strategia terapeutica nella malattia avanzata claudia bighin istituto nazionale per la ricerca sul...
TRANSCRIPT
Strategia terapeutica nella malattia avanzata
Claudia BighinIstituto Nazionale per la Ricerca sul
CancroGenova
Roma, 19 Febbraio 2005
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
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
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
Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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
Selective Estrogen Receptor Modulators
First generation Toremifene, Droloxifene, Idoxifene
Second /Third generation Raloxifene, Arzoxifene, EM-800, etc.
Status: Advantage over Tam not shown
Third Generation Aromatase Inhibitors Trials vs. Tamoxifen
Metastatic SettingStatus: Advantage over Tam
Neoadjuvant SettingStatus: Advantage over Tam
Adjuvant SettingStatus: Advantage over Tam
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
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
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
1° lineaABC
Adiuvante
2° lineaABC
Neoadiuvante
DCISPrevenzione
Inibitori dell’ aromatasi
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
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
Endocrine therapy in advanced pre-menopausal breast cancer
Ovarian Ablation OA vs Tamoxifen Monotherapy vs Combination AI
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
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
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
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
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
Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
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.
Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
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
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
Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer?
Valero and HortobagyiJCO 15 March 2003
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
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
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
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
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)
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
Chemotherapy as First Choice.
Drugs, Doses and Schedules Duration Integration of Chemotherapy and
Endocrine therapy Integration of Chemotherapy and
New Biological Agents
Appropriate Integration of Chemo / Endocrine Therapy
Metastatic breast cancer patients Adjuvant breast cancer patients
CT and ET in patients candidates to both treatments
Sequential treatment Concurrent treatment
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
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
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
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
Available Treatments for Metastatic Breast Cancer
Endocrine therapy Chemotherapy Novel Biological Agents Surgery/RT -> isolated recurrence
(Stage IV NED) Supportive Therapy
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
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
Overall survival from time of recurrence
17 months15 months
22 months27 months
58 months
SH Giordano, Cancer 2004