Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information

Alternate Title

Combination Chemotherapy With or Without a Stem Cell Transplant in Treating Patients With Metastatic Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	18 to 60	NCI	E-PBT01 NCCTG-913201, PBT-1, SWOG-9412, NCI-T90-0180D, PBT01

Objectives

I.  Compare time to failure and overall survival of patients with metastatic 
breast cancer responding after 4-6 courses of conventional induction 
chemotherapy who are randomly assigned to 24 months of conventional 
maintenance chemotherapy with CMF (cyclophosphamide/methotrexate/fluorouracil) 
vs. high-dose chemotherapy with cyclophosphamide/thiotepa/carboplatin followed 
by autologous bone marrow and peripheral stem cell rescue.

II.  Compare the toxicity of these 2 regimens.

III.  Compare the financial costs of these 2 regimens.

IV.  Evaluate the quality of life associated with these 2 treatments.

Entry Criteria

Disease Characteristics:

Histologically documented adenocarcinoma of the breast

Metastatic or recurrent disease
  No leptomeningeal or brain metastases
  Inflammatory breast cancer requires distant metastases
  Adequate hepatic function (see below) required with liver metastases
  Metastases to ipsilateral regional lymph nodes
     (supraclavicular or cervical) only may be treated by mastectomy or
     locoregional radiotherapy

Hormonal receptor status:
  Estrogen receptor (ER)-negative or unknown
  ER-positive (at least 10 fmol/mg cytosol protein) bone/soft tissue disease
     eligible only if progressed on at least 1 hormone manipulation in the
     adjuvant or metastatic setting
  ER-positive, visceral disease eligible without prior hormone therapy

Bidimensionally measurable or evaluable disease, as follows:
  Not irradiated or progressed since radiotherapy

  Evaluable disease defined as:
     Blastic and mixed blastic/lytic lesions with no anticipated need for
     palliative radiotherapy during first 3 courses

     Pure osteolytic lesions

     Positive bone scan as only evidence of metastasis permitted provided
     patient has analgesic requirement or decreased performance status
        Evidence must be unequivocal if bone x-ray is negative

     Hepatic metastases greater than 2 cm on CT or MRI or of any size if
     biopsy-proven

     Abdominal or pelvic mass on CT or MRI

     Multinodular or confluent lung or skin metastases

     Cytologically positive pleural effusion

  No large third-space fluid accumulation that cannot be drained

  No large pericardial effusion

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  One course of induction therapy as specified in the protocol allowed prior
  to entry

  No other chemotherapy for metastatic disease, except patient may have
  relapsed after primary treatment for stage IV disease by virtue of
  metastasis only to ipsilateral supraclavicular nodes

  At least 6 months between adjuvant chemotherapy and recurrence

Endocrine therapy:
  Prior hormone manipulation required for bone or visceral metastasis unless
  rapidly progressing

  At least 4 weeks since or no benefit from oophorectomy for metastatic or
  recurrent disease

Radiotherapy:
  None to pelvic bones or lower spine
  No anticipated requirement for palliation during first 3 courses

Surgery:
  At least 2 weeks since major surgery

Patient Characteristics:

Age:
  18 to 60

Sex:
  Women only

Menopausal status:
  Premenopausal or postmenopausal

Performance status:
  ECOG 0 or 1

Hematopoietic:
  ANC at least 1,500
  Platelets at least 100,000

Hepatic:
  Bilirubin not greater than 2.0 mg/dL
  AST/alkaline phosphatase not greater than 2 times normal
  If liver function compromised by metastatic disease:
     Bilirubin not greater than 5.0 mg/dL
     AST not greater than 600 U/mL

Renal:
  After hydration:
     Creatinine not greater than 1.5 mg/dL and/or
     Creatinine clearance at least 60 mL/min

Cardiovascular:
  No significant cardiovascular disease, i.e.:
     No congestive heart failure
     No myocardial infarction within 3 months
     No arrhythmia requiring medication
     No poorly controlled hypertension (diastolic over 100 mm Hg)

Pulmonary:
  No significant non-neoplastic pulmonary disease

Other:
  No active infection
  No active peptic ulcer disease
  No brittle insulin-dependent diabetes mellitus
  No hospitalization for psychiatric illness, including severe depression or
     psychosis
  No current alcohol or drug abuse
  No pregnant or nursing women
  Not HIV seropositive and no clinical evidence of AIDS
  No active second malignancy within 10 years except:
     Curatively treated nonmelanomatous skin cancer
     In situ cervical carcinoma

Expected Enrollment

549 patients will be accrued.  At least 99 patients with CR after Induction 
and 247 with PR will be required; accrual is expected to take 3 years for both 
groups.

Outline

This study is randomized for post-induction therapy.  Patients are stratified 
by participating institution, prior doxorubicin therapy, estrogen receptor 
status, menopausal status, dominant metastatic site, and response to induction 
therapy.

All patients receive induction therapy with cyclophosphamide, doxorubicin, and 
fluorouracil every 28 days for a total of 4-6 cycles.  Patients who have 
received a lifetime cumulative doxorubicin dose of 400 mg per square meter or 
more or who achieve a lifetime dose of 500 mg per square meter during therapy 
are treated with methotrexate with or without prednisone in lieu of 
doxorubicin.

All patients then undergo bone marrow and/or peripheral stem cell collection 
using granulocyte colony-stimulating factor.

Patients who achieved a partial or complete response following induction are 
randomized for post-induction therapy.  The first group receives high-dose 
cyclophosphamide, thiotepa, and carboplatin followed by rescue with autologous 
bone marrow and/or peripheral stem cells and GM-CSF support.  The second 
receives standard-dose cyclophosphamide, methotrexate, and fluorouracil.

Daly MB, Goldstein LJ, Topolsky D, et al.: Quality of life experience in women randomized to high-dose chemotherapy (HDC) and stem cell support (SCT) or standard dose chemotherapy for responding metastatic breast cancer in Philadelphia Intergroup Study (PBT-1). [Abstract] Proceedings of the American Society of Clinical Oncology 19: A327, 2000.

Schulman KA, Glick HA, Goldstein LJ, et al.: Economic analysis of high-dose chemotherapy (HDC) and stem cell support (SCT) vs standard dose chemotherapy for women with responding metastatic breast cancer in the Philadelphia Intergroup Study (PBT-1). [Abstract] Proceedings of the American Society of Clinical Oncology 19: A325, 2000.

Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 342 (15): 1069-76, 2000.[PUBMED Abstract]

Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Phase III randomized trial of high-dose chemotherapy (HDC) and stem cell support (SCT) shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorourcil (CMF) for women with metastatic breast cancer who are responding to conventional induction chemotherapy: the 'Philadelphia' Intergroup study (PBT-1). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A1, 1a, 1999.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Edward Stadtmauer, MD, Protocol chair		Ph: 215-662-7910 Email: edward.stadtmauer@uphs.upenn.edu

Philadelphia Bone Marrow Transplant Group

Edward Stadtmauer, MD, Protocol chair		Ph: 215-662-7910 Email: edward.stadtmauer@uphs.upenn.edu

Southwest Oncology Group

Kenneth Mangan, MD, FACP, Protocol chair		Ph: 215-214-3129 Email: mangank@tuhs.temple.edu

North Central Cancer Treatment Group

James Ingle, MD, Protocol chair		Ph: 507-284-3731 Email: ingle.james@mayo.edu

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