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| ID | Type | Description | Link |
|---|---|---|---|
| IBCSG-15-95 | |||
| EU-96021 |
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known if high-dose combination chemotherapy plus peripheral stem cell transplantation is more effective than standard combination chemotherapy for breast cancer.
PURPOSE: Randomized phase III trial to compare high-dose combination chemotherapy plus peripheral stem cell transplantation with standard combination chemotherapy in treating women with stage II or stage III breast cancer.
OBJECTIVES: I. Compare the survival, disease-free survival, and systemic disease-free survival of women with high-risk, operable stage II/III breast cancer treated with three courses of dose-intensive epirubicin/cyclophosphamide (EC) supported by granulocyte colony-stimulating factor (G-CSF) and G-CSF-mobilized peripheral blood stem cells vs. standard EC followed by cyclophosphamide/methotrexate/fluorouracil. II. Compare the toxicity, duration of quality-adjusted time without symptoms and toxicity, and quality of life associated with these two treatments. III. Evaluate the cost effectiveness of these two treatments.
OUTLINE: This is a randomized study. Patients are stratified by estrogen receptor status and menopausal status. Within 6 weeks of surgery, patients in the first group receive epirubicin (preferred) or doxorubicin plus cyclophosphamide every 3 weeks for 4 courses followed by conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) every 4 weeks for 3 courses. Patients in the second group undergo stem cell mobilization and harvest with granulocyte colony-stimulating factor (G-CSF) followed within 10 weeks of surgery by high-dose chemotherapy with epirubicin and cyclophosphamide followed by peripheral blood stem cell rescue and G-CSF. All patients receive adjuvant tamoxifen, and patients who underwent lumpectomy prior to entry are required to receive adjuvant radiotherapy (radiotherapy is optional for patients who underwent mastectomy prior to entry). Patients are followed every 3 months for 2 years, then q 6 months for 3 years, then yearly.
PROJECTED ACCRUAL: 210 patients will be accrued over 4 years to provide 195 evaluable patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard chemotherapy | Active Comparator | EC/AC x 4 followed by CMF x 3 and tamoxifen to 5 years after randomization. |
|
| Dose-intensive EC | Experimental | High-dose EC x 3 supported by peripheral blood progenitor cells and tamoxifen to 5 years after randomization. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| filgrastim | Biological | Filgrastim 10 mg/kg/d sc for 6 days after randomization. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Disease-free survival. | Time from randomization to recurrence (including recurrence isolated to the breast), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first. | 16 years after randomization. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival. | Time from randomization to death from any cause. | 16 years after randomization. |
| Toxicity. | Morbidity information was recorded using standard toxicity criteria. |
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DISEASE CHARACTERISTICS: Histologically proven breast carcinoma in one of the following categories: 10 or more involved axillary nodes 5 or more involved axillary nodes and either: Primary tumor estrogen receptor (ER)-negative (less than 10 femtomoles per milligram of cytosol protein) T3 tumor (regardless of ER status) Total mastectomy or breast-conserving procedure (lumpectomy or quadrantectomy) required within 6 weeks prior to randomization Tumor confined to breast and axillary nodes (T1a-c, T2, or T3, N1-2, M0 by the UICC staging system) The following conditions exclude entry: Satellite skin nodules distant from the primary tumor Supraclavicular node involvement Inoperable, matted axillary nodes Fixation of primary tumor to chest wall (excluding pectoralis major) Bilateral breast cancer (any mass in opposite breast unless biopsy-proven benign) Hot spots on bone scintigram (unless confirmed to be benign) Skeletal pain of unknown cause Hormone receptor status: ER status determination preferred, but not required
PATIENT CHARACTERISTICS: Age: 16-65 Sex: Women only Menopausal status: Any status Performance status: ECOG 0-2 Hematopoietic: WBC at least 4,000 Platelets at least 100,000 Hepatic: Bilirubin no greater than 1.1 mg/dL (20 micromoles/L) AST no greater than twice normal Renal: Creatinine no greater than 1.3 mg/dL (120 micromoles/L) Cardiovascular: Left ventricular ejection fraction greater than 50% by MUGA Other: No second malignancy except: Basal cell carcinoma Adequately treated carcinoma in situ of the cervix No significant nonmalignant disease that would preclude participation No psychiatric or addictive disorder that would compromise informed consent or participation No pregnant or nursing women Adequate contraception strongly advised for fertile women
PRIOR CONCURRENT THERAPY: No prior therapy for breast cancer other than surgery (see Disease Characteristics)
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| Name | Affiliation | Role |
|---|---|---|
| Russell Basser, MD | Melbourne Health | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Newcastle Mater Misericordiae Hospital | Newcastle | New South Wales | NSW 2310 | Australia | ||
| Royal Prince Alfred Hospital, Sydney |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18458044 | Background | Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, Holmberg SB, Lindtner J, Snyder R, Thurlimann B, Murray E, Viale G, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008 Jun 20;26(18):3006-14. doi: 10.1200/JCO.2007.14.9336. Epub 2008 May 5. | |
| 17237474 |
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| CMF regimen |
| Drug |
Cyclophosphamide 100 mg/m2 orally days 1 - 14, methotrexate 40 mg/m2 iv days 1 and 8, 5-fluorouracil 600 mg/m2 iv days 1 and 8. Repeat every 28 days. |
|
| cyclophosphamide | Drug | For high-dose EC arm: cyclophosphamide 4 gm/m2 iv as 4 divided doses. For standard chemotherapy arm: cyclophosphamide 600 mg/m2 iv day 1 of 21-day EC cycles, and cyclophosphamide 100 mg/m2 orally on days 1-14 of 28-day CMF cycles. |
|
| doxorubicin hydrochloride | Drug | Doxorubicin 60 mg/m2 iv on day 1 of 21-day cycles of AC. |
|
| epirubicin hydrochloride | Drug | Epirubicin 90 mg/m2 iv on day 1 of 21-day cycles of EC. |
|
| fluorouracil | Drug | 5-fluorouracil 600 mg/m2 iv days 1 and 8 of 28-day cycles of CMF. |
|
| mesna | Drug | MESNA (7.2 gm/m2) on days 2 and 3 of 21-day cycles of dose-intensive EC. |
|
| methotrexate | Drug | Methotrexate 40 mg/m2 iv on days 1 and 8 of 28-day cycles of CMF. |
|
| tamoxifen citrate | Drug | Tamoxifen 20mg daily for 5 years or until relapse. |
|
| peripheral blood stem cell transplantation | Procedure | Peripheral blood progenitor cells (PBPC) infusion on day 5 of each 21-day cycle of dose-intensive EC. |
|
| low-LET electron therapy | Radiation | Radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution. |
|
| low-LET photon therapy | Radiation | radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution. |
|
| 5 years after randomization. |
| Quality of life. | Quality of life was assessed using standard International Breast Cancer Study Group instruments. | 16 years after randomization. |
| Sydney |
| New South Wales |
| 2050 |
| Australia |
| Royal Adelaide Hospital | Adelaide | South Australia | 5000 | Australia |
| Queen Elizabeth Hospital | Adelaide | South Australia | 5011 | Australia |
| Royal Melbourne Hospital | Parkville | Victoria | 3050 | Australia |
| Swiss Institute for Applied Cancer Research | Bern | CH-3008 | Switzerland |
| Inselspital, Bern | Bern | CH-3010 | Switzerland |
| Centre Hospitalier Universitaire Vaudois | Lausanne | CH-1011 | Switzerland |
| Istituto Oncologico della Svizzera Italiana | Lugano | CH-6900 | Switzerland |
| Kantonsspital - Saint Gallen | Sankt Gallen | CH-9007 | Switzerland |
| Universitaetsspital | Zurich | CH-8091 | Switzerland |
| Background |
| Keshaviah A, Dellapasqua S, Rotmensz N, Lindtner J, Crivellari D, Collins J, Colleoni M, Thurlimann B, Mendiola C, Aebi S, Price KN, Pagani O, Simoncini E, Castiglione Gertsch M, Gelber RD, Coates AS, Goldhirsch A. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol. 2007 Apr;18(4):701-8. doi: 10.1093/annonc/mdl492. Epub 2007 Jan 20. |
| 19468030 | Result | Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. doi: 10.1093/annonc/mdp024. Epub 2009 May 25. |
| 16421418 | Result | International Breast Cancer Study Group; Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. doi: 10.1200/JCO.2005.03.5196. |
| 10076722 | Result | Basser RL, Abraham R, To LB, Fox RM, Green MD. Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer. Ann Oncol. 1999 Jan;10(1):53-8. doi: 10.1023/a:1008390203340. |
| 10458221 | Result | Basser RL, To LB, Collins JP, Begley CG, Keefe D, Cebon J, Bashford J, Durrant S, Szer J, Kotasek D, Juttner CA, Russell I, Maher DW, Olver I, Sheridan WP, Fox RM, Green MD. Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up. J Clin Oncol. 1999 Jan;17(1):82-92. doi: 10.1200/JCO.1999.17.1.82. |
| 9816037 | Result | Basser RL, To LB, Begley CG, Juttner CA, Maher DW, Szer J, Cebon J, Collins JP, Russell I, Olver I, et al. Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells. Clin Cancer Res. 1995 Jul;1(7):715-21. |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| D000069585 | Filgrastim |
| C034456 | CMF regimen |
| D003520 | Cyclophosphamide |
| D004317 | Doxorubicin |
| D015251 | Epirubicin |
| D005472 | Fluorouracil |
| D015080 | Mesna |
| D008727 | Methotrexate |
| D013629 | Tamoxifen |
| D036102 | Peripheral Blood Stem Cell Transplantation |
| ID | Term |
|---|---|
| D016179 | Granulocyte Colony-Stimulating Factor |
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D016298 | Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D013438 | Sulfhydryl Compounds |
| D013457 | Sulfur Compounds |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D013267 | Stilbenes |
| D001597 | Benzylidene Compounds |
| D001555 | Benzene Derivatives |
| D018380 | Hematopoietic Stem Cell Transplantation |
| D033581 | Stem Cell Transplantation |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D014180 | Transplantation |
| D013514 | Surgical Procedures, Operative |
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