Current Cooperative Group Phase III Clinical Trials in Early-Stage Breast Cancer

February 1, 2001

The 4th National Institutes of Health (NIH) Consensus Conference on Adjuvant Therapy of Breast Cancer, held November 1-3, 2000, concluded that decreasing breast cancer mortality rates in the United States were due, at least in part, to advances made in adjuvant treatment. This fact lends credence to the importance of incremental improvements that have resulted from randomized, controlled clinical trials of adjuvant therapy, and underscores the value of this approach. With 185,000 new diagnoses of breast cancer expected in the United States in 2000, over 100,000 women may be candidates for some form of adjuvant therapy each year.[1]

The 4th National Institutes of Health(NIH) Consensus Conference on Adjuvant Therapy of Breast Cancer,held November 1-3,2000, concluded that decreasing breast cancer mortality rates in the UnitedStates were due, at least in part, to advances made in adjuvant treatment. Thisfact lends credence to the importance of incremental improvements that haveresulted from randomized, controlled clinical trials of adjuvant therapy, andunderscores the value of this approach. With 185,000 new diagnoses of breastcancer expected in the United States in 2000, over 100,000 women may becandidates for some form of adjuvant therapy each year.[1]

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to studies in early-stage breast cancer.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, Internet access is available at http://cancernet.nci.nih.gov/pdqfull.html, or contact the Cancer Information Service offices (1-800-4-CANCER).

The Consensus Conference Statement (www.consensus.nih.gov)noted several new important research directions for adjuvant therapy. Theseincluded the study of new hormonal therapies in lieu of, or in addition to,tamoxifen (Nolvadex); the integration of trastuzumab (Herceptin) andbisphosphonates into adjuvant regimens; further study of the appropriate use oftaxanes; and the evaluation of sentinel node biopsy and postmastectomy adjuvantradiotherapy in women with one to three axillary nodes.

Hormonal Therapy

Some current trials of the US Cooperative Groups are addressingthese questions. Randomized studies testing the optimal duration of tamoxifenhave not yet demonstrated a benefit for extending tamoxifen beyond 5 years.While ongoing studies are testing 5 years of tamoxifen vs longer durations, aCanadian-led international collaborative study (JMA.17), which includes the USIntergroup (Cancer and Leukemia Group B [CALGB], the Eastern CooperativeOncology Group [ECOG], the North Central Cancer Treatment Group [NCCTG], and theSouthwest Oncology Group [SWOG]) is comparing letrozole (Femara; athird-generation aromatase inhibitor) to placebo in women who are disease-freeafter 5 years of adjuvant tamoxifen.[2,3] It is anticipated that about 20% ofstudy patients who are disease free after 5 years will relapse within the first4 years following cessation of tamoxifen. Crossover to an aromatase inhibitor—whichhas been shown to be beneficial in the metastatic setting—may be beneficial inthis setting. However, there are concerns about increases in osteoporosis andheightened lipid levels. The frequency of these adverse factors is being studiedin a selected subset of patients (MA.17B and MA.17L).

Monoclonal Antibody

Two large adjuvant trials (the National Surgical Adjuvant Breastand Bowel Project [NSABP] B-31 and N9831) have recently begun to integratetrastuzumab (a humanized monoclonal antibody against the HER2/neu oncoprotein)into standard adjuvant regimens. The inclusion of trastuzumab is based on theimpressive results shown in the metastatic disease setting where trastuzumabcombined with chemotherapy demonstrated a survival advantage.[4]

To be eligible for these two trials, patient tumors must testpositive for HER2/neu, either 3+ by immunohistochemistry (IHC) or positive byfluorescent in situ hybridization (FISH). As patients in both trials receivedoxorubicin before trastuzumab, there is careful cardiac monitoring of allpatients via multiple-gated acquisition (MUGA) scans. Both trials are dividedinto two phases: An initial cohort of 1,000 patients will be entered to evaluatetoxicity and feasibility; if toxicity is acceptable, a larger cohort(approximately 2,000 patients) will then be entered to evaluate efficacy.

Bisphosphonates

The bisphosphonates represent a novel approach to breast cancertherapy. They target the microenvironment of bone—a frequent metastatic site—ratherthan the tumor itself.[5] These pyrophosphate analogs inhibit bone resorptionand have a proven role in preventing osteoporosis. In patients with advancedbreast cancer, they have been shown to reduce the incidence of hypercalcemia andpathologic fractures.[6]

The NSABP has just commenced a trial (NSABP B-34) comparing anoral bisphosphonate, clodronate, to placebo, with each being administered dailyfor 3 years. Prior chemotherapy or tamoxifen is permitted, and patients of allages and nodal and receptor statuses are eligible. The trial—which utilized alarge, simple trial design—represents the largest adjuvant study performedwith bisphosphonates to date. Three previous trials have produced mixed results,and this NSABP trial will likely provide a more definitive answer.[7-9]

Taxanes

Several other trials are trying to discern the optimal scheduleof taxanes. The initial Intergroup trial, C9344, demonstrated a survival benefitfor the sequential addition of paclitaxel (Taxol) to the standard AC regimen(doxorubicin/cyclophosphamide [Cytoxan, Neosar] in women with node-positivebreast cancer.[10] Results from NSABP B-28, a trial similar in design to theCALGB-led Intergroup trial, were presented at the recent NIH ConsensusConference. This trial did not find a significant survival benefit with theaddition of paclitaxel.

Additional studies in the United States and abroad are comparingchemotherapy regimens with and without taxanes. Refinement of their role shouldbe forthcoming as data become available. Currently, NSABP B-30 is testingwhether combined therapy is superior to a sequential approach. This trial iscomparing ACT (doxorubicin/docetaxel [Taxotere]/cyclophosphamide) vs AT(doxorubicin/docetaxel) vs AC-T (doxorubicin/cyclophosphamide followed bydocetaxel).

Additionally, the Intergroup is comparing the two taxanes,paclitaxel and docetaxel, using the established sequential regimen. ThisECOG-led study, E1199, is treating node-positive or high-risk, node-negativepatients with doxorubicin and cyclophosphamide for four cycles, followed byrandomization to docetaxel or paclitaxel given on a weekly or every-3-weekschedule.

Sentinel Node Biopsy

Sentinel node biopsy is a promising new approach to stage theaxilla and reduce morbidity associated with traditional axillary lymph nodedissection. Despite several trials that demonstrate a strong correlation betweenthe sentinel node(s) and the status of the axillary nodes, there is concern thatno trial has yet proven that survival outcomes are equivalent only when thesentinel node procedure is used. Trial NSABP B-32 is designed to provide such ananswer.

In this trial, surgeons are trained in the procedure via ahands-on prestudy session, and are only permitted to randomize patients onceproficiency with the technique has been obtained. In B-32, women are randomizedto sentinel node biopsy or axillary dissection. Those who have a positivesentinel node have a complete axillary dissection, while women with negativeaxillary nodes are followed without further surgery.

The American College of Surgeons Oncology Trials Group (ACOSOG)Z0010 and Z0011 trials are also studying the role of sentinel nodes. Patientswho desire a sentinel node biopsy may enter the Z0010 trial. Those who are foundto have a positive sentinel node are offered randomization (trial Z0011) toaxillary dissection or no further surgery. Patients with a negative sentinelnode are registered in Z0010 and followed for local recurrence and survival.Both the NSABP and ACOSOG efforts have important laboratory components that willcompare patient outcomes with results from immunohistochemistryon sentinel node and bone marrow specimens.

Postmastectomy Radiotherapy

An additional area under evaluation in the Cooperative Groups isthe role of postmastectomy regional radiation. For many years, the medicaloncology community had dismissed regional radiotherapy as having an impact onlocal control, but no effect on overall survival. Several new clinical trialsand an updated metaanalysis of all randomized trials indicate that the effect ofregional radiotherapy on breast cancer mortality may be significant [11-14].

The recent Consensus Conference Statement concluded that therole of postmastectomy radiotherapy was well established for women with four ormore positive axillary lymph nodes. However, controversy persists in women withone to three nodes. In Intergroup trial, S9927, which is being led by SWOG,women with one to three positive nodes are being randomized to regionalradiotherapy (chest wall, supraclavicular and infraclavicular nodes, andinternal mammary nodes) vs no further treatment. Eligible patients can receiveadjuvant treatment outside of a trial or in another clinical trial before entryinto this study.

Timely answers to these important research questions require theparticipation of large numbers of physicians and patients. Mechanisms forencouraging increased participation have been developed nationally by theNational Cancer Institute (NCI). In addition to the existing community clinicaloncology programs (CCOPs) and community affiliate programs of individualCooperative Groups, a new Cancer Trials Support Unit (CTSU) has been developedby the NCI to permit greater access than ever before to Cooperative Group trials(www.ctsu.org).

Phase III

Title: Phase III Prognostic Study of Sentinel Node andBone Marrow Micrometastases in Women With Stage I or IIA Breast Cancer
Protocol Number: ACOSOG-Z0010
Participating Institutions: American College of Surgeons Oncology Group
Protocol Status: Active
Contact: Armando E. Giuliano, American College of Surgeons Oncology Group,(310) 829-8089; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Axillary Lymph NodeDissection in Women With Stage I or IIA Breast Cancer Who Have a PositiveSentinel Node
Protocol Number: ACOSOG-Z0011
Participating Institutions: American College of Surgeons Oncology Group
Protocol Status: Active
Contact: Armando E. Giuliano, American College of Surgeons Oncology Group,(310) 829-8089; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Study of Doxorubicin andCyclophosphamide Followed By Paclitaxel or Docetaxel in Women With Node Positiveor High Risk Node Negative Stage II or IIIA Breast Cancer
Protocol Number: E-1199
Participating Institutions: Eastern Cooperative Oncology Group, Cancerand Leukemia Group B, North Central Cancer Treatment Group, Southwest OncologyGroup
Protocol Status: Active
Contact: Joseph A. Sparano, Eastern Cooperative Oncology Group, (718)904-2555; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Screening Study Following Local Excision inSelected Patients with Ductal Carcinoma in Situ (DCIS) of the Breast
Protocol Number: E-5194
Participating Institutions: Eastern Cooperative Oncology Group, EmoryUniversity
Protocol Status: Active
Contact: Lorie L. Hughes, Eastern Cooperative Oncology Group, (404)233-4960; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: A Phase III Randomized Double Blind Study ofLetrozole Versus Placebo in Women With Primary Breast Cancer Completing Five orMore Years of Adjuvant Tamoxifen
Protocol Number: JMA.17
Participating Institutions: National Cancer Institute of Canada, Cancerand Leukemia Group B, Eastern Cooperative Oncology Group, North Central CancerTreatment Group, Southwest Oncology Group
Protocol Status: In review
Contact: James N. Ingle, MD, (507) 284-1887

Title: The Influence of Letrozole on Bone Mineral Densityin Women With Primary Breast Cancer Completing Five or More Years of AdjuvantTamoxifen
Protocol Number: MA.17B
Participating Institutions: National Cancer Institute of Canada, Cancerand Leukemia Group B, Eastern Cooperative Oncology Group, North Central CancerTreatment Group, Southwest Oncology Group
Protocol Status: In review
Contact: Edith A. Perez, MD, (613) 545-6430

Title: The Influence of Letrozole on Serum LipidConcentrations in Women With Primary Breast Cancer Who Have Completed Five Yearsof Adjuvant Tamoxifen: A Comparison Study to NCIC CTG MA.17
Protocol Number: MA.17L
Participating Institutions: National Cancer Institute of Canada, Cancerand Leukemia Group B, Eastern Cooperative Oncology Group, North Central CancerTreatment Group, Southwest Oncology Group
Protocol Status: In review
Contact: Kishor Wasan, MD, (613) 545-6430

Title: Correlation of Menstrual Cycle Phase at the Timeof Surgery with Disease-Free Survival in Women with Stage I/II Breast Cancer
Protocol Number: N9431
Participating Institutions: North Central Cancer Treatment Group,National Surgical Adjuvant Breast and Bowel Project
Protocol Status: Active
Contact: Clive S. Grant, North Central Cancer Treatment Group, (507)284-2644; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Doxorubicin PlusCyclophosphamide Followed by Paclitaxel With or Without Trastuzumab (Herceptin)in Patients With HER-2 Overexpressing Breast Cancer
Protocol Number: N9831
Participating Institutions: North Central Cancer Treatment Group, Cancerand Leukemia Group B, Eastern Cooperative Oncology Group, Southwest OncologyGroup
Protocol Status: Active
Contact: Edith A. Perez, North Central Cancer Treatment Group, (904)953-7283; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Adjuvant Doxorubicinand Cyclophosphamide Followed by Docetaxel Versus Doxorubicin and DocetaxelVersus Doxorubicin, Docetaxel, and Cyclophosphamide in Women With Breast Cancerand Positive Axillary Nodes
Protocol Number: NSABP B-30
Participating Institutions: National Surgical Adjuvant Breast and BowelProject
Protocol Status: Active
Contact: Sandra M. Swain, National Surgical Adjuvant Breast and BowelProject, (301) 496-4916; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Doxorubicin andCyclophosphamide Followed by Paclitaxel With or Without Trastuzumab (Herceptin)in Women With Node Positive Breast Cancer That Overexpresses HER2
Protocol Number:
NSABP B-31
Participating Institution:
National Surgical Adjuvant Breast and BowelProject
Protocol Status: Active
Contact: Edward H. Romond, National Surgical Adjuvant Breast and BowelProject, (859) 323-8043; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Sentinel NodeDissection With or Without Conventional Axillary Dissection in Women WithClinically Node Negative Breast Cancer
Protocol Number: NSABP B-32
Participating Institution: National Surgical Adjuvant Breast and BowelProject
Protocol Status: Active
Contact: David N. Krag, National Surgical Adjuvant Breast and BowelProject, (802) 656-5830; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Adjuvant ClodronateWith or Without Systemic Chemotherapy and/or Tamoxifen in Women With Early-StageBreast Cancer
Protocol Number: NSABP B-34
Participating Institutions: National Surgical Adjuvant Breast and BowelProject
Protocol Status: Active
Contact: Alexander H.G. Paterson, National Surgical Adjuvant Breast andBowel Project, (403) 670-1707; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of Tamoxifen With orWithout Radiotherapy in Women With Ductal Carcinoma In Situ (DCIS) of the Breast
Protocol Number: RTOG-9804
Participating Institutions: Radiation Therapy Oncology Group, Cancer andLeukemia Group B
Protocol Status: Active
Contact: Beryl McCormick, Radiation Therapy Oncology Group, (212)639-6828; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of NeoadjuvantDoxorubicin and Cyclophosphamide With or Without Filgrastim (G-CSF) in WomenWith Inflammatory or Estrogen Receptor-Negative Locally Advanced Breast Cancer
Protocol Number: S0012
Participating Institution: Southwest Oncology Group
Protocol Status: Active
Contact: Georgiana Kehr Ellis, Southwest Oncology Group, (206) 288-2048
Southwest Oncology Group; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of MedroxyprogesteroneAcetate and Observation for Prevention of Endometrial Pathology in Patients WithPostmenopausal Breast Cancer Treated With Adjuvant Tamoxifen
Protocol Number: S9630
Participating Institution: Southwest Oncology Group
Protocol Status: Active
Contact: Ronald Keith Potkul, Southwest Oncology Group, (708) 327-3314; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

Title: Phase III Randomized Study of PostmastectomyRadiotherapy in Women With Stage II Breast Cancer With One to Three PositiveNodes
Protocol Number: S9927
Participating Institutions: Southwest Oncology Group, American College ofSurgeons Oncology Trials Group, Cancer and Leukemia Group B, Eastern CooperativeOncology Group, North Central Cancer Treatment Group, Radiation Therapy OncologyGroup
Protocol Status: Active
Contact: Lori J. Pierce, Southwest Oncology Group, (734) 936-7810; for a complete listing ofstudy contacts, click hereLatest Information:http://cancernet.nci.nih.gov/

References:

1. Greenle R, Taylor M, Bolden S, et al: Cancer statistics 2000.CA Cancer J Clin 50:7-33, 2000.

2. Clinical Trial Service Unit, Radcliffe Infirmary, Oxford.Adjuvant tamoxifen longer against shorter (ATLAS). Protocol. April, 1995. ATLASOffice, Clinical Trials Service Unit. Radcliffe Infirmary, Oxford OX2 6HE, UK.

3. CRC Trials Unit, Birmingham. Adjuvant tamoxifen treatmentoffer more? (aTTom). Protocol. CRC Trials Unit, Clinical Research Block, QueenElizabeth Hospital, Birmingham B15 2TH, UK.

4. Norton L, Slamon D, Leyland-Jones B, et al: Overall survivaladvantage to simultaneous chemotherapy plus the humanized anti-HER2 monoclonalantibody Herceptin in HER2-overexpressing metastatic breast cancer (abstract).Proc Am Soc Clin Oncol 18:127a, 1999.

5. Mundy GR: Mechanisms of bone metastasis. Cancer 80(suppl8):1546-1556, 1997.

6. Mundy G: Bisphosphonates and anticancer drugs. New Engl J Med339(6):398-400, 1998.

7. Diel I, Solomyer EF, Costa S, et al: Reduction in newmetastases in breast cancer with adjuvant clodronate treatment. New Engl J Med339:357-363, 1998.

8. Powles TJ, Paterson AHG, Neventaus S, et al: Adjuvantclodronate reduces the incidence of bone metastases in patients with primaryoperable breast cancer (abstract). Proc Am Soc Clin Oncol 17:468a, 1998.

9. Saarto T, Blomqvist C, Virkkunen P, et al: No reduction ofbone metastases with adjuvant clodronate in node-positive breast cancer patients(abstract). Proc Am Soc Clin Oncol 18:489a, 1999.

10. Henderson JC, Berry D, Demetri G, et al: Improveddisease-free and overall survival from the addition of sequential paclitaxel butnot from the escalation of doxorubicin dose level in the adjuvant chemotherapyof patients with node-positive primary breast cancer (abstract). Proc Am SocClin Oncol 17:101a, 1998.

11. Overgaard M, Hansen PS, Overgaard J, et al: Postoperativeradiotherapy in high-risk premenopausal women with breast cancer who receiveadjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N EnglJ Med 337(14):949-55, 1997.

12. Overgaard M, Jensen MB, Overgaard J, et al: Postoperativeradiotherapy in high-risk postmenopausal breast-cancer patients given adjuvanttamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.Lancet 353(9165):1641-1648, 1999.

13. Ragaz J, Jackson SM , Le N, et al: Adjuvant radiotherapy andchemotherapy in node-positive premenopausal women with breast cancer. N Engl JMed 337:956-962, 1997.

14. Early Breast Cancer Trialists’ Collaborative Group(EBCTCG): Favourable and unfavourable effects on long-term survival ofradiotherapy for early breast cancer: An overview of randomised trials. Lancet355:1757-1770, 2000.