Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul...

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

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

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.

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


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


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

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

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

Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul...

Documents

Transcript of Strategia terapeutica nella malattia avanzata Claudia Bighin Istituto Nazionale per la Ricerca sul...