Breast Committee Agenda - SWOG 2002/Breast.pdf · July-Dec 2001 Jan-June 2001 July-Dec 2000 All...

APRIL 19 - 21, 2002 SOUTHWEST ONCOLOGY GROUP BREAST 1

BREAST COMMITTEE

Chair: Robert B. Livingston, M.D. Co-Chair: Julie R. Gralow, M.D.

Statisticians: Stephanie J. Green, Ph.D. Danika Lew, M.A. Sheryl McCoy, M.S. Caroline Jiang, M.S.

Data Coordinators: Diana Lowry, B.A. Karin Rantala, R.H.I.T. Jean M. Barce, B.A. Stephanie Edwards

Protocol Coordinator: Tamra N. Oner, B.S.

Pathology: Allen M. Gown, M.D. Radiation Oncology: Lori J. Pierce, M.D.

Surgery: V. Suzanne Klimberg, M.D. Cancer Control Liaison: Silvana Martino, D.O.

Nurses: Dorothy Coleman, R.N., M.S. Marcia L. Grove-Conrad, R.N.

Clinical Research Associates:

Pamela Williams, R.N., M.S.N. Lynn B. Warren, C.R.A. Deanna Pelensky-Harrer, CCRA

2 BREAST SOUTHWEST ONCOLOGY GROUP APRIL 19 - 21, 2002

CONTENTS

Breast Committee Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Initial Registrations to Therapeutic Studies . . . . . . . . . . . . . . . . . . . . . 5

Patient Registration by Study and Arm . . . . . . . . . . . . . . . . . . . . . . . 6

E1199 Phase III Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

JMA17 Phase III Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

JMA17B Ancillary Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

N9831 Phase III Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

S8814 Phase III Intergroup (INT 0100). . . . . . . . . . . . . . . . . . . . . . . 16

S9313 Phase III Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

S9342 Cancer Control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20


S9832 Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27


S0012 Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

S0029 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

S0102 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

S0215 Phase II Pilot. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37


Breast Committee Agenda

Announcements

Scientific Presentation

Update on Adjuvant Therapy Dr. Livingston

Active Adjuvant Studies

B-30 (CTSU) Adjuvant Adriamycin, Taxotere, and Cyclophosphamide (ATC), Three-Arm Randomized Trial in Node Positive Breast Cancer

Dr. Livingston

JMA17 Letrozole vs Placebo After Five Years of Adjuvant Tamoxifen Dr. Martino

N9831 AC-Taxol +/- Herceptin for HER-2 Positive Breast Cancer, Three-Arm Randomized Trial in Node Positive Breast Cancer

Dr. Martino

R9804 (CTSU) Phase III Trial of Tamoxifen Alone vs Tamoxifen + RT for DCIS Dr. Pierce

S9927 Post-Mastectomy RT for Patients with 1-3 Positive Nodes Dr. Pierce

Active Advanced Disease Studies

S0012 AC vs AC+G-CSF in Locally Advanced Disease (Protocol change to add Taxol.)

Drs. Ellis and Livingston

S0029 Taxotere for Advanced Breast Cancer in Patients Aged 70 Years and Older

Drs. Martino and Albain

S0102 Docetaxel + Vinorelbine in Advanced HER-2 Negative Breast Cancer

Dr. Gralow

Active Cancer Control Studies

S9342 Late Cardiac Effects in Women Treated on S8897 Dr. Ganz

S9630 Trial to Prevent Endometrial Pathology in Women Receiving Tamoxifen

Drs. Potkul and Albain

S9832 Enhancing Well-Being During Breast Cancer Recurrence Dr. Gotay

Active Ancillary Studies

JMA17B Influence of Letrozole on Bone Mineral Density, Companion to JMA17

Dr. Livingston


Proposed Studies

S0215 Docetaxel + Vinorelbine + Herceptin in Advanced HER-2 Positive Disease

Dr. Kash

Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer Dr. Gralow

Adjuvant Trials Dr. Livingston

Continuous AC vs Standard AC and Docetaxel vs Docetaxel + Capecitabine in Receptor Negative Primary Breast Cancer

Dr. Budd

Sentinel Node Mapping in Multicentric Disease Dr. Klimberg

Anastrozole vs Anastrozole/Fulvestrant for Advanced Breast Cancer

Dr. Mehta

LHRH Analog Administration during Chemotherapy to Reduce Ovarian Dysfunction after Adjuvant Chemotherapy for Early Stage, Receptor-Negative Breast Cancer

Dr. Moore

MA.21 (NCIC) EC + Filgrastim + Epoetin alfa followed by Taxol vs AC-Taxol vs CEF for Node Positive or High Risk Node Negative Breast Cancer

Dr. Livingston

Closed Studies

C9741 Sequential ATC vs Concurrent AC Followed by T at 14 or 21 Day Intervals in Women with Node Positive Stage II/IIIA Breast Cancer

Dr. Martino

E1199 AC-Taxol vs AC-Taxotere for Node Positive Breast Cancer Dr. Martino

E2197 AT vs AC in High-Risk Node Negative and 1-3 Positive Node Patients

Dr. Martino

S8814 Phase III Intergroup Adjuvant Study in ER+, Postmenopausal, N+ Patients

Dr. Albain

S8897 Phase III Intergroup Adjuvant Study in N- Patients Dr. Hutchins

S9313 Phase III Intergroup Trial of Sequential vs Combined High Dose AC in High Risk Node Negative Patients

Dr. Haskell

S9445 Prognostic Factor Ancillary to S8814 Dr. Ravdin

S9520 Controlled Phase II Study of Doxorubicin and Paclitaxel as Frontline Chemotherapy for Women with Metastatic Breast Cancer

Dr. Ravdin

S9623 ABMT in Patients with ≥4 Positive Axillary Lymph Nodes Drs. Bearman and Peters

S9626 Megestrol Acetate as Treatment for Symptoms of Ovarian Failure in Women Treated for Breast Cancer

Dr. Goodwin


Initial Registrations to Therapeutic Studies

by 12 month Intervals BREAST COMMITTEE

0

500

1,000

1,500

2,000

Time of registration

JAN 1997DEC 1997

221

172

169

376

JAN 1998DEC 1998

160

180

180

114

JAN 1999DEC 1999

330

466

657

54

JAN 2000DEC 2000

260

422

456

29

JAN 2001DEC 2001

429

535

605

40

MEMBER AFFILIATES CCOP NON-SWOG


Patient Registration by Study and Arm

BREAST COMMITTEE

July-Dec

2001 Jan-June 2001 July-Dec

2000 All Patients

E1199 Breast, Adj, N+, AC-T (Doc v Pac) * AC then Paclitaxel 175 q3 wks 106 93 82 324 AC then Paclitaxel 80 q wk 107 87 82 322 AC then Docetaxel 100 q3 wks 101 93 79 318 AC then Docetaxel 35 q wk 98 97 74 318 412 370 317 1,282 JMA17 Breast, Adj, Letrozole v Placebo * Blinded Treatment 215 207 164 873 N9831 Breast, Adj, AC-Paclitaxel+/-Trastuzumab * AC + Paclitaxel 36 29 9 74 AC + Paclitaxel→Trastuzumab 31 31 8 70 AC + Paclitaxel+Trastuzumab→Trastuzumab 40 28 11 79 107 88 28 223 S9342 Breast, Cardiac Effects, Ancillary to S8897 5-8 yr MUGA Scans 0 0 0 163 10-11 yr MUGA Scans 6 3 0 9 6 3 0 172 S9623 Breast, Adj, ATC vs Chemo+AHPCS, Ph III ADR + Taxol + CTX 0 6 8 308 ADR/CTX + Hi Dose Chemo + AHPCS 0 6 20 294 0 12 28 602 S9630 Breast, MPA vs Obs for Prevention of Endometrial Pathology

Tamoxifen Alone 15 17 15 123 Tamoxifen + MPA 12 19 16 126 27 36 31 249 S9719 Breast, Clonal Hematopoiesis Ancillary to S9623

Specimen Submission 0 3 5 29 S9832 Breast, Enhancing Well Being Intervention 22 29 11 136 Control 22 27 21 135 44 56 32 271

* For non-SWOG coordinated studies only SWOG registrations are shown.


E1199/III

Patient Registration by Study and Arm BREAST COMMITTEE (Continued)

July-Dec

2001 Jan-June 2001 July-Dec

2000 All Patients

S9927 Breast, Adj, Post-Mastectomy RT, Ph III Observation 4 7 2 13 Local-Regional RT 4 6 2 12 8 13 4 25 S0012 Breast, LocAdv/Inflam, AC v AC+G Standard AC x 5 1 0 0 1 Continuous AC + G-CSF 2 0 0 2 3 0 0 3 S0102 Breast, Adv, Her2-, Doc+Vinorelbine Docetaxel+ Vinorelbine + G-CSF 10 1 0 11


E1199/III

E1199 Phase III Intergroup Coordinating Group: ECOG

Doxorubicin-Cyclophosphamide Therapy Followed by Paclitaxel or Docetaxel Given Weekly or Every 3 Weeks in Patients with Axillary

Node-Positive or High Risk Node-Negative Breast Cancer

Intergroup Participants: ECOG, SWOG, CALGB, NCCTG

Study Coordinators: J Sparano (ECOG), S Martino, J Ingle (NCCTG), V Jones (CALGB)

Statisticians: S Green, D Lew

Data Coordinator: D Lowry

Date Activated: 12/1/1999

Date Closed: 1/8/2002

Schema

RANDOMIZE

AC

AC

Docetaxel every three weeksAC

AC

Paclitaxel every three weeks

Weekly Docetaxel

Weekly Paclitaxel

Objectives To determine whether docetaxel improves disease-free survival and overall survival when compared to paclitaxel following four cycles of doxorubicin-cyclophosphamide therapy.

To determine whether weekly administration of taxanes (paclitaxel or docetaxel) for 12 weeks improves disease-free survival and overall survival when compared with the conventional (every 3 weeks) schedule for four cycles following four cycles of doxorubicin-cyclophosphamide therapy.

To compare the toxicity of docetaxel given weekly for 12 weeks to that of docetaxel given every 3 weeks for four cycles.

To compare the toxicity of paclitaxel given weekly for 12 weeks to that of paclitaxel given every 3 weeks for four cycles.

To compare the toxicity of paclitaxel given every 3 weeks for four cycles to that of docetaxel given every 3 weeks for four cycles.

To compare the toxicity of paclitaxel given weekly for 12 weeks to that of docetaxel given weekly for 12 weeks.

Patient Population Patients must have operable histologically confirmed adenocarcinoma of the female breast, with either histologically involved lymph nodes (T1-3, N1-2, M0, Stage II-IIIA) or high risk axillary node-negative disease (T2N0, stage IIA; T3N0, stage IIB). Patients who have positive axillary lymph node metastasis should have at least six axillary lymph nodes removed at axillary dissection. Patients who have had less than six lymph nodes removed are eligible if the lymph nodes were obtained by a sentinel node biopsy


E1199/III

procedure and were negative for metastasis. Patients with bilateral disease are eligible if axillary dissection revealed positive lymph nodes for at least one of the primaries.

Randomization must be performed within 84 days of mastectomy, or within 84 days of axillary dissection if the patient's most extensive breast surgery was a breast sparing procedure. Margins must be clear. No prior chemotherapy or radiation therapy for this malignancy is allowed. Patients may have received tamoxifen for purposes of prevention or up to four weeks of tamoxifen therapy for this malignancy.

Patients must have adequate hematologic, hepatic, and renal function. Patients must have no prior history of cardiac disease. Patients must be at least 18 years old.

Investigators are encouraged to enroll patients with HER2 overexpressing tumors on trial N9831 instead of this trial.

Stratification/Descriptive Factors Patients will be stratified by (1) HER2/neu: negative vs positive vs unknown; (2) age: < 50 vs ≥ 50; (3) ER status: positive vs negative vs unknown; (4) nodal status: 1-3 vs 4-9 vs 10+; (5) tumor size: ≤ 5 cm vs > 5 cm vs unknown; (6) current bisphosphonates: yes vs no; and (7) surgery: mastectomy vs breast conservation therapy.

Accrual Goals Planned accrual for this study is 5000 patients.

Summary Statement This study was activated in ECOG on October 13, 1999, and in SWOG on December 1, 1999. As of December 31, 2001, there were 4914 patients registered to this study, 1282 of them from SWOG. The study was closed to accrual on January 8, 2002.

The complete November 2001 summary of this study from ECOG is available on the Southwest Oncology Group web site.

Registration by Institution Registrations ending December 31, 2001

Institutions Total Reg Institutions

Total Reg

So Calif, U of 63 U of Tennessee MC/San Antonio, U of TX 15Central IL CCOP 55 Greater Phoenix CCOP 14Loyola University 52 Madigan Army Med Ctr/Puget Sound 14Upstate Carolina 49 Nevada Cancer Center/So Calif, U of 13LSU-Shreveport 45 Scott & White CCOP 13Dayton CCOP 44 St Louis CCOP 13Utah, U of 38 St Francis/Stormont/Kansas, U of 12Atlanta Reg CCOP 34 Arizona, U of 11Northwest CCOP 29 Doctors Medical Ctr/Davis, U of CA 11William Beau Hosp/Michigan, U of 26 Henry Mayo Newhall/Los Angeles, U of CA 11Columbia River CCOP 25 S Georgia Med Ctr/BAMC/WHMC 11Hawaii CCOP, Univ of 25 Santa Rosa CCOP 11Puget Sound 23 Cleveland Clinic OH 10Kansas City CCOP 21 Harrington/TexasTech/San Antonio, U of TX 10Grand Rapids CCOP 20 Schumpert Med Ctr/San Antonio, U of TX 10Columbia University 19 Sutter Hlth Western/Davis, U of CA 10LSU-New Orleans CCOP 19 Wayne State Univ 10Mansfield Gen Hosp/Cleveland Clinic OH 18 Arkansas, U of 9Davis, U of CA 17 St Edward Mercy MC/Arkansas, U of 9Fairview Health Sys/Cleveland Clinic OH 16 Thompson Ca Surv Ctr/San Antonio, U of TX 9St Joseph's Med Ctr/Davis, U of CA 16 Hem/Onc Associates/Cleveland Clinic OH 8Washington Reg MC/Arkansas, U of 16 St Anthony Hospital/Colorado, U of 8BAMC/WHMC 15 SW Reg Cancer Ctr/San Antonio, U of TX 8City of Hope Med Ctr 15 Virginia Mason CCOP 8Exempla Lutheran MC/Colorado, U of 15 All Other Institutions 279Montana CCOP 15 Total (134 Institutions) 1,282South Texas Onc/Hem/San Antonio, U of TX 15


JMA17/III

JMA17 Phase III Intergroup Coordinating Group: NCIC

A Phase III Randomized Double Blind Study of Letrozole Versus Placebo in Women with Primary Breast Cancer Completing Five or More Years of

Adjuvant Tamoxifen

Intergroup Participants: NCIC, SWOG, CALGB, ECOG, EORTC, IBCSG, NCCTG

Study Coordinators: P Goss (NCIC), S Martino, E Perez (NCCTG), N Robert (ECOG), H Muss (CALGB), M Castiglione (IBCSG), M Piccart (EORTC)


Data Coordinator: K Rantala


Schema

R

A

N

D

O

M

I

Z

E

Letrozole x 5 years

Placebo x 5 years

4 1/2 - 6 years

Adjuvant Tamoxifen

Objectives To determine the disease-free survival and overall survival for women who have previously received at least five years of adjuvant tamoxifen, randomized to receive either letrozole 2.5 mg daily or placebo daily for five years.

To evaluate the incidence of contralateral breast cancer.

To evaluate the long term clinical and laboratory safety of letrozole with special attention on lipid profile as assessed by blood sampling, cardiovascular morbidity and mortality, the incidence of all bone fractures, changes in bone density, and common toxicities.

To evaluate overall quality of life.

Patient Population Patients must have had histologically or cytologically confirmed breast carcinoma that

was surgically removed at the time of original diagnosis, with no evidence of metastasis. The primary tumor must not have been receptor negative (i.e., both ER and PgR negative). There must be no evidence of breast cancer recurrence at randomization.

Patients must have completed at least 4 1/2 years but not more than six years of adjuvant tamoxifen. Randomization must be within three months of tamoxifen discontinuation. Patients may have received prior adjuvant chemotherapy or radiation therapy at the time of original diagnosis.

Patients must be post-menopausal and have an ECOG performance status of 0-2. Patients must have adequate hematologic and hepatic function. Patients must not be registered to any other adjuvant breast cancer trial.


JMA17/III

Stratification/Descriptive Factors Patients will be stratified by (1) receptor status at diagnosis: positive vs unknown; (2) lymph node status at diagnosis: negative vs positive vs unknown; and (3) prior adjuvant chemotherapy: yes vs no.

Cancer Control Credits The NCI Division of Cancer Prevention (DCP) has assigned 0.5 cancer control credits per registration for this study.

Accrual Goals Planned accrual for this study is 4800.

Summary Statement This study was activated in the NCIC on August 24, 1998, and in SWOG on November 15, 1998. As of December 31, 2001, there had been 3985 registrations, 873 of them from SWOG.

The complete February, 2001 summary of this study from NCIC is available on the Southwest Oncology Group web site.

On February 5, 2001 the sample size was increased from 2380 patients to 4800 patients as evidence from newer data suggest the recurrence rate on the trial is likely to be lower than originally estimated.



Total Reg

Central IL CCOP 51 Central Baptist Hosp/Cincinnati MC, U of 13Southeast CCC CCOP 37 Utah, U of 13Greenville CCOP 36 Columbia River CCOP 12Northwest Med Ctr/Arkansas, U of 30 Madigan Army Med Ctr/Puget Sound 12Puget Sound 30 Michigan, U of 12Northwest CCOP 28 Our Lady, Bellefonte/Cleveland Clinic OH 12LSU-Shreveport 26 Virginia Mason CCOP 12So Calif, U of 25 Wayne State Univ 12Grand Rapids CCOP 24 West Florida Med Ctr/Arkansas, U of 11BAMC/WHMC 23 William Beau Hosp/Michigan, U of 11Scott & White CCOP 20 Akron Gen Med Ctr/Cleveland Clinic OH 10Atlanta Reg CCOP 19 Eisenhower Army MC/BAMC/WHMC 10Ozarks Reg CCOP 19 Hawaii CCOP, Univ of 10Sutter Hlth Western/Davis, U of CA 19 Henry Ford Hosp 10Upstate Carolina 19 St Louis CCOP 10Loyola University 17 John Muir Med Ctr/Davis, U of CA 9Columbus CCOP 16 Montana CCOP 9Dayton CCOP 15 Cleveland Clinic OH 8Santa Rosa CCOP 15 Northridge Hosp/Los Angeles, U of CA 7Wichita CCOP 15 All Other Institutions 172St Lukes/Mt States/Utah, U of 14 Total (99 Institutions) 873


JMA17B

JMA17B Ancillary Intergroup Coordinating Group: NCIC

The Influence of Letrozole on Bone Mineral Density in Women with Primary Breast Cancer Completing Five or More Years of Adjuvant

Tamoxifen: A Companion Study to NCIC CTG MA.17

Intergroup Participants: NCIC, SWOG, NCCTG

Study Coordinators: R Josse (NCIC), R Livingston, E Perez (NCCTG)




Objectives To compare the effects on bone mineral density (BMD) in the L2-L4 (postero-anterior) region of the spine and hip in a cohort of post menopausal women treated with letrozole or placebo for five years following five years of adjuvant tamoxifen therapy for breast cancer.

Patient Population Patients must be randomized on and eligible for the JMA17 core protocol.

Patients must have no evidence of osteoporosis, malabsorption syndrome, clinically relevant vitamin D deficiency, active hyper- or hypo-parathyroidism, Paget's disease, uncontrolled thyroid disease, Cushing's disease, other pituitary diseases, or other bone diseases.

Patients must not have received previous treatment with anticonvulsants or anabolic steroids within the past 12 months, high doses of corticosteroids or sodium fluoride for an extended time, any drug including bisphosphonates for the prevention of osteoporosis within the past six months, or long term use of coumarins.

Patients must have BMD ≥ 2.0 SD below the mean value of peak bone mass in young normal women. Acceptable quality DEXA of the L2-L4 postero-anterior (PA) spine and hip must be taken within four weeks of randomization to the JMA17 core protocol, as well as serum for bone biomarkers.

Accrual Goals The accrual goal is 100 eligible and evaluable patients per treatment arm of JMA17.


N9831/III

N9831 Phase III Intergroup Coordinating Group: NCCTG

Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment

for Women With HER-2 Overexpressing Node Positive Breast Cancer

Intergroup Participants: NCCTG, SWOG, CALGB, ECOG

Study Coordinators: E Perez (NCCTG), S Martino, N Davidson (ECOG), P Kaufman (CALGB)




Schema

RANDOMIZE

Arm A:Paclitaxel

Arm B:Paclitaxel

Arm C:Paclitaxel + Trastuzumab

Trastuzumab

Trastuzumab

REGISTER

AC

*

* Patients whose tumors are not HER-2 overexpressing on centralreview will go to event monitoring and will not be randomized on study.

Objectives To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of disease-free survival (DFS) and overall survival (OS).

To compare the combination of AC followed by weekly paclitaxel with the combination AC followed by the combination of weekly paclitaxel and trastuzumab in terms of DFS and OS.

To compare the sequential schedule of the combination AC, weekly paclitaxel, and trastuzumab with the combination of AC

followed by the combination of weekly paclitaxel and trastuzumab in terms of DFS and OS.

To compare the cardiotoxicities of (1) AC followed by weekly paclitaxel, (2) AC followed by weekly paclitaxel followed by weekly trastuzumab, and (3) AC followed by weekly paclitaxel and trastuzumab followed by weekly trastuzumab.

To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to HER-2 and HER-1 measured in the serum prior to treatment are prognostic for DFS and OS.


N9831/III

To determine the concordance of central review of HER-2 overexpression as measured by HerceptTest(DAKO) and Vysis FISH.

Patient Population Patients must have operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes (T1-3, pN1-2, M0) with no dermal lymphatic involvement. Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by immunohistochemistry. cN2 disease is not eligible. Patients must have ER and PgR determination. Patients must strongly express HER-2/neu as defined in the protocol. Ten unstained slides are required for central HER-2 testing, and must be received at NCCTG within the first month of registration.

Randomization must be performed within 84 days of mastectomy, or within 84 days of axillary dissection if the patient's most extensive breast surgery was a breast sparing procedure. Margins must be clear. No prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer is allowed. No prior anthracycline or taxane for any malignancy is allowed. Patients may have received tamoxifen or raloxifene for purposes of chemoprevention or up to four weeks of tamoxifen therapy or other hormonal agent for this malignancy.

Patients must have adequate hematologic and hepatic function. Patients must have no active cardiac disease, and LVEF must be within normal range. Patients must be at least 18 years old.

Stratification/Descriptive Factors Patients will be stratified by (1) positive nodes: axillary dissection with 1-3 nodes vs axillary dissection with 4-9 nodes vs axillary dissection

with 10+ nodes vs positive sentinel node with no axillary dissection performed; and (2) receptor status: ER positive or PgR positive vs other.

Accrual Goals The accrual goal for this study is 3000 eligible patients, 1000 in each arm. Three formal interim analyses are planned, when approximately 50%, 67%, and 75% of the total events have occurred.

Summary Statement This study was activated by NCCTG on May 19, 2000, and in SWOG on July 1, 2000. As of December 31, 2001, there were 783 patients registered to this study, 223 of them from SWOG.

The protocol was amended on January 15, 2002, with changes described in the NCCTG Addendum #7, including a change in the patient enrollment process. Patients will no longer be randomized based on community laboratory HER-2 testing results. Instead, patients will be randomized after central review has confirmed HER-2 positivity. Patients may be enrolled based on community HER-2 testing using FISH or HerceptTest, and AC chemotherapy can be initiated. If a patient's tumor specimen on central review is neither HER-2 amplified by FISH nor 3+ by HerceptTest, the patient will go to event monitoring and receive adjuvant therapy per investigator's discretion.

As of January 28, 2002, new patient enrollment to Arm C is temporarily on hold per recommen-dation of the Data Monitoring Committee, pending further review regarding cardiac tolerability.

The complete October 2001 summary of this study from NCCTG is available on the Southwest Oncology Group web site.


N9831/III



Total Reg

Southeast CCC CCOP 17 Davis, U of CA 4Loyola University 14 Good Samaritan Hosp/Loyola University 4Puget Sound 12 Harrington/TexasTech/San Antonio, U of TX 4Hawaii CCOP, Univ of 10 John Wayne Cancer In/City of Hope Med Ctr 4Northwest CCOP 10 Kansas City CCOP 4So Calif, U of 9 Salem Hospital/Oregon Hlth Sci Univ 4South Texas Onc/Hem/San Antonio, U of TX 8 St Lukes/Mt States/Utah, U of 4Good Samaritan HS/Kansas, U of 6 Columbia River CCOP 3Michigan, U of 6 Grand Rapids CCOP 3Wayne State Univ 6 Providence Hosp 3Arizona, U of 5 St Bernards Reg MC/Arkansas, U of 3Greater Phoenix CCOP 5 St Joseph Med Ctr/Boston Univ Med Ctr 3Yakima Valley Mem/Puget Sound 5 Thompson Ca Surv Ctr/San Antonio, U of TX 3Arkansas, U of 4 Valley Hospital/Columbia University 3City of Hope Med Ctr 4 All Other Institutions 49Cleveland Clinic OH 4 Total (65 Institutions) 223


S8814/III

S8814 Phase III Intergroup (INT 0100) Coordinating Group: SWOG

Phase III Comparison of Adjuvant Chemoendocrine Therapy with CAF and Concurrent or Delayed Tamoxifen to Tamoxifen Alone in Postmenopausal

Patients with Involved Axillary Lymph Nodes and Positive Receptors

Intergroup Participants: SWOG, CALGB (9194), ECOG (4188), NCCTG (883051), NCIC (MA9)

Study Coordinators: K Albain, C Cobau (ECOG), J Ingle (NCCTG), E Levine (CALGB), K Pritchard (NCIC)





Objectives To compare disease-free survival and overall survival of postmenopausal primary breast cancer patients with involved axillary nodes and positive estrogen and/or progesterone receptors treated with standard adjuvant therapy with long-term tamoxifen, or with chemoendocrine therapy with CAF, followed by long-term tamoxifen, or with concurrent chemoendocrine therapy with tamoxifen and CAF.

To compare the toxicities of the three therapies.

Patient Population This study is open to postmenopausal female patients with histologically proven ER or PgR positive adenocarcinoma of the breast with at least one histologically positive lymph node. Primary tumor and axillary nodes must be movable in relation to the chest wall. Patients with clinically matted nodes, skin ulcerations, peau d'orange skin changes, clinical skin involvement, positive deep mastectomy margins, inflammatory lesions or edema of the arm peroperatively are excluded. Patients with apocrine, adenoidcystic or squamous cell carinoma, or sarcoma are excluded. Patients must have no evidence of residual or metastatic disease. Patients must have no involvement of the opposite breast (exception: patients who have non-invasive ductal carcinoma in situ of the opposite breast AND have had a prophylactic contralateral mastectomy are still eligible).

Within 12 weeks prior to randomization patients must have undergone a radical, modified radical or partial mastectomy, or lumpectomy with at least a level I and II axillary dissection. At least six nodes must be examined. Radiation therapy is required if breast sparing surgery was performed; for mastectomy patients RT is an option only if the patient has tumor > 5 cm, four or more positive nodes, or extension of tumor into axillary fat. Radiation must be completed before registration, or planned to be given (but not started), according to protocol guidelines. Patients who have received prior hormonal therapy or chemotherapy for breast cancer are excluded (exception: patients may have received two weeks or less of tamoxifen, if stopped prior to registration). Previous progesterone or estrogen containing preparations (not for breast cancer) are allowed provided therapy is discontinued prior to registration.

Patients must have adequate renal, hepatic, cardiac and bone marrow function.

Stratification/Descriptive Factors Stratification factors are: 1) involved nodes: 1-3 vs 4 or more; 2) ER/PgR status: PgR+(ER+ or -) vs PgR-(ER+); 3) time from surgery to randomization: six weeks or less vs more than six weeks; and 4) cooperative group: ECOG vs NCCTG vs CALGB vs SWOG vs NCIC.


S8814/III

Descriptive factors are 1) postmenopausal estrogen at time of diagnosis: yes vs no; 2) surgery/radiation treatment: breast sparing surgery + immediate RT vs breast sparing surgery + planned RT after chemotherapy vs mastectomy only vs mastectomy + immediate RT vs mastectomy + planned RT after chemotherapy; 3) tamoxifen prior to registration: yes vs no; and 4) tumor size: <2 cm vs 2-5 cm vs >5 cm.

Accrual Goals The accrual goal is 1410 eligible patients, with 350 registered to the tamoxifen arm and 530 to each of the CAF arms. An interim analysis is planned when 3/4 of the patients have been accrued.

Summary Statement The following abstract was submitted to ASCO in December 2001.

Adjuvant Chemohormonal Therapy for Primary Breast Cancer Should Be Sequential Instead of Concurrent: Initial Results from Intergroup Trial 0100 (SWOG-8814).

PURPOSE: Both adjuvant chemotherapy and tamoxifen (T) are of proven value for hormone receptor-positive (R+) breast cancer. But, there are no data regarding the proper timing of these two systemic modalities. Laboratory evidence suggests that T antagonizes the cytotoxicity of certain chemotherapy drugs. Thus, we conducted a phase III trial to determine 1) if CAF+T (oral cyclophosphamide, Adriamycin, 5FU X6; T, 5 years) is superior to T alone in postmenopausal women with node(+), R(+) disease, the results of which were previously reported showing a strong survival benefit for CAF+T; and 2) if CAF followed by T (CAF-T) is superior to concurrent

therapy followed by T (CAFT-T), reported herein.

METHODS: After stratification by nodes, PgR and interval from surgery, patients were randomized to T, CAF-T, or CAFT-T in a 2:3:3 ratio. One-sided testing at p=.04 was planned for the hypothesis that CAF-T is superior to CAFT-T.

RESULTS: Of 1477 eligible patients, 361 received T, 566 CAF-T and 550 CAFT-T. Toxicities were similar between CAF-T and CAFT-T. Median follow-up is 8.5 years. At 6 years DFS curves began to diverge. Eight-year DFS estimates are 67% for CAF-T and 62% for CAFT-T, with a one-sided p=.045 after adjustment for stratification factors. Both CAF arms are superior to T alone (8-year DFS = 55%). Multivariate analysis showed that 4(+) nodes, PgR(-), T3 tumors and African American race were predictors of adverse DFS. The CAFT-T/CAF-T hazard ratio was 1.18 (95% CI .98-1.43) after adjustment for these factors. The survival comparison is currently not significant, but the curves began to separate after 8 years with more late events on CAFT-T than CAF-T. Additional follow-up for survival is required, since due to the strong CAF benefit over T alone, there are fewer events than projected in the CAF arms.

CONCLUSION: Delaying T until after CAF resulted in an estimated DFS advantage of 18% when compared to the concurrent use of these agents. These data are consistent with the hypothesis that T may antagonize drugs used in this or similar regimens and support a practice standard of starting adjuvant T when chemotherapy is completed.


S9313/III

S9313 Phase III Intergroup Coordinating Group: SWOG

Phase III Comparison of Adjuvant Chemotherapy with High-Dose Cyclophosphamide Plus Doxorubicin (AC) versus Sequential Doxorubicin

Followed by Cyclophosphamide (A->C) in High-Risk Breast Cancer Patients with 0-3 Positive Nodes

Intergroup Participants: SWOG, CALGB (9394), ECOG (S9313), NCCTG (93-30-51)

Study Coordinators: C Haskell, C Osborne, J Ingle (NCCTG), G Sledge (ECOG), C Shapiro (CALGB)





Schema

doxorubicin + cyclophosphamide

cyclophosphamide

C)

tamoxifen* x 5 yr

tamoxifen* x 5 yrdoxorubicin

(A

(AC)

*Postmenopausal and hormone receptor-positive premenopausal patients

RANDOMIZATI

ON

Objectives To compare disease-free survival, overall survival, and toxicity of high-risk primary breast cancer patients with 0-3 positive axillary lymph nodes treated with adjuvant high-dose chemo-therapy with doxorubicin plus cyclophosphamide (AC) or high-dose sequential chemotherapy with doxorubicin followed by cyclophosphamide (A->C).

To obtain tumor blocks from these patients for future biologic studies of relevance to this patient population.

Patient Population Patients must have been diagnosed with primary invasive adenocarcinoma of the breast. Patients must not have sarcoma, lymphoma, or apocrine, adenocystic or squamous cell carcinoma of the breast. Patients must not have recurrent breast cancer. Disease must satisfy one of the following: A) tumor ER negative and PgR negative, and > 1 cm in greatest diameter, B) tumor > 2.0 cm in greatest diameter or C) 1-3 axillary nodes involved with tumor. Patients with locally advanced disease at diagnosis are ineligible. Patients must be judged free of breast cancer (NED) prior to registration.


S9313/III

Patients must have had either a mastectomy or breast sparing surgery. The mastectomy, or the axillary dissection for those patients with breast sparing surgery, must be performed within 84 days before registration. At least six nodes must be examined. Patients may not have received prior chemotherapy for this breast cancer or any systemic treatment for prior breast cancer. Patients must not have had external beam radiotherapy for this breast cancer prior to registration. Interstitial radiation therapy at the time of breast sparing procedure is acceptable. Patients whose most extensive breast surgery was a breast sparing procedure must be planning to receive radiotherapy after chemotherapy is complete.

Patients must have adequate hematologic, renal, hepatic, and cardiac function, and adequate health for long-term follow-up.

Stratification/Descriptive Factors Patients will be randomized within cooperative groups. Descriptive factors are: 1) menopausal status: pre vs post; 2) estrogen receptor status: ER+ vs ER- vs Unk; 3) progesterone receptor status: PgR+ vs PgR- vs Unk; 4) type of surgery: modified radical mastectomy vs breast sparing procedure; 5) tumor size: >1 to ≤2cm vs >2 to ≤5cm vs >5cm; 6) time since definitive surgery: ≤ 6 weeks vs > 6 weeks; 7) number of positive nodes: 0 vs 1-3.

Accrual Goals The accrual goal is 1500 eligible patients per arm.

Summary Statement The following abstract was submitted to ASCO in December 2001.

BACKGROUND: Chemotherapy efficacy is considered a function of dose intensity (DI).

Theoretically, DI is greater with sequential than with concurrent combination chemotherapy.

PURPOSE: Compare disease-free survival (DFS), overall survival (OS), and toxicity of breast cancer patients with 0-3 positive lymph nodes treated with the same total dose of chemotherapy over 18 weeks using an AC schedule versus an A->C schedule.

METHODS: Between 4/18/94 and 5/1/97, 3,176 patients were randomized to receive AC or A->C. Both groups were to receive 324 mg/m2 of A and 7,200 mg/m2 of C iv over 18 weeks with concurrent filgrastim. The DI (mg/m2/wk) of AC was 18 of A and 400 of C over 18 weeks. The DI of A->C was 27 of A over 12 weeks and 1200 of C over 6 weeks.

RESULTS: The groups are well balanced for prognostic factors; 78 patients are ineligible; median follow-up is 5.3 years. Estimated 5-year DFS is 80%, 81% for AC, A->C respectively (one-sided p=0.15; 627 events). AC/A->C hazard ratio estimate for DFS is 1.09, with 95% confidence interval (.93, 1.27). OS differences are also not significant. Acute toxicity of A->C was greater than AC, with 88% of AC and 83% of A->C patients completing treatment as planned. Grade 4 hematologic toxicity was more common with A->C (65%) than with AC (48%) (p<.00001), as was Grade 4 emesis (p=0.03). One toxic death occurred (on A->C).

CONCLUSIONS: These results rule out the 30% improvement in DFS with sequential therapy that the study was designed to detect. A->C and AC have similar efficacy, but A->C was more toxic. Follow-up will continue, but at 5 years AC has a better therapeutic index.


S9342

S9342 Cancer Control

A Study of the Late Cardiac Effects of Two Different Adjuvant Chemotherapy Regimens in Women with Node Negative Breast Cancer

Treated on S8897

Study Coordinators: P Ganz, K Albain, L Hutchins

Statisticians: S Green, S McCoy

Data Coordinator: J Barce


Objectives To compare the frequency of sub-clinical congestive heart failure in women treated with CMF or CAF chemotherapy in S8897 as measured by resting MUGA scan at 5-8 and 10-11 years after randomization.

To estimate the frequency of late cardiac effects (congestive heart failure, cardiac ischemic events, clinical symptoms) in women treated with CMF or CAF chemotherapy on S8897.

To prospectively monitor annual cardiac events between the 5th and 10th year after randomization.

Patient Population Patients must be registered to Arms I-IV of S8897 and have completed at least one course of the assigned chemotherapy. Registration to S9342 must occur between five years three months and eight years post S8897 randomization or between 10 and 11 years post randomization. A MUGA must have been obtained within three months prior to registration, or must be planned within one month after registration.

Pregnant or nursing women must agree not to have a nuclear medicine study, but may otherwise participate. Women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during and for one

month after the MUGA scan. Patients must be disease-free, without a past recurrence.


Accrual Goals The accrual goal is at least 70 patients per treatment group registered in years 5-8 and an additional 25 patients per group registered in years 10-11.

Summary Statement As of December 31, 2001, 163 patients had been registered to this study in the 5-8 years post randomization group, 80 from CMF arms and 83 from CAF arms. Nine additional patients have been registered from the 10-11 years post randomization group, four from CAF arms and five from CMF arms.

Funding is still available for reimbursement of all MUGA scans for patients registered to this study.

The annual cardiac history form submission rates for patients qualifying for assessments are as follows: 5-year assessment, 100%; 6-year assessment, 96%; 7-year assessment, 97%; 8-year assessment, 86%; 9-year assessment, 67%; and 10-year assessment, 74%.


S9342

Initial Registrations By 3 Month Intervals

0

10

20

30

40

Time of Registration

JANMAR1997

1APRJUN1997

8

JULSEP1997

10

OCTDEC1997

19

JANMAR1998

6

APRJUN1998

19

JULSEP1998

22

OCTDEC1998

31

JANMAR1999

16

APRJUN1999

5

JULSEP1999

13

OCTDEC1999

8

JANMAR2000

4

APRJUN2000

1APRJUN2001

3

JULSEP2001

2

OCTDEC2001

4

Total



Total Reg

Wichita CCOP 21 St Francis/Stormont/Kansas, U of 4Greenville CCOP 12 Sutter Hlth CRG-East/Davis, U of CA 4Ozarks Reg CCOP 12 Virginia Mason CCOP 4Kansas City CCOP 8 Arizona, U of 3Henry Ford Hosp 7 Irvine, U of CA 3Arkansas, U of 6 Northwest CCOP 3LSU-Shreveport 6 San Antonio, U of TX 3Oregon Hlth Sci Univ 6 South Alabama CCOP 3Salina Reg Hlth Ctr/Kansas, U of 6 Dixie Medical Center/Utah, U of 2So Calif, U of 6 East Texas Med Ctr/San Antonio, U of TX 2Columbus CCOP 5 Michigan, U of 2St Edward Mercy MC/Arkansas, U of 5 Muskogee Reg Med Ctr/Oklahoma, Univ of 2Dayton CCOP 4 Providence Hospital/Cleveland Clinic OH 2Grand Rapids CCOP 4 All Other Institutions 19Harrington/TexasTech/San Antonio, U of TX 4 Total (48 Institutions) 172Loyola University 4


S9630/III


A Randomized Comparison of Medroxyprogesterone Acetate and Observation for Prevention of Endometrial Pathology in Postmenopausal

Breast Cancer Patients Treated with Tamoxifen

Intergroup Participants: SWOG, CALGB

Study Coordinators: R Potkul, K Albain, C Saloman, S Wilczynski, S Khan (CALGB)

Statisticians: D Pauler, S McCoy



Schema

RANDOMIZE Tamoxifen plus Medroxyprogesterone Acetate x 5 years

Tamoxifen alone x 5 years

StartTamoxifen*

*Randomization must occur within 28 days. Objectives Primary Objectives

To compare endometrial pathologic diagnoses (in particular, proliferative changes, simple or cystic hyperplasia, complex [adenomatous] hyperplasia, hyperplasia with atypia and carcinoma) for postmenopausal, tamoxifen-treated breast carci-noma patients, randomly assigned to tamoxifen alone or tamoxifen plus cyclical medroxy-progesterone acetate.

To compare endometrial pathologic diagnoses resulting in tamoxifen discontinuation (persistent endometrial hyperplasia, atypia or carcinoma) and intermittent bleeding in breast carcinoma patients described above.

Secondary Objectives

To characterize the incidence of spontaneous regression and progression of simple or cystic hyperplasia.

To compare changes over time in endometrial oncogene expression and receptor status for the patients described above.

To describe associations among changes in gene expression, receptor status, endometrial abnor-mality, length of tamoxifen exposure, and prior chemotherapy in the patients described above.

To determine the feasibility of collecting centrally frozen tissue hysterectomy specimens from tamoxifen-treated breast carcinoma patients for the purpose of analyzing the regulation of 17 Beta-hydroxysteroid dehydrogenase activity in endometrial tissue.


S9630/III

To establish a repository of paraffin blocks and frozen endometrial tissue from tamoxifen-treated breast cancer patients.

Patient Population Patients must have been diagnosed with primary invasive adenocarcinoma of the breast staged as T1-3, N0-1, and M0. Patients must not have sarcoma, lymphoma, or apocrine, adenocystic or squamous cell cancer of the breast. Patients must not have had recurrent invasive breast cancer and must be currently free of breast cancer (no evidence of disease). Patients must have had definitive local treatment of the primary lesion (mastectomy or breast-sparing procedure) and have undergone either an axillary node dissection or sampling or a sentinal node biopsy.

Adjuvant chemotherapy is permitted. The therapy may have been completed, may be ongoing, or may be planned to start with the tamoxifen. Patients must not have received any hormonal treatment, other than tamoxifen per protocol for their breast cancer. Patients must be planning to start five years of adjuvant tamoxifen or must have started tamoxifen ≤ 28 days prior to registration and be planning to receive adjuvant tamoxifen for five years. Any post-menopausal estrogen therapy must be discontinued prior to registration.

Patients who are currently eligible for or who were treated on any adjuvant intergroup trial are not eligible for this study. Patients must be female and postmenopausal as defined in the protocol. Patients who have undergone a hysterectomy are ineligible. Patients with endometrial hyperplasia, proliferative changes, atypical hyperplasia, or carcinoma as determined by endometrial biopsy are ineligible.

Stratification/Descriptive Factors Patients are stratified by: (1) prior adjuvant chemotherapy: yes vs no; and (2) number of positive nodes: 0-3 vs > 3.


Accrual Goals The accrual goal is 330 eligible patients.

Summary Statement As of December 31, 2001, 249 patients had been randomized. Fifty-two patients are currently ineligible, 43 due to insufficient documentation. Thirty-two of these patients could become eligible with the submission of the required documentation. Major deviations are recorded for one patient who had a total hysterectomy after randomization, twelve patients who incorrectly were given Megace instead of medroxy-progesterone acetate, six patients randomized to the tamoxifen plus cyclical medroxyprogesterone acetate arm who did not take any study drug, and one patient on the tamoxifen only arm who was underdosed by 50% during the first week of treatment.

One hundred sixty-one patients have been evaluated for toxicities. Currently ineligible patients who could become eligible if documentation is submitted are included in the table. Eight of the 85 patients evaluated for toxicity on the tamoxifen plus cyclical medroxyprogesterone acetate arm experienced a Grade 3 toxicity: masculinization, weight gain, respiratory infection, vaginitis, neutropenia/ granulocytopenia, deep vein thrombosis, back pain and purpura. The Grade 3 "Toxicity of unknown category" was chest tightness. One patient randomized to this arm experienced Grade 4 depression. Four of the 76 patients randomized to the tamoxifen only arm experienced Grade 3 toxicities: vascular occlusion in the eye; sinus bradycardia and bone pain; crescendo angina and urinary tract infection. The Grade 3 "Hematologic-other" has not yet been specified. One patient randomized to this arm died from a myocardial infarction judged to be related to treatment. Common toxicities have been hot flashes, fatigue and edema.

In July 1999 the study was revised to allow patients with DCIS, LCIS with microinvasion, or Paget's disease to be eligible.

As of March 15, 2002, the study was revised to extend overall accrual to 330 patients in order to meet study objectives. To aid in this endeavor, institutions are strongly encouraged to submit all upcoming as well as delinquent baseline, year 2 and year 5 data.


S9630/III

Initial Registrations By 6 Month Intervals

0

10

20

30

40

50

60

Time of Registration

JAN 1997JUN 1997

3

JUL 1997DEC 1997

9

JAN 1998JUN 1998

22

JUL 1998DEC 1998

23

JAN 1999JUN 1999

27

JUL 1999DEC 1999

13

JAN 2000JUN 2000

58

JUL 2000DEC 2000

31

JAN 2001JUN 2001

36

JUL 2001DEC 2001

27

Total



Total Reg

Loyola University 36 Cancer Care NW/Puget Sound 4 Scott & White CCOP 21 N Colorado Med Ctr/Colorado, U of 4 Central IL CCOP 16 St Charles Med Ctr/Puget Sound 4 CALGB 12 Wichita CCOP 4 St Francis/Stormont/Kansas, U of 11 Columbia River CCOP 3 Columbus CCOP 10 Grand Rapids CCOP 3 Virginia Mason CCOP 10 Montana CCOP 3 Northridge Hosp/Los Angeles, U of CA 9 N Michigan Hosp/Wayne State Univ 3 Kansas City CCOP 8 So Calif, U of 3 Sierra Nevada Mem/Davis, U of CA 8 Arizona, U of 2 Cottage Health Sys/Los Angeles, U of CA 7 Henrico Doctors Hosp/Galveston, U of TX 2 Covenant Health Sys/San Antonio, U of TX 6 Merle West Med Ctr/Davis, U of CA 2 Irvine, U of CA 6 Oakwood Hospital/Michigan, U of 2 Ozarks Reg CCOP 6 Southfield Onc Inst/Michigan, U of 2 BAMC/WHMC 5 St Mary's Hosp/St Louis University 2 Hawaii CCOP, Univ of 5 Wooster Clinic/Cleveland Clinic OH 2 Upstate Carolina 5 All Other Institutions 18 Utah, U of 5 Total (52 Institutions) 249


S9630/III

Registration, Eligibility, and Evaluability Registrations ending December 31, 2001; Data as of January 30, 2002

TOTAL Tamoxifen

Alone Tamoxifen

+ MPA NUMBER REGISTERED 249 123 126

INELIGIBLE 52 29 23 Insufficient Documentation 43 24 19 Irreversible 11 5 6 Reversible 32 19 13 ELIG./ PEND. ELIG. 197 94 103 Analyzable, Pend. Elig. 49 28 21 TOXICITY ASSESSMENT Evaluable 139 64 75 Too Early 58 30 28

Patient Characteristics Registrations ending December 31, 2001; Data as of January 30, 2002

Tamoxifen Alone

(n=94) Tamoxifen + MPA

(n=103) AGE Median

58 .5

59 .0

Minimum 40 41 Maximum 82 82 RACE White (Non-Hispanic)

81

86% 96

93%

Black (Non-Hispanic) 3 3% 1 1% Hispanic 5 5% 2 2% Asian or Pacific Islander 4 4% 4 4% American Indian 1 1% 0 0% PRIOR ADJUVANT CHEMOTHERAPY Yes

26

28% 34

33%

No 68 72% 69 67% NUMBER OF POSITIVE NODES 0-3

92

98% 96

93%

4 or more 2 2% 7 7%


S9630/III

Number of Patients with a Given Type and Degree of Toxicity All eligible and selected ineligible patients included

Toxicities with No Entries for Grades 2 to 5 Have Been Suppressed Registrations ending December 31, 2001; Data as of January 30, 2002

Tamoxifen Alone Tamoxifen + MPA (n=76) (n=85)

Grade

Grade

TOXICITY Unk 0 1 2 3 4 5 Unk 0 1 2 3 4 5 Allergic rhinitis 0 75 0 1 0 0 0 0 85 0 0 0 0 0Anxiety/agitation 0 73 3 0 0 0 0 0 82 1 2 0 0 0Arrhythmia, NOS 0 75 0 0 1 0 0 0 84 1 0 0 0 0Blurred vision 0 75 0 1 0 0 0 0 84 0 1 0 0 0Bone pain 1 73 1 0 1 0 0 0 82 1 2 0 0 0Cardiac ischemia/infarction 0 75 0 0 0 0 1 0 85 0 0 0 0 0Cardiovascular-other 0 75 0 0 1 0 0 0 85 0 0 0 0 0Constipation/bowel obstruction 0 76 0 0 0 0 0 0 82 2 1 0 0 0Depression 0 70 6 0 0 0 0 1 75 3 5 0 1 0Diarrhea without colostomy 0 74 1 1 0 0 0 0 85 0 0 0 0 0Dizziness/light headedness 0 73 2 1 0 0 0 0 82 2 1 0 0 0Double vision 0 75 0 1 0 0 0 0 85 0 0 0 0 0Dry eye 0 76 0 0 0 0 0 0 84 0 1 0 0 0Dyspnea 0 75 0 1 0 0 0 0 85 0 0 0 0 0Edema 0 66 5 5 0 0 0 0 75 9 1 0 0 0Eye-other 1 74 0 0 1 0 0 0 83 1 1 0 0 0Fatigue/malaise/lethargy 1 61 11 3 0 0 0 2 62 13 8 0 0 0Flatulence 0 76 0 0 0 0 0 0 84 0 1 0 0 0GGT increase 0 76 0 0 0 0 0 0 84 0 1 0 0 0Headache 0 71 4 1 0 0 0 0 80 3 2 0 0 0Hematologic-other 0 73 1 1 1 0 0 0 85 0 0 0 0 0Hot flashes 2 32 19 23 0 0 0 3 33 25 24 0 0 0Hypercholesterolemia 0 76 0 0 0 0 0 0 84 0 1 0 0 0Hyperglycemia 0 74 1 1 0 0 0 1 82 2 0 0 0 0Infection w/o 3-4 neutropenia 0 74 0 2 0 0 0 0 83 0 2 0 0 0Inner ear-hearing loss 0 76 0 0 0 0 0 0 84 0 1 0 0 0Insomnia 0 68 4 4 0 0 0 1 74 7 3 0 0 0Leukopenia 0 74 2 0 0 0 0 0 82 2 1 0 0 0Masculinization of female 0 76 0 0 0 0 0 0 84 0 0 1 0 0Myalgia 1 69 5 1 0 0 0 1 76 8 0 0 0 0Myalgia/arthralgia, NOS 0 75 0 1 0 0 0 0 84 0 1 0 0 0Neutropenia/granulocytopenia 0 76 0 0 0 0 0 0 84 0 0 1 0 0Pain-other 0 73 3 0 0 0 0 0 82 0 2 1 0 0Pelvic pain 0 76 0 0 0 0 0 0 84 0 1 0 0 0Petechiae/purpura 0 76 0 0 0 0 0 0 84 0 0 1 0 0Phlebitis 0 75 0 1 0 0 0 0 84 0 1 0 0 0Rash/desquamation 0 72 3 1 0 0 0 0 79 5 1 0 0 0Respiratory infect w/o neutrop 0 76 0 0 0 0 0 0 84 0 1 0 0 0Respiratory infection, unk ANC 0 76 0 0 0 0 0 0 84 0 0 1 0 0Sweating 0 73 1 2 0 0 0 0 82 1 2 0 0 0Thrombosis/embolism 0 76 0 0 0 0 0 0 84 0 0 1 0 0Toxicity of unknown category 0 76 0 0 0 0 0 0 84 0 0 1 0 0Urinary tr infection, unk ANC 0 75 0 0 1 0 0 0 85 0 0 0 0 0Vaginal bleeding 0 71 3 2 0 0 0 3 77 5 0 0 0 0Vaginal dryness 0 70 4 2 0 0 0 0 81 3 1 0 0 0Vaginitis 0 71 5 0 0 0 0 0 79 5 0 1 0 0Weight gain 0 65 11 0 0 0 0 0 76 7 1 1 0 0Weight loss 0 73 2 1 0 0 0 0 77 5 3 0 0 0 MAXIMUM GRADE ANY TOXICITY Number

3 17 19 32 4 0 1 7 17 23 29 8 1 0


S9832/III

S9832 Phase III

Enhancing Well-Being During Breast Cancer Recurrence

Study Coordinators: C Gotay, C Moinpour, K Albain, S Martino, B Taylor

Statisticians: D Pauler, S McCoy



Schema

RANDOMIZE

Telephone Counseling Intervention

Control (usual care)

First recurrence ofbreast cancer

Objectives To assess the effectiveness of a telephone counseling intervention delivered by breast cancer survivors on well-being of patients experiencing a first recurrence of breast cancer.

To examine the impact of sociodemographic, clinical, and psychosocial predictors of well-being in patients experiencing a first recurrence of breast cancer.

To examine changes in well-being over time since recurrence.

Patient Population Patients must have received definitive surgical treatment for Stage I, II, or IIIA breast cancer and have been diagnosed with a first recurrence of breast cancer within the past 56 days. "First recurrence" is defined as any distant metastatic site, or chest wall, scar, or nodal recurrence (ipsilateral breast tumor recurrence following lumpectomy and isolated contralateral new primary breast cancers are excluded).

Patients must not have a current psychiatric diagnosis that would interfere with their ability to participate in the intervention. Patients must be female. Patients must be able to read/understand English, and must have completed all baseline quality of life questionnaires.

Stratification/Descriptive Factors Treatment randomization will be stratified by: (1) Age: < 50 years vs ≥ 50 years; (2) Time since initial diagnosis: < 2 years vs ≥ 2 years; and (3) Recurrence site: soft tissue only vs bone with or without soft tissue vs visceral with or without bone and/or soft tissue.


Accrual Goals Three hundred eligible patients will be accrued to this study.

Summary Statement As of December 31, 2001, 271 patients had been registered to this study. Twenty-one patients are currently ineligible, 15 due to insufficient documentation. A major deviation has been recorded for one patient who did not have the post-registration questionnaires administered until month 11.

In January 2001, the study was revised to eliminate specifications about treatment for recurrence.


S9832/III

The quality of life form submission rates for patients qualifying for assessments are as follows:

baseline assessment, 99%; 3 month assessment, 87%; and 6 month assessment, 85%.



Total Reg

Upstate Carolina 22 St Vincent Hlth Ctr/Cleveland Clinic OH 5 Wichita CCOP 20 East Alabama Med Ctr/Mississippi, U of 4 Dayton CCOP 19 Loyola University 4 Northwest CCOP 14 Arkansas, U of 3 Columbia River CCOP 11 Horton Memorial Hosp/Columbia University 3 St Francis/Stormont/Kansas, U of 11 Meridia South Pointe/Cleveland Clinic OH 3 Grand Rapids CCOP 10 New Mexico MBCCOP 3 Ozarks Reg CCOP 10 Ozarks CGOP/Kansas, U of 3 William Beau Hosp/Michigan, U of 10 Providence Hosp 3 Duluth CCOP 9 Puget Sound 3 Central IL CCOP 8 Atlanta Reg CCOP 2 Greenville CCOP 8 Bakersfield Mem Hosp/Los Angeles, U of CA 2 New Mexico, U of 8 Irvine, U of CA 2 Hawaii CCOP, Univ of 7 MedStar Onc Network/Davis, U of CA 2 South Alabama CCOP 7 N Colorado Med Ctr/Colorado, U of 2 Virginia Mason CCOP 7 Scott & White CCOP 2 Cleveland Clinic OH 6 Sierra Nevada Mem/Davis, U of CA 2 Columbus CCOP 5 Wayne State Univ 2 Henry Ford Hosp 5 All Other Institutions 14 John Muir Med Ctr/Davis, U of CA 5 Total (53 Institutions) 271 St Jude Medical Ctr/Los Angeles, U of CA 5

Registration, Eligibility, and Evaluability Registrations ending December 31, 2001; Data as of January 30, 2002

TOTAL Intervention Control NUMBER REGISTERED 271 136 135

INELIGIBLE 21 13 8 Insufficient Documentation 15 8 7 Irreversible 5 2 3 Reversible 10 6 4 ELIG./ PEND. ELIG. 250 123 127 Analyzable, Pend. Elig. 42 21 21


S9832/III


Intervention

(n=123) Control (n=127)

AGE Median

53 .0

54 .0

Minimum 33 25 Maximum 93 90 AGE < 50

48

39% 49

39%

≥ 50 75 61% 78 61% RACE White (Non-Hispanic)

105

85% 112

88%

Black (Non-Hispanic) 7 6% 6 5% Hispanic 5 4% 6 5% Asian or Pacific Islander 4 3% 2 2% American Indian 2 2% 1 1% SITE OF RECURRENCE Soft tissue only

46

37% 50

39%

Bone +/- soft tissue 38 31% 41 32% Visceral 39 32% 36 28% TIME SINCE FIRST DIAGNOSIS < 2 yrs

36

29% 40

31%

≥ 2 yrs 87 71% 87 69%


S9927/III


Randomized Trial of Post-Mastectomy Radiotherapy in Stage II Breast Cancer in Women with One to Three Positive Axillary Nodes

Intergroup Participants: SWOG, ACOSOG, CALGB, ECOG, NCCTG, RTOG

Study Coordinators: L Pierce, T Pisansky (NCCTG), S Edge (ACOSOG), E Strom (RTOG), L Solin (ECOG), L Marks (CALGB)


Data Coordinator: S Edwards


Schema

RANDOMIZE

Local-Regional Radiotherapy

Observation

Mastectomy andAxillary Dissection

*

* Patients may be randomized either prior to, during, or immediately aftercompletion of systemic chemotherapy.

Objectives To compare overall and disease-free survival in pre- and post-menopausal women with Stage II breast cancer and 1-3 positive nodes treated with or without radiation therapy following mastectomy and adjuvant chemotherapy.

To assess local-regional control for this cohort of patients.

To assess the potential toxicities of radiotherapy delivered using CT-directed treatment in this cohort of patients.

Patient Population Patients must have histologically confirmed adenocarcinoma of the breast, with the primary tumor ≤ 5 cm and 1-3 positive axillary lymph

nodes. Patients must not have pathologic N3 or T3 disease, or clinical or pathologic N2 or T4 disease, or M1 disease. Patients must not have gross extracapsular disease or residual disease in the axilla. Patients with apocrine, adenocystic, or squamous carcinomas or sarcomas of the breast or bilateral breast cancer are not eligible.

Patients must have undergone a modified radical mastectomy sparing the pectoralis minor muscle with a level I and II axillary dissection. A minimum of 10 nodes must have been removed and pathologically examined. Surgical margins at time of mastectomy must be negative for both invasive carcinoma and for non-invasive ductal carcinoma. Patients who have undergone mastectomy after local failure following


S9927/III

lumpectomy are not eligible. Patients may be registered such that radiation therapy begins within eight months after mastectomy and within six weeks of completing systemic chemotherapy. Patients may be registered either prior to, during, or immediately after completion of systemic chemotherapy. Patients must not have received any prior trastuzumab therapy. Patients must not have received any prior chemotherapy except for treatment of the current breast cancer. Patients must not have received prior chest wall or nodal radiation therapy at any time for any reason.

Patients must be at least 21 years of age and have a Zubrod performance status of 0-1.

Stratification/Descriptive Factors Patients will be stratified according to systemic chemotherapy: (1) Adriamycin or Epirubicin: yes vs no; (2) taxane: yes vs no; and (3) duration of

chemotherapy: < 3 months vs 3-6 months vs > 6 months.

Accrual Goals The accrual goal is 2500 eligible patients. Formal interim analyses will be performed after approximately 75% of patient accrual is complete and again approximately 1.5 years after completion of accrual.

Summary Statement This study was opened on June 15, 2000. Twenty-five patients had been enrolled as of December 31, 2001. Three patients are currently ineligible, one due to tumor size > 5 cm and two due to incomplete data. Registration is now allowed prior to, during, or immediately after completion of systemic chemotherapy. No severe toxicities have been noted to date. The two patients not evaluable for toxicity assessment refused RT after randomization.


Institutions Total Reg

RTOG 11CALGB 4ECOG 3Columbia River CCOP 2NCCTG 2Grand Rapids CCOP 1N Michigan Hosp/Wayne State Univ 1Utah, U of 1Total (8 Institutions) 25

Registration, Eligibility, and Evaluability Registrations ending December 31, 2001; Data as of February 8, 2002

TOTAL Observation Local-

Regional RT NUMBER REGISTERED 25 13 12 INELIGIBLE 3 1 2 Insufficient Documentation 2 1 1 Reversible 2 1 1 ELIG./ PEND. ELIG. 22 12 10 Analyzable, Pend. Elig. 7 4 3 TOXICITY ASSESSMENT Evaluable 6 0 6 Not Evaluable 2 0 2 Too Early 2 0 2 Not Applicable 12 12 0


S9927/III

Patient Characteristics Registrations ending December 31, 2001; Data as of February 8, 2002

Observation

(n=12) Local-Regional RT

(n=10) AGE Median

48 .5

50 .0

Minimum 35 39 Maximum 66 65 RACE White (Non-Hispanic)

10

83% 10

100%

Black (Non-Hispanic) 1 8% 0 0% Hispanic 1 8% 0 0% PRIOR ADRIAMYCIN/EPIRUBICIN Yes

10

83% 9

90%

No 2 17% 1 10% PRIOR TAXANE Yes

8

67% 6

60%

No 4 33% 4 40% DURATION OF CHEMOTHERAPY < 3 months

1

8% 1

10%

3-6 months 10 83% 9 90% ≥ 6 months 1 8% 0 0%


S0012/III

S0012 Phase III

A Randomized Comparison of Standard Doxorubicin and Cyclophosphamide Versus Weekly Doxorubicin and Daily Oral

Cyclophosphamide Plus G-CSF as Neoadjuvant Therapy for Inflammatory and Estrogen-Receptor Negative Locally Advanced Breast Cancer

Study Coordinators: G Ellis, R Livingston

Statisticians: S Green, C Jiang



Schema

RANDOMIZE AC + G-CSF weekly x 15 weeks

AC x 5 cycles (21 day cycle)

Resection with AxillaryNode Dissection

Objectives To compare the pathologic microscopic response rate in patients treated with weekly doxorubicin and daily oral cyclophosphamide given with G-CSF support to that in patients treated with the standard doxorubicin and cyclophosphamide regimen given every three weeks.

To compare the toxicities of these two regimens.

To compare the delivered dose intensity of these two regimens.

To assess the association between pathologic complete response and clinical complete response at the primary tumor site in these patients.

Patient Population Patients must have a histologically confirmed diagnosis of locally advanced or inflammatory breast carcinoma. Patients with locally advanced, non-inflammatory breast cancer must be estrogen receptor negative. Patients must have selected Stage IIB or selected Stage III disease judged primarily unresectable by an experienced breast surgeon. There must not be metastatic disease.

Patients must not have received any prior chemotherapy for any cancer.

Patients must have adequate cardiac, hematologic, renal, and hepatic function and a Zubrod performance status of 0-2. Known HIV positive patients are ineligible. Patients with hypertension or age > 60 years must have a normal baseline MUGA scan or echocardiogram.

Stratification/Descriptive Factors Patients will be stratified by disease status: inflammatory vs other.

Accrual Goals The accrual goal is 150 eligible patients per arm. One interim analysis will be performed after microscopic pathologic CR status is determined on the first 150 patients.

Summary Statement As of December 31, 2001, three patients had been registered to this study, two from Puget Sound and one from CTSU. An amendment to add Taxol to both arms and to expand eligibility is under development.


S0029/II

S0029 Phase II

Single Agent Docetaxel for Metastatic Breast Cancer in Patients Aged 70 and Older

Study Coordinators: S Martino, K Albain




Objectives To assess the feasibility of enrolling patients ages 70 years or older with advanced breast cancer to a structured Phase II trial including pharmaco-kinetic sampling.

To assess overall survival, 2-year survival and response (confirmed and unconfirmed complete and partial) in this elderly population when treated with docetaxel.

To estimate the toxicity and tolerability of the regimen in this specific population group.

To assess the feasibility of using standardized self report measures of comorbidity, depression and functional status in an elderly population of patients with cancer.

To assess parameters of clinical pharmacology of docetaxel in patients aged 70 years and older, including half life value(s), AUC and steady state levels.

To assess whether patients under 60 years have clinical pharmacologic parameters similar to those reported in the literature (to validate our assay system).

To explore, at a preliminary level, the feasibility of studying genetic polymorphisms and gene expression levels of enzymes involved in drug metabolism and resistance to docetaxel in this patient population.

Patient Population Patients must be female with a pathologically confirmed diagnosis of breast cancer. Patients

must have measurable disease with histologic, cytologic or strong clinical evidence of distantly metastatic breast cancer. Patients with known brain or CNS metastases are not eligible.

Patients must not have received prior chemotherapy for advanced metastatic or recurrent disease. Prior adjuvant or neoadjuvant chemotherapy is acceptable. Prior adjuvant or neoadjuvant paclitaxel or docetaxel therapy is allowed as long as the last dose was at least six months previously. Any number of prior hormonal therapy regimens for either the adjuvant setting or for metastatic disease is allowed.

Patients must be 70 years or older, or less than 60 years, and they must have a Zubrod performance status of 0-2. Patients known to be HIV positive are not eligible. Patients must have adequate renal, hepatic and hematologic function.

Stratification/Descriptive Factors Patients are stratified by age: <60 years vs 70 years or older.

Accrual Goals Sixty patients aged 70 years or older will be accrued. In addition, 20 patients under age 60 will be accrued.

Summary Statement This study opened to accrual on August 1, 2001. As of December 31, 2001, no patients had been registered.


S0102/II

S0102 Phase II

Docetaxel and Vinorelbine Plus Filgrastim for HER-2 Negative Stage IV Breast Cancer

Study Coordinators: J Gralow, R Livingston




Objectives To estimate one year survival in HER-2 negative Stage IV breast cancer patients using a combination of docetaxel and vinorelbine with concurrent G-CSF support.

To estimate the response rate (both complete response and partial response) and time to progression in patients treated with this regimen.

To estimate the qualitative and quantitative toxicities of this regimen.

To obtain tissue blocks for the determination of the presence of beta-tubulin mutation.

Patient Population Patients must be women with Stage IV, HER-2 negative, microscopically confirmed carcinoma of the breast. Patients must not have uncontrolled CNS metastases.

Patients must have received no more chemotherapy than one prior adjuvant program for primary disease (as an adjuvant or neoadjuvant therapy). Patients must not have received prior taxane therapy (paclitaxel,

docetaxel). Any ongoing hormonal therapy must be discontinued prior to registration. Patients must have completed all prior chemotherapy at least six months prior to registration. Prior radiation is allowed, provided that the patient completed radiation at least 21 days prior to registration. Prior surgery is allowed as long as the patient is registered at least 14 days after surgery and has recovered from the surgery.

Patients must have a performance status 0-2 by the Zubrod criteria with adequate hematologic and hepatic function. Patients must not have pre-existing clinically significant peripheral neuropathy except for abnormalities due to cancer. Patients must not have sensitivity to E. Coli-derived proteins or history of severe hypersensitivity to drugs formulated with polysorbate 80.


Summary Statement Eleven patients had been enrolled as of December 31, 2001.


Institutions Total Reg

City of Hope Med Ctr 3Columbia River CCOP 2Gulf Coast MBCCOP 2Alaska Regional Hosp/Puget Sound 1Grand Rapids CCOP 1Montana CCOP 1Southeast CCC CCOP 1Total (7 Institutions) 11


S0102/II


Docetaxel+ Vinorelbine + G-CSF (n=11)

AGE Median

52 .0

Minimum 39 Maximum 73 RACE White (Non-Hispanic)

9

82%

Black (Non-Hispanic) 2 18%


S0215/II/PILOT

S0215 Phase II Pilot

Docetaxel and Vinorelbine Plus Filgrastim With Weekly Trastuzumab for HER-2 Positive, Stage IV Breast Cancer

Study Coordinators: J Kash, K Albain



Objectives To estimate one year survival in HER-2 positive Stage IV breast cancer patients using a combination of doxetaxel and vinorelbine with concurrent G-CSF support and weekly trastuzumab.

To estimate the response rate (complete and partial, confirmed and unconfirmed) in the subset of patients with measurable disease.

To estimate progression-free survival in patients treated with this regimen.

To estimate the qualitative and quantitative toxicities of this regimen.

To obtain tissue blocks for the examination of predictors of response to microtubule interacting agents (such as beta-tubulin mutations).

Patient Population Patients must be women with Stage IV, HER-2 positive, histologically confirmed carcinoma of the breast. HER-2 positivity must be demonstrated by FISH assay. Patients must not have uncontrolled CNS metastases.

Patients must have received no more than one prior chemotherapy program for primary disease (as an adjuvant or neoadjuvant therapy). Patient must not have received prior taxane therapy (paclitaxel, docetaxel). Prior cummulative dose of doxorubicin must not exceed 360 mg/m². Patients must have completed all prior chemotherapy at least six months prior to registration. Any ongoing hormonal therapy must be discontinued prior to registration. Prior radiation and/or surgery are allowed.

Patients must have a Zubrod performance status of 0, 1 or 2 with adequate hematologic, hepatic and cardiac function. Patients must not have pre-existing clinically significant peripheral neurop-athy except for abnormalities due to cancer. Patients must not have hypersensitivity to docetaxel or other drugs formulated with polysorbate 80.



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Breast Committee Agenda - SWOG 2002/Breast.pdf · July-Dec 2001 Jan-June 2001 July-Dec 2000 All...

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Transcript of Breast Committee Agenda - SWOG 2002/Breast.pdf · July-Dec 2001 Jan-June 2001 July-Dec 2000 All...