Zoladex ca mammae

Breast cancer is by far the most frequent cancer among women with an estimated

1.6 million new cases diagnosed with more than 500,000 deaths each year

(GLOBOCAN 2012)

INDONESIAGlobocan 2012

Annual Hazard of Recurrence Peaks at 2 Years Regardless of Baseline Prognostic Factors

0

5

10

15

20

25

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5

Ha

zard

of

recu

rren

ce b

y ye

arl

y in

ter

val

Time (years)

Total populationNode 0Node (+4)

PostmenopausalPremenopausal

ER+ER-Tumour size <1 cmTumour size >3 cm

Ref :Saphner T et al. J Clin Oncol. 1996; 14: 2738–2746

• Estrogen are essential for the normal growth and proliferation of target cells, such as breast epithelial cells, also stimulate growth of breast carcinoma.

• Their normal physiological effects by binding to specific nuclear proteins, known as oestrogen receptors (ERs).

• Around 2/3 post menopausal patients diagnosed to havebreast cancer are Estrogen-Receptor positive, and around1/2 of tumours found in premenopausal women are oestrogen-sensitive.

ESTROGEN

Ref :

Annals of Oncology 14: 1017–1025, 2003

.

Hypothalamus

Gonadotropins

(FSH + LH)

Ovary

Estrogens

Progesterone

Prolactin

Growth Hormone

Pituitary gland

Pre / Postmenopausal

Adrenal gland

Progesterone

Androgens

Estrogens

Corticosteroids

Premenopausal

Adrenocorticotropic

hormone (ACTH)

Estrogen Production in Premenopausal

and Postmenopausal Patients

ovary is the main site of oest

rogen production at premeno

pausal,

whereas in post-menopausal

women the adrenal glands a

nd peripheral tissues are the

main sources.1

Ref :

1. NCCN Guidelines Version 1.2015

ESTROGEN PRODUCTION

100 years in the development of endocrine therapy

Date of the first publication

1896

1922

1939

1944

1951

1952

1953

1953

1971

1973

1982

1987

1993

Reference: Howell, A. et al. Reviews on Endocrine-related Cancer. 1993; 43: 5-21

Type of therapy

Oophorectomy

Ovarian irradiation

Androgens

Synthetic oestrogens

Progestins

Pituitary irradiation

Adrenalectomy

Hypophysectomy

Antioestrogens

Aromatase inhibitors

LHRH agonists

Antiprogestins

‘Pure’ antioestrogens

Principal author

Beatson

Courmelles

Ulrich

Haddow

Esher

Douglas

Huggins

Luft

Cole

Griffiths

Klijn

Romieu

Howell

Ref :


GUIDELINEENDOCRINE

THERAPY

Subsequent endocrine therapy for systemic disease

Ref :


• For premenopausal breast cancer : ovary is the main site of oestrogen production at

• premenopausal

• Ovarian Ablation :

• Surgical oophorectomy : immediate and permanent drop in ovarian estrogen production

• Ovarian Irradiation : incomplete or reversible in some women

• Medical ovarian ablation : LHRH analogue/LHRHa (Goserelin ) The possible advantages of LHRH analogues are their ease of administration and reversible effects

• Cytotoxic chemotherapy : less than 50% of women under 40 years of age will be rendered postmenopausal by standard adjuvant chemotherapyregimens, whereas the majority of women aged 40 or more years of age will become permanently menopausal

HORMONAL THERAPY

- Ovarian ablation

Effect of ovarian ablation for women < 50 years of age

Ovarian ablation signific

antly increasing 15 year

s disease free survival a

nd 15 years survival

Ovarian functional suppression/ablation significantly reduces recurrence rate and breast cancer

death rate

Reference :Adapted from EBCTG. Lancet. 2005. 365 : 1687-1717

LHRH analogue Effect of LHRHa on LH and estradiol Levels

‘Zoladex’ 3.6mg depot

0 1 2 3 4 5 6 7 8 12 16 20

35

30

25

20

15

10

5

0

LH

(m

U/m

l)

Time (weeks)

(n=7)

1 2 3 4 5 6

West CP, et al. Clin Endocrinol 1987; 26: 213–20.

Oe

str

ad

iol (p

g/m

l)

‘Zoladex’ 3.6mg depot

1 2 3 4 5 6

300

250

200

150

100

50

0

0 1 2 3 4 5 6 7 8 12 16 20

Time (weeks)

(n=7)

LH = Luteinising hormone

Age-specific breast cancer incidence rates in selected cancer registries

Bray F et al. Breast Cancer Res 2004, 6:229-239

Asia : Rates in Singapore, particularly among the Chinese, are also relatively high

for the region

Recovery from Chemotherapy-induced Amenorrhea:

According to Age

Kim HA, et al. The Incidence of Chemotherapy-induced Amenorrhea and Recovery in Young (<45-year-old) Breast Cancer Patients.

J Breast Cancer. 2009 Mar;12(1):20-26 (South Korea)

Proportion patient with Amenorrhea decreasing for Age < 40

Chemotherapy-Induced Amenorrhea (CIA) for

Hormone Receptor Positive (HR +) & Prognosis

Jung M et al. The clinical outcome of chemotherapy-induced amenorrhea in premenopausal young patients with breast cancer with

long-term follow-up. Ann Surg Oncol. 2010 Dec;17(12):3259-68. (South Korea)

DFS OS

P=0.022

P=0.041

Patient no CIA showed poor Disease Free Survival (DFS) and Over all Survival (OS)

ZOLADEX® in the management

of breast cancer

St Gallen 2013

Goldhirsch A. et al. Annals of Oncology 2013; 24: 2206–2223,

ZOLADEX®: Mechanism of Action

(1/2)

LHRH

(hypothalamus)

Pituitary gland

Estrogen

Progesterone

Ovary

ZOLADEX® —

downregulation

of LHRH

receptors

Gonadotrophins

(FSH + LH)

Breast

LHRH, luteinizing hormone-releasing hormone;

FSH, follicle-stimulating hormone; LH,

luteinizing hormone. 1. Kovacs M. PNAS. 2001; 98(21):12197–12202

go

se

reli

n

Pituitary

Cell LH

Pituitary

Cell LH

ZOLADEX®: Mechanism of Action

(2/2)

Hypersecretion of LH following acute

administration of ZOLADEX®

Hyposecretion of LH following chronic

administration of ZOLADEX ®

LH, luteinizing hormone.

ZOLADEX® 3.6 mg suppresses serum oestradiol to

postmenopausal level by the eighth day.

Matta WH, et al. Endocrinologic and clinical evaluation following a single administration of a GnRH agonist (ZOLADEX),in a depot formulation to premenopausal women.Fertil Steril 1988;49:163-165

Surgery

R

a

n

d

o

m

i

z

a

t

i

o

n

ZOLADEX® 3.6 mg/28 days for 2 years

CMF* x 6 cycles

CMF* x 6 cycles followed by ZOLADEX®

3.6 mg/28 days for 18 months

ER+ or ER– or ER unknown

Planned radiotherapy (Yes/No)

Institution

1:1:1

(N=1063)

Pre-/Peri-menopausal Stratification

Castiglione-Gertsch M, et al. J Natl Cancer Inst. 2003;95:1833–1846.

*CMF: Cyclophosphamide 100 mg/m2 oral on days 1-14; Methotrexate 40 mg/m2 IV on days 1, 8; 5-Fluorouracil 600 mg/m2 IV on days 1, 8

IBCSG VIII: Trial Design

Objective

To examine the role of adjuvant treatment using chemotherapy, ovarian suppression with goserelin, or the sequential combination of both modalities in pre- and peri-menopausal patients with lymph node–negative breast cancer

Primary Outcome:

Disease-free survival

IBCSG VIII Result : DFS in ER+ Patients by Age

*Retrospective analysis CMF ZOLADEX ® 3.6 mgZOLADEX® 3.6 mg CMF

ER+, Age 39 Years

1 2 3 4 5 6 800

20

40

80

100

60

7Years

Events

14

17

6

n

38

47

41

5-Yr %

62

64

85

p

0.02

0.94

0.02

Pe

rce

nta

ge o

fal

ive

an

d

dis

eas

e-f

ree

pat

ien

ts (

%)

Years

ER+, Age 40 Years

n

191

200

203

Events 5-Yr% p

36

38

38

85

85

87

0.99

0.90

0.83

0

20

40

80

100

60

1 2 3 4 5 6 80 7

Castiglione-Gertsch M, et al. J Natl Cancer Inst. 2003;95:1833–1846.

*CMF = Cyclophosphamide 50 mg/m2 IV on

days 1, 8 or 100 mg/m2 oral on days 1-14;

Methotrexate 40 mg/m2 on days 1, 8; 5-

Fluorouracil 600 mg/m2 IV on days 1, 8

ZOLADEX ® 3.6 mg demonstrated similar efficacy to CMF with respect to DFS in pre-/peri-menopausal women with hormone-sensitive, node-negative disease

Davidson NE, et al. J Clin Oncol. 2005;23:5973–5982.

R

a

n

d

o

m

i

z

a

t

i

o

n

1:1:1

CAF

6 x 28-day cycles

CAF x 6 cycles followed by

ZOLADEX® 3.6mg/28 days for 5 years

CAF x 6 cycles followed by ZOLADEX® ’

3.6mg/28 days for 5 years + tamoxifen

20mg/day for 5 years

CAF = Cyclophosphamide 100 mg/m2/d orally on

days 1-14; Doxorubicin 30 mg/m2 IV on days 1 and

8; Fluorouracil 500 mg/m2 IV on days 1 and 8

Multicenter, US

comparative trial

Surgery ±

radiotherapy

• 1503 eligible patients (29% aged younger than 40 years)

• Median follow-up 9.6 years (551 recurrences)

INT0101 Trial: Study Design

Primary End Points :

Time to recurrence, disease-free interval, and survival in pre-menopausal node +ve, receptor +ve breast cancer

CAFZ vs CAF: p=NSCAFZT vs CAFZ: p<0.01

0 1 2 3 4 5 6 7 8 9 10

0.0

0.2

0.4

0.6

0.8

1.0

9-yr DFS

CAF 57%

CAF + Zoladex ® 3.6mg (CAFZ) 60%

CAF + Zoladex ® 3.6mg + tamoxifen (CAFZT) 68%

INT-0101 Trial: Disease-free SurvivalP

rob

abili

ty

Disease-free survival (years)

ZOLADEX® + tamoxifen after chemotherapy shows significant improving DFS than chemotherapy alone in young and pre-menopausal patients with node +ve, high-risk breast cancer


DFS, disease-free survival;

1 2 3 5 6 7 8

1.0

0.8

0.6

0.4

0.2

Pro

ba

bil

ity

Disease Free Survival (years)9 100

0

9yr DFS

CAF 48%

CAFZ 55%

CAFZT 64%

INT-0101 Trial: Disease-Free Survival

For Women < 40 years


For women < 40 years seemed to benefit from the addition of ZOLADEX® to CAF

Randomised trials, from four collaborative groups, with an essentially

common protocol; 2,710 eligible patients

Node+ve or node–ve (stage I or II) disease; no exclusion based on

ER status

Standard therapy = ± radiotherapy ± chemotherapy

Surgery

‘Zoladex’ 3.6mg/28 days +

tamoxifen 20–40mg/day for 2 years

Standard

therapy.

‘Zoladex’ 3.6mg/28 days

for 2 years

Tamoxifen 20–40mg/day

for 2 years

No further treatment

randomise

1:1:1:1

Baum et al. Eur J Cancer, 2006; 42:895-904

ZIPP : Study Design

ZIPP : Zoladex in Pre-menopausal Patients

ZIPP: Outcomes

Baum M, et al. Euro J Cancer. 2006;42:895-904.

0 2 4 6 8 1210

Time since randomisation (years)

Pro

po

rtio

n a

liv

e a

nd

ev

en

t-fr

ee

0.0

0.2

0.4

0.6

0.8

1.0GoserelinControl

0 2 4 6 8 1210

Time since randomisation (years)P

rop

ort

ion

aliv

e

0.0

0.2

0.4

0.6

0.8

1.0GoserelinControl

Number at risk:

No goserelin 1356 1062 702 381 134 22 0

Goserelin 1354 1108 772 418 156 31 0

Number at risk:

No goserelin 1356 1216 877 486 178 33 0

Goserelin 1354 1214 893 501 198 37 0

ZOLADEX ® combined with standard therapy is more effective than standard

therapy alone in pre-menopausal women with early breast cancer1,2

Kaplan-Meier curve of event-free survival in patients

receiving goserelin or no goserelin in addition to standard

adjuvant therapy.

Kaplan-Meier curve of overall survival in patients receiving

goserelin or no goserelin in addition to standard adjuvant

therapy.

HR 0.81;95%, CI 0.67-0.99,

P=0.038HR 0.80;95%, CI 0.69-0.92,

P=0.002

Goserelin (2 yrs):

(1) improved DFS (0.80;p=0.002) (2) improved OS (0.81;p=0.038)

Baum M, et al. Euro J Cancer. 2006;42:895-904.

ZIPP: Outcomes

Key Takeaways

Patient < 40 years old have higher tendency to not achievedChemotherapy Induced Amenorrhea (CIA) and have poor prognosis (DFS& OS)

Goserelin (ZOLADEX® 3.6 mg) suppresses serum oestradiol topostmenopausal level

Goserelin (ZOLADEX® 3.6 mg) combined with standard therapy is moreeffective than standard therapy alone in pre-menopausal women withearly breast cancer

Zoladex ca mammae

Health & Medicine

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