%CI:1.51-2.12
0.82
95%CI:0.75-0.90
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Poly vs. Monochemotherapy. Randomized Trials
Anthra. vs. Anthra-based
FEC vs E FEC-MV vs
E-M FEC vs
Mitoxantrone Doxo-Vin. vs
Doxo Doxo-P vs
Doxo
Taxane vs. Non-Anthra
CMFV vs P MV vs D MF vs D NF vs D
Taxanes vs. Taxane-based
• D-Xeloda vs Docetaxel
• P-Gem vs Paclitaxel
• P-Doxo vs Paclitaxel
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Poly vs. Monochemotherapy. Randomized Trials
Anthra. vs. Anthra-based
No difference in TTP, OS
Similar activity
Safety or QoL consistently favors monotherapy
Doxo-Tax more active than doxo, but same OS
Taxane vs. Non-Anthra
Taxanes monoTx consistently better than non-anthra regimens
Taxanes vs. Taxane-based
• Xeloda adds to docetaxel
• Gemcitabine adds to paclitaxel (survival?)
• Doxo adds to paclitaxel (same OS)
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Poly vs. Monochemotherapy. Randomized Trials Anthracycline Monotherapy represents
a reasonable option for most patients with metastatic breast cancer
Taxotere 3-wk or Taxol weekly (Seidman, ASCO 04) monotherapy represents a reasonable option to anthracycline monotherapy
Polychemotherapy in particular with taxane-anthracycline based regimens is especially suitable when response is the primary endpoint
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Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
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Appropriate Integration of Chemo / Endocrine Therapy
Metastatic breast cancer patients Adjuvant breast cancer patients
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CT and ET in patients candidates to both treatments
Sequential treatment Concurrent treatment
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Study No. trials
No. pts
Rx RR OS HR
Meta-analysis
25
3,606
CT Vs
CT+ET
46%
56%
OR 1.56 95%CI:1.36-1.8
0.99
95%CI:0.92-1.07
Fossati R. et al. J Clin Oncol 10:3439, 1998
Concurrent chemotherapy and endocrine therapy
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Study Pts No. pts
Rx RR OS
Cavalli (Br Med J’83)
pre
55 54
OOX+CT OOX->CT
46% 43%
25 21
Cavalli (Br Med J’83) Post 152
145 TAM+CT TAM->CT
40% 33%
24 28
-> CT given 6-8 weeks after ET
Concurrent vs Sequential Therapy
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ET as Maintenance Therapy. Potential Advantages To prolong TTP without side effects of
long-term CT Potential higher activity because of
the low tumor burden (responding patients)
Compared to concurrent administration, to avoid exposure and potential development of resistant clones in non-responding patients
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Study No. pts
RX OS (median)
retrospective 65 104
Maintenance ET Control
42 19.5
p<.0001
Berruti et al. Anticancer Res 1997
ET as maintenance therapy after 1st line epirubicin
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Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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Breast Cancer Metastases in Liver: Laser-induced Interstitial Thermotherapy
1993-2002, 232 patients (liver only or liver&bone; no. of mts < 6; Ø 5 cm)
45% both lobes involved 19% local unresectable tumor 8% recurrent after liver resection 3% general contraindication for surgery 25% refusal of surgery
Median OS 4.3 yrs – 5-yr OS 41%
Mack G et al. Radiology 233:400, 2004
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Survival outcome in breast cancer patients with isolated metastases
S.E. Singletary, The Oncologist 2003
Site of Metastases
N° pts
Treatment
Survival
Median (months
)
5-year (%)
10 year (%)
LUNG 744S + CT +
Tam42 – 79 35 - 80 8 - 60
LIVER 155 S + CT 24 - 44 22 - 46 NS
BRAIN 213 S + RT + CT 15 - 37 7 - 38 20
![Page 45: Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul Cancro Genova Roma, 19 Febbraio 2005.](https://reader033.fdocuments.net/reader033/viewer/2022061305/55143062550346ec488b5f4b/html5/thumbnails/45.jpg)
Overall survival from time of recurrence
17 months15 months
22 months27 months
58 months
SH Giordano, Cancer 2004