Strategia terapeutica nella malattia avanzata

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Strategia terapeutica nella malattia avanzata

• Claudia Bighin
• Istituto Nazionale per la Ricerca sul Cancro
• Genova
• 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 (gt2 years) Short Disease Free Interval (lt 2 years)
Positive steroid hormone receptors Negative steroid hormone receptors
Response to prior endocrine therapy Failure to first endocrine therapy
Age gt35 years Any age group
Modified from Henderson, 1990 Cancer
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General Criteria to Select Patients for Systemic
Therapy
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Available Treatments for Metastatic Breast Cancer

• Endocrine therapy
• Chemotherapy
• Novel Biological Agents
• Surgery/RT -gt 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 -gt 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 Setting
• Status Advantage over Tam
• Neoadjuvant Setting
• Status Advantage over Tam
• Adjuvant Setting
• Status Advantage over Tam

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Selected Second-line Randomized Phase III Trials
with AI
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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 183758, 2000
Bonneterre et al. J Clin Oncol 183748,
2000 Mouridsen et al. J Clin Oncol 19 2596,
2001 Mouridsen et al. J Clin Oncol 212101,
2003 Paridaens et al. Proc ASCO 2004 Abs. 515
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Neoadjuvant Randomized Phase III Trials with AI
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Inibitori dell aromatasi
DCIS Prevenzione
Neoadiuvante
Adiuvante
1 linea ABC
2 linea ABC
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Fulvestrant vs Anastrozole 2nd line, after
Tamoxifen
Study N pts Median FU (mo) TTP (mo) OR ()
Osborne, JCO 02 Howell, 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 1992 Taylor, 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 Outcome
Boccardo, Ann Oncol 94 Jonat, EJC 95 Klijn, JNCI 00 HR or HR? Any HR HR or HR? 48 318 161 OA (XRT/surg) vs OAT vs Z vs ZT ZT vs T B vs T vs BT No diff No diff in OS PFS gt with ZT PFS and OS gt with BT
Meta-analysis combination gt 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 -gt 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
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
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High vs low dose-intensive CT
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Are anthracycline-taxane regimens the new
standard of care in the treatment of metastatic
breast cancer?

• Valero and Hortobagyi
• JCO 15 March 2003

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Anthracycline-paclitaxel phase III studies
Study No.pts Random OR CR TTP OS
Jassem JCO 01 267 A50P220/3h F500A50C500 68 55 19 8 8.3 6.2 23.3 18.3
Biganzoli JCO 02 275 A60P175/3h A60C600 58 54 7 3 6 6 20.6 20.5
Carmichael ASCO 01 705 E75P200/3h E75C600 67 56 Nr Nr 6.7 6.5 13.8 13.7
Luck ASCO 00 560 E60P175/3h E60C600 46 41 9 6 9.7 8.2 Nr Nr
Statistical significant
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Anthracycline-taxotere phase III studies
Study No.pts Random OR CR TTP OS
Nabholtz JCO 03 429 A50T75 A50C600 59 47 10 7 9.3 7.9 22.5 21.7
Mackey ASCO 02 484 T75A50C600 F600A50C500 55 44 7 3 No diff No diff
Bonneterre BJC 04 142 E75T75 F500E75C500 59 32 2 1 7.8 5.9 34 28
Bontenbal ECCO 03 216 A50T75 F500A50C500 64 41 Nr Nr 8.1 6.6 22.6 16.1
Statistical significant
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PolyCT vs single agent
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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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Concurrent chemotherapy and endocrine therapy
Fossati R. et al. J Clin Oncol 103439, 1998
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Concurrent vs Sequential Therapy
-gt CT given 6-8 weeks after ET
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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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ET as maintenance therapy after 1st line
epirubicin
Berruti et al. Anticancer Res 1997
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Available Treatments for Metastatic Breast Cancer

• Endocrine therapy
• Chemotherapy
• Novel Biological Agents
• Surgery/RT -gt 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
  liverbone no. of mts lt 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 233400, 2004
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Survival outcome in breast cancer patients with
isolated metastases
Site of Metastases N pts Treatment Survival Survival Survival
Site of Metastases N pts Treatment Median (months) 5-year () 10 year ()
LUNG 744 S CT Tam 42 79 35 - 80 8 - 60
LIVER 155 S CT 24 - 44 22 - 46 NS
BRAIN 213 S RT CT 15 - 37 7 - 38 20
S.E. Singletary, The Oncologist 2003
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Overall survival from time of recurrence
58 months
27 months
22 months
17 months
15 months
SH Giordano, Cancer 2004