- Email: [email protected]
PRIME: A randomised trial assessing the role of post-operative breast radiotherapy in older patients
S44’
Poster
Session
II.
OutcondVew
Inhibitor). Data are sparse because, in addition to breast cancer in younger women being a rare disease, positive results for CT in the 1970s (mainly for women in their forties) and misleading overview reports on TAM in the 1980’s and 1990’s inhibited evaluation of endocrine therapies for younger women. Thus, the adjuvant treatment of choice for individual premenopausai women with endocrine responsive disease is largely a matter of physician prejudice based on assessment of risk of relapse and relative role of endocrine versus cytotoxic approaches. To offer a randomized clinical trial as the treatment of choice for the largest number of premenopausal women with endocrine responsive disease, three tailored treatment investigations are being conducted globally by the BIG and the North American Breast Intergroup with the IBCSG serving as the coordinating group. The specific designs are the subject of another St. Gallen Conference abstract.
P104
Tailored treatment investigations for premenopausal women with endocrine responsive (ER+ and/Or PGf?+l breast cancer: The SOFT. , TEXT. , and PERCHE Trials ’
P. Francis’.‘.3, G. Fleming, M.L. Nasi, 0. Pagani, E. Perez, B. Walley. ‘for the International Ereasl Cancer Study Group (IECSG); a Breast international Group (BIG); 3 North American Breast Intergroup Chemotherapy (CT), tamoxifen (TAM), and ovarian ablation/suppression (OFS) are effective adjuvant therapies for premenopausal women with ER+ breast cancer. The aromatase inhibitor, exemestane (EXE), also warrants study in this population. In a BIG - North American Intergroup collaboration coordinated by IBCSG, three complementary trials (tailored treatment investigations) will be conducted to assess adjuvant therapies for premenopausal women with ER+ and/or PgR+ breast cancer (JCO 2002;20:1956-57). One trial is for women whose doctors ordinarily use TAM alone as endocrine therapy (either after surgery alone or after completion of CT), and two trials are for women whose doctors prefer to use OFS from the start of adjuvant therapy. The Suppression of Ovarian Function Trial (SOFT: IBCSG 24-02) is for women who remain premenopausal after surgery alone (randomization within I2 weeks) or after completion of adjuvant and/or neoadjuvant CT (randomization between 2 weeks and 6 months after the final CT dose). Premenopausal status is determined by estradiol (E2) level. Patients who receive TAM or an aromatase inhibitor during the B-month post-CT period are eligible. Randomized treatments are: TAM (20 mg daily for 5 years); TAM plus OFS (either triptorelin (GnRH agonist) 3.75 mg by injection every 28 days for 5 years or surgical oophorectomy or ovarian irradiation); and EXE (25 mg daily for 5 years) plus OFS. The Tamoxifen and Exemestane Trial (TEXT: IBCSG 25-02) is for women who receive OFS from the start of adjuvant therapy (randomization within I2 weeks of surgery). Randomization is to either TAM or EXE. In TEXT, OFS must be achieved by triptorelin for at least the first 6 months on study. CT, if given, should be started with the triptorelin and followed by the TAM or EXE. Use of CT is by investigator/patient choice or by randomized assignment in the PERCHE trial. The Premenopausal Endocrine Responsive Chemotherapy trial (PERCHE: IBCSG 26-02) features randomization either to OFS plus TAM or EXE, or to CT plus OFS plus TAM or EXE. Women for whom the role of adding CT to “complete estrogen blockade” is uncertain, should be offered PERCHE (to determine whether or not CT is used) and then TEXT (to determine choice of TAM or EXE). Activation is anticipated in March 2003. Target accruals are 3000 patients within 5 years for SOFT, 1875 patients within 4.5 years for TEXT, and 1750 patients within 7 years for PERCHE. Pharmacia/Pfizer is the pharmaceutical partner.
P105
Friclq,
protocols
PRIME: A randomised trial assessing the role of post-operative breast radiotherapy in older patients
I.K. Kunkler’, R.J. Prescott*, L.J. Williams*, C.C. King2, J.M. Dixon3, Ft. Lindley4. R. Leonard5, J. Cairns6, A. Rodger’, R. Sainsburys. ’University of Edliburgh. Depatiment of Clinical Oncolog): Edinburgh, United Kingdom; 2 Unive@y of Edinburgh, Medical Statistics Unit, Edinburgh, United Kingdom; 3 LJniver@v of Edinburgh, Edinburgh Breast l/nil, Edinburgh, United Kingdom; 4 Univetsiv of Edinburgh, Depatiment of Neurosciences, Edinburgh, United Kingdom; 5 Univetsiw of Swansea, Department of Cancer Studies, Swansea, United Kingdom; 6 University of Aberdeen, Health Economics Research Unit, Aberdeen, United Kingdom; ‘Monash University Prince Alfred Hospitat, Victoria. Australia; e Universi?y College London, Department of Surge% London, United Kingdom Post-operative breast irradiation has been the standard treatment following breast conserving surgery (BCS) and adjuvant endocrine therapy (ET), irrespective of age. However, the differences between older and younger patlents in response to treatment are poorly defined, since patients over 70 are frequently excluded from trials on the basis of age. Just over half of the cases of breast cancer occur in women aged 65 and older. In Scot-
14 March
2003
land alone, a 12% rise in breast cancer is predicted between 1996 - 2006 in women over 75. Additional cases suitable for BCS will be detected with the extension of the UK Breast Screening Programme to include women up to the age of 70. The use of breast irradiation in patients over 65 declines substantially with age due to physician and patient related factors (BallardBarbash et al. JNCI 1996;88(11):716-26). There is a body of retrospective and randomised data which suggests that the nsk of local recurrence afler BCS and ET may decline with age. At the same time, there are competing risks of death, particularly vascular, in older patients. PRIME (Post-operative Radiotherapy In Minimum-risk Elderly) is a randomised phase Ill trial assessing the effect of breast radiotherapy on local control, quality of life, morbidity and cost-effectiveness in ‘low risk’ older, node negative, patients treated by breast conserving surgery and adjuvant endocrine therapy. This trial is currently open in the UK and intends to recruit 240 patients, of which 106 have already been recruited. Phase II of PRIME aims to recruit 1000 patients (500 per arm) and is open to international recruitment. The goal of this trial is to assess the role of post-operative breast radiotherapy on local recurrence and survival, with the primary endpoint of ipsilateral breast cancer recurrence rates.
1P106 1 Phase 111randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in hormone-responsive postmenopausal breast cancer patients (National Surgical Adjuvant Study of Breast Cancer [NSAS BC] 03) Y. Takatsuka, T. Aihara. On behaff of CSPOR-BC? Kansai Rosai Hospitfal, Department of Surge% Hyogo. Japan Tamoxifen (TAM) is a well-established hormonal therapy for the adjuvant treatment of early breast cancer in postmenopausal women, showing a reduction in mortality of 26% in patients with oestrogen receptor-positive (ER+) tumours (5 yrs TAM vs no TAM: EBCTCG. Lancet 1998; 351: 1451-1467). In the ATAC trial, the aromatase inhibitor anastrozole (AN) showed a significant improvement of 22% in terms of disease-free survival (DFS) in hormone receptor-positive patients (AN vs TAM p=O.O05). and in terms of safety in the overall population (The ATAC Trialists Groups. Lancet 2002; 359: 21312139). In addition to the ATAC trial, there are several other ongoing trials with anastrozole in the adjuvant setting: four in postmenopausal patients (ARNO, Italian, ABCSG 6a and 8) and one in premenopausal patients (ABCSG 12), all of whom are ER+/progesterone receptor-positive. The present ongoing study, being carried out in Japanese patients, is a randomized. open-label, multicentre trial designed to compare the effiiacy and safety of 5 years’ TAM treatment with 5 years’ sequential treatment with TAM for 1-4 years followed by AN treatment for the remainder of the 5-year period, as adjuvant hormonal therapy in postmenopausal women with hormone-responsive breast cancer. Eligibility criteria dictates that patients are under the age of 75 years with stage I-Ill8 breast cancer who have received surgery +/-61617; chemotherapy +/-61617; radiation therapy and have been receiving TAM treatment for 1-4 years just prior to entering the study. In addition, patients have ER+ or progesterone receptor-positive (PR+) tumours and are performance status 0-l. Patients are randomized to either receive ongoing TAM or to switch from TAM to AN treatment. The primary endpoints are DFS and incidence of adverse events. Recruitment has just started, with a target of 2500 patients. Secondary endpoints include recurrence-free survival, overall survival, health-related quality of life and health economics will also be examined.
PI07
Cost-effectiveness projections of anastrazole (AN) vs. tamoxifen (T) as Initial adjuvant therapy in ER-positive early breast cancer using data from the ATAC trial
B.E. Hillner. Virginia Commonwealth Universi~ & Massey Cance Ce, Richmond VA, USA The ATAC adjuvant trial in post-menopausal women with early breast cancer found at a median of 33 mo. a significant reduction in disease recurrence with AN compared to T but no benefit from combined (C) therapy. The debate about whether to support AN as the new preferred first-line hormonal therapy has focused on its preliminary nature, lack of a survival advantage, concerns about osteoporosis, and has not considered cost-effectiveness (CE). This projected CE analysis was performed independent of support from the manufacturer or regulatory agencies. Methods & Assumptions: The model used updated recurrence data (San Antonio abstract, 2002) with a 47 mo. median follow-up. Cohorts of 64 y.o. women (mean age in trial) were given AN or T for 5 yrs or first recurrence and followed for IO or 20 yrs. Daily recurrence risks were inferred from observed events and projected to remain constant. Benefits and costs were
Poster
Session
II.
OutcondVew
Inhibitor). Data are sparse because, in addition to breast cancer in younger women being a rare disease, positive results for CT in the 1970s (mainly for women in their forties) and misleading overview reports on TAM in the 1980’s and 1990’s inhibited evaluation of endocrine therapies for younger women. Thus, the adjuvant treatment of choice for individual premenopausai women with endocrine responsive disease is largely a matter of physician prejudice based on assessment of risk of relapse and relative role of endocrine versus cytotoxic approaches. To offer a randomized clinical trial as the treatment of choice for the largest number of premenopausal women with endocrine responsive disease, three tailored treatment investigations are being conducted globally by the BIG and the North American Breast Intergroup with the IBCSG serving as the coordinating group. The specific designs are the subject of another St. Gallen Conference abstract.
P104
Tailored treatment investigations for premenopausal women with endocrine responsive (ER+ and/Or PGf?+l breast cancer: The SOFT. , TEXT. , and PERCHE Trials ’
P. Francis’.‘.3, G. Fleming, M.L. Nasi, 0. Pagani, E. Perez, B. Walley. ‘for the International Ereasl Cancer Study Group (IECSG); a Breast international Group (BIG); 3 North American Breast Intergroup Chemotherapy (CT), tamoxifen (TAM), and ovarian ablation/suppression (OFS) are effective adjuvant therapies for premenopausal women with ER+ breast cancer. The aromatase inhibitor, exemestane (EXE), also warrants study in this population. In a BIG - North American Intergroup collaboration coordinated by IBCSG, three complementary trials (tailored treatment investigations) will be conducted to assess adjuvant therapies for premenopausal women with ER+ and/or PgR+ breast cancer (JCO 2002;20:1956-57). One trial is for women whose doctors ordinarily use TAM alone as endocrine therapy (either after surgery alone or after completion of CT), and two trials are for women whose doctors prefer to use OFS from the start of adjuvant therapy. The Suppression of Ovarian Function Trial (SOFT: IBCSG 24-02) is for women who remain premenopausal after surgery alone (randomization within I2 weeks) or after completion of adjuvant and/or neoadjuvant CT (randomization between 2 weeks and 6 months after the final CT dose). Premenopausal status is determined by estradiol (E2) level. Patients who receive TAM or an aromatase inhibitor during the B-month post-CT period are eligible. Randomized treatments are: TAM (20 mg daily for 5 years); TAM plus OFS (either triptorelin (GnRH agonist) 3.75 mg by injection every 28 days for 5 years or surgical oophorectomy or ovarian irradiation); and EXE (25 mg daily for 5 years) plus OFS. The Tamoxifen and Exemestane Trial (TEXT: IBCSG 25-02) is for women who receive OFS from the start of adjuvant therapy (randomization within I2 weeks of surgery). Randomization is to either TAM or EXE. In TEXT, OFS must be achieved by triptorelin for at least the first 6 months on study. CT, if given, should be started with the triptorelin and followed by the TAM or EXE. Use of CT is by investigator/patient choice or by randomized assignment in the PERCHE trial. The Premenopausal Endocrine Responsive Chemotherapy trial (PERCHE: IBCSG 26-02) features randomization either to OFS plus TAM or EXE, or to CT plus OFS plus TAM or EXE. Women for whom the role of adding CT to “complete estrogen blockade” is uncertain, should be offered PERCHE (to determine whether or not CT is used) and then TEXT (to determine choice of TAM or EXE). Activation is anticipated in March 2003. Target accruals are 3000 patients within 5 years for SOFT, 1875 patients within 4.5 years for TEXT, and 1750 patients within 7 years for PERCHE. Pharmacia/Pfizer is the pharmaceutical partner.
P105
Friclq,
protocols
PRIME: A randomised trial assessing the role of post-operative breast radiotherapy in older patients
I.K. Kunkler’, R.J. Prescott*, L.J. Williams*, C.C. King2, J.M. Dixon3, Ft. Lindley4. R. Leonard5, J. Cairns6, A. Rodger’, R. Sainsburys. ’University of Edliburgh. Depatiment of Clinical Oncolog): Edinburgh, United Kingdom; 2 Unive@y of Edinburgh, Medical Statistics Unit, Edinburgh, United Kingdom; 3 LJniver@v of Edinburgh, Edinburgh Breast l/nil, Edinburgh, United Kingdom; 4 Univetsiv of Edinburgh, Depatiment of Neurosciences, Edinburgh, United Kingdom; 5 Univetsiw of Swansea, Department of Cancer Studies, Swansea, United Kingdom; 6 University of Aberdeen, Health Economics Research Unit, Aberdeen, United Kingdom; ‘Monash University Prince Alfred Hospitat, Victoria. Australia; e Universi?y College London, Department of Surge% London, United Kingdom Post-operative breast irradiation has been the standard treatment following breast conserving surgery (BCS) and adjuvant endocrine therapy (ET), irrespective of age. However, the differences between older and younger patlents in response to treatment are poorly defined, since patients over 70 are frequently excluded from trials on the basis of age. Just over half of the cases of breast cancer occur in women aged 65 and older. In Scot-
14 March
2003
land alone, a 12% rise in breast cancer is predicted between 1996 - 2006 in women over 75. Additional cases suitable for BCS will be detected with the extension of the UK Breast Screening Programme to include women up to the age of 70. The use of breast irradiation in patients over 65 declines substantially with age due to physician and patient related factors (BallardBarbash et al. JNCI 1996;88(11):716-26). There is a body of retrospective and randomised data which suggests that the nsk of local recurrence afler BCS and ET may decline with age. At the same time, there are competing risks of death, particularly vascular, in older patients. PRIME (Post-operative Radiotherapy In Minimum-risk Elderly) is a randomised phase Ill trial assessing the effect of breast radiotherapy on local control, quality of life, morbidity and cost-effectiveness in ‘low risk’ older, node negative, patients treated by breast conserving surgery and adjuvant endocrine therapy. This trial is currently open in the UK and intends to recruit 240 patients, of which 106 have already been recruited. Phase II of PRIME aims to recruit 1000 patients (500 per arm) and is open to international recruitment. The goal of this trial is to assess the role of post-operative breast radiotherapy on local recurrence and survival, with the primary endpoint of ipsilateral breast cancer recurrence rates.
1P106 1 Phase 111randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in hormone-responsive postmenopausal breast cancer patients (National Surgical Adjuvant Study of Breast Cancer [NSAS BC] 03) Y. Takatsuka, T. Aihara. On behaff of CSPOR-BC? Kansai Rosai Hospitfal, Department of Surge% Hyogo. Japan Tamoxifen (TAM) is a well-established hormonal therapy for the adjuvant treatment of early breast cancer in postmenopausal women, showing a reduction in mortality of 26% in patients with oestrogen receptor-positive (ER+) tumours (5 yrs TAM vs no TAM: EBCTCG. Lancet 1998; 351: 1451-1467). In the ATAC trial, the aromatase inhibitor anastrozole (AN) showed a significant improvement of 22% in terms of disease-free survival (DFS) in hormone receptor-positive patients (AN vs TAM p=O.O05). and in terms of safety in the overall population (The ATAC Trialists Groups. Lancet 2002; 359: 21312139). In addition to the ATAC trial, there are several other ongoing trials with anastrozole in the adjuvant setting: four in postmenopausal patients (ARNO, Italian, ABCSG 6a and 8) and one in premenopausal patients (ABCSG 12), all of whom are ER+/progesterone receptor-positive. The present ongoing study, being carried out in Japanese patients, is a randomized. open-label, multicentre trial designed to compare the effiiacy and safety of 5 years’ TAM treatment with 5 years’ sequential treatment with TAM for 1-4 years followed by AN treatment for the remainder of the 5-year period, as adjuvant hormonal therapy in postmenopausal women with hormone-responsive breast cancer. Eligibility criteria dictates that patients are under the age of 75 years with stage I-Ill8 breast cancer who have received surgery +/-61617; chemotherapy +/-61617; radiation therapy and have been receiving TAM treatment for 1-4 years just prior to entering the study. In addition, patients have ER+ or progesterone receptor-positive (PR+) tumours and are performance status 0-l. Patients are randomized to either receive ongoing TAM or to switch from TAM to AN treatment. The primary endpoints are DFS and incidence of adverse events. Recruitment has just started, with a target of 2500 patients. Secondary endpoints include recurrence-free survival, overall survival, health-related quality of life and health economics will also be examined.
PI07
Cost-effectiveness projections of anastrazole (AN) vs. tamoxifen (T) as Initial adjuvant therapy in ER-positive early breast cancer using data from the ATAC trial
B.E. Hillner. Virginia Commonwealth Universi~ & Massey Cance Ce, Richmond VA, USA The ATAC adjuvant trial in post-menopausal women with early breast cancer found at a median of 33 mo. a significant reduction in disease recurrence with AN compared to T but no benefit from combined (C) therapy. The debate about whether to support AN as the new preferred first-line hormonal therapy has focused on its preliminary nature, lack of a survival advantage, concerns about osteoporosis, and has not considered cost-effectiveness (CE). This projected CE analysis was performed independent of support from the manufacturer or regulatory agencies. Methods & Assumptions: The model used updated recurrence data (San Antonio abstract, 2002) with a 47 mo. median follow-up. Cohorts of 64 y.o. women (mean age in trial) were given AN or T for 5 yrs or first recurrence and followed for IO or 20 yrs. Daily recurrence risks were inferred from observed events and projected to remain constant. Benefits and costs were