IBCSG Trial VIIIAdjuvant Chemotherapy, Goserelin,

or Their Sequential Combinationfor Pre/Perimenopausal Patients with

Node-negative Breast Cancer

International Breast Cancer Study Group

IBCSG VIII:Rationale of the Study

In the mid-1980ies:• Some beneficial effect of ovarian ablation,

considered overtreatment for N-• Chemotherapy beneficial especially for

premenopausal women with N+ disease• The majority of patients with N- disease were

offered no adjuvant treatment after surgery• CT-induced amenorrhea associated with

improved DFS (limited duration and permanent)

IBCSG VIII: Aims

To test the therapeutic role of short duration ovarian function suppression in pre-/perimenopausal patients with N- breast cancer by asking the following questions:

• Could LH-RH analogue (x 24) be as effective as CMF x 6 alone?

• Could the sequence (CMF x 6 → LH-RH analogue x 18) improve results compared with CMF alone?

IBCSG Trial VIIIPre/perimenopausal, node-negative diseaseAccrual: 1990-1999; Total patients: 1111

StrataRANDOMIZE

No adjuvant therapy (drop 4/92)

Goserelin x 24 mos.

CMFx6

CMFx6 → Goserelin x 18 mos.

Institution

ER status

RT

IBCSG VIII: Statistical Considerations

• Primary endpoint: DFS• 224 events for 80% power• 202 events in current analysis• Median follow-up: 5.8 years

IBCSG VIII: Patient CharacteristicsGoserelin

x 24CMF x 6 CMF x 6 →

Goserelin x 18Patients 346 360 357

Age at entry≤ 39 y 20% 19% 21%40 – 49 y 63% 66% 61%≥ 50 y 17% 15% 18%

IBCSG VIII: Patient Characteristics

Goserelin CMF x 6 CMF x 6x 24 Goserelin x 18

Tumor size≤ 2 cm 61% 60% 63%> 2 cm 38% 39% 36%unknown 1% 1% 1%

Nodes examinedmedian 16 16 16

IBCSG VIII: Patient Characteristics

Goserelin CMF x6 CMFx6x 24 Goserelin x 18

ER-status

Absent: 0 11% 10% 11%

Low: 1-9 19% 19% 17%

Positive: 10+ 66% 68% 68%

Unknown 4% 3% 3%

ER-absent plus ER-low were stratified as ER-negative

IBCSG VIII: ComplianceGoserelin

Goserelin x 24 CMF x 6 Goserelin x 18

Total patients 346 357Completed goserelin 281 (82%) 274 (77%)No goserelin 10 (3%) 36 (10%)Incomplete goserelin 55 (15%) 48 (13%)

IBCSG VIII: ComplianceCMF

CMFx6 CMFx6 Goserelin x 18

Total Patients 360 357Completed CMFx6 327 (90%) 320 (89%)No Chemotherapy 6 (2%) 11 (3%)<6 cycles of CMF 28 (8%) 27 (8%)

IBCSG VIII: Cessation of Menses Age ≥ 40

No Rx Gos CMFx6 CMF-Gos

0

10

20

30

40

50

60

70

80

90

100

1 4 7 10 13 16 19 22 25 28 31 34

Month from Randomization

Perc

ent w

ithou

t Men

ses

IBCSG VIII: Cessation of MensesAge ≤ 39

0

10

20

30

40

50

60

70

80

90

100

1 4 7 10 13 16 19 22 25 28 31 34

Month from Randomization

Perc

ent w

ithou

t Men

ses

No Rx Gos CMFx6 CMF-Gos

IBCSG VIII: DFS and OS

IBCSG VIII: DFS by ER

IBCSG VIII: DFS for ER+ by Age

IBCSG VIII: STEPP for ER+ CMF vs. Goserelin

Median Age of Subpopulations

IBCSG VIII: STEPP for ER+ CMF→ Goserelin vs. CMF

Median Age of Subpopulations

IBCSG VIII: STEPP for ER+ CMF→ Goserelin vs. Goserelin

Median Age of Subpopulations

IBCSG VIII Conclusions (1)

• IBCSG VIII: patient selection by risk (N-) rather than endocrine responsiveness

• Treatment effects appear to differ according to ER-status and age.

• As expected now, goserelin alone is less effective than CMF containing regimens for the ER– cohort.

IBCSG VIII Conclusions (2)

For ER+ cohort (conclusions less certain):

• No tamoxifen was given and goserelinwas only administered for up to 2 years.

• Results for goserelin and CMF are similar.

• The sequence of CMF → goserelin may reduce the risk of an event compared with either modality alone, especially for younger patients.

Tailored Treatment InvestigationsPremenopausal patients with endocrine-responsive disease

(ER > 10% and/or PgR > 10%)

SOFT: Suppression of Ovarian Function Trial (BIG 2-02)tamoxifen vs OFS + tamoxifen vs OFS + exemestane

TEXT: Tamoxifen and Exemestane Trial (BIG 3-02)OFS + tamoxifen vs OFS + exemestane

PERCHE: Premenopausal Endocrine-Responsive Chemotherapy Trial (BIG 4–02)

CT + OFS + tam/exe vs OFS + tam/exe

SOFT and TEXT include North American Intergroup participationCoordinating Group: International Breast Cancer Study Group (IBCSG)Pharmaceutical Partner: Pharmacia

Thanks to patients, physicians, nurses, and data managers of the IBCSG

• Australia New Zealand (ANZ 5 centers)• Swiss Group (SAKK 8 centers)• Ljubljana (Slovenia)• Aviano (Italy)• Madrid (Spain)• Cape Town (R. of S. Africa)• Göteborg (Sweden)• Milan (Italy)• Brescia (Italy)• Vicenza (Italy)• …and many other members of the IBCSG