Liposomal Doxorubicin Compared With Observation or Cyclophosphamide and Methotrexate in Treating Older Women Who Have Undergone Surgery for Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as methotrexate, cyclophosphamide, and liposomal doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving liposomal doxorubicin after surgery is more effective than observation or cyclophosphamide and methotrexate in treating breast cancer. PURPOSE: This randomized phase III trial is studying liposomal doxorubicin to see how well it works compared with observation or cyclophosphamide and methotrexate in treating older women who have undergone surgery for breast cancer.

Detailed Description
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OBJECTIVES: Primary Compare the breast cancer-free interval in elderly women with resectable, hormone receptor-negative breast cancer treated with pegylated doxorubicin hydrochloride liposome (PDL) vs observation or PDL vs cyclophosphamide and methotrexate. Secondary Compare the tolerability of these regimens in these patients. Compare the safety and toxic effects of these regimens in these patients. Compare the overall and progression-free survival of patients treated with these regimens. Compare the quality of life of patients treated with these regimens. Compare the sites of failure in patients treated with these regimens. Compare the competing causes of death in patients treated with these regimens. Compare the rate of second non-breast malignancy in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center. Patients are assigned, based on patient preference, to 1 of 2 treatment groups. Group 1: Patients are randomized to 1 of 2 arms (arms I and II). Arm I: Patients receive pegylated doxorubicin hydrochloride liposome (PDL) IV over 1 hour on day 1. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo observation only. Group 2: Patients are randomized to 1 of 2 treatment arms (arms III and IV). Arm III: Patients receive PDL as in arm I. Arm IV: Patients receive oral cyclophosphamide once daily on days 1-7 and oral methotrexate twice daily on days 1 and 4. Treatment repeats every week for 16 courses in the absence of disease progression or unacceptable toxicity. All patients may undergo radiotherapy according to institutional standards either during surgery or after the completion of chemotherapy. Quality of life is assessed at baseline and at 3, 6, and 12 months. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 1,296 patients will be accrued for this study.

Official Title
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Phase III Trial Evaluating the Role of Adjuvant Pegylated Liposomal Doxorubicin (PLD, Caelyx, Doxil) for Women (Age 66 Years or Older) With Endocrine Nonresponsive Breast Cancer Who Are Not Suitable for Being Offered a  Standard Chemotherapy Regimen

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: methotrexate
* Drug: pegylated liposomal doxorubicin hydrochloride
* Procedure: adjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Disease must be confined to the breast and axillary nodes without detected masses elsewhere No history of prior ipsilateral or contralateral invasive breast cancer Resected disease No more than 16 weeks since last surgery to remove the tumor No known clinical residual locoregional disease Margins must be negative for invasive breast cancer and ductal carcinoma in situ No locally advanced, inoperable breast cancer including any of the following: Inflammatory breast cancer Supraclavicular node involvement Enlarged internal mammary nodes unless pathologically negative Synchronous bilateral invasive breast cancer (diagnosed in the past 2 months) allowed if all tumors are hormone receptor-negative Must not be a candidate for endocrine therapy or standard chemotherapy Hormone receptor-negative disease PATIENT CHARACTERISTICS: Female Menopausal status: postmenopausal ECOG performance status 0-2 Platelet count ≥ 100,000/mm^3 Granulocyte count ≥ 1,500/mm^3 WBC ≥ 3,000/mm^3 AST and ALT ≤ 1.5 times upper limit of normal (ULN) Bilirubin normal Creatinine clearance ≥ 50 mL/min Creatinine < 1.35 mg/dL No significant malabsorption syndrome or disease affecting gastrointestinal tract function No myocardial infarction within the past 6 months No pulmonary embolism within the past 6 months No deep vein thrombosis within the past 6 months No New York Heart Association class III or IV heart disease LVEF ≥ 50% by echocardiography, radionucleotide ventriculography, or MUGA No evidence of acute ischemia by ECG No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or bladder, or ipsilateral or contralateral breast carcinoma in situ No active, uncontrolled infection No active hepatitis B or C virus infection No other chronic infection Patients must not have any of the following geriatric syndromes: Dementia Delirium Major depression (as diagnosed by a psychiatrist) Recent falls Spontaneous bone fractures Neglect Abuse No evidence of medically relevant conduction system abnormalities that would preclude study entry No other nonmalignant, uncontrolled systemic diseases, psychiatric illness, or addictive or cognitive disorder that would preclude study participation or compliance PRIOR CONCURRENT THERAPY: At least 4 weeks since prior raloxifene, tamoxifen citrate, or other selective estrogen receptor modulators (SERMs) No concurrent recombinant human epoetin alfa or pegfilgrastim No prior neoadjuvant or adjuvant therapy for breast cancer except radiotherapy Concurrent trastuzumab (Herceptin®) allowed No concurrent hormonal replacement therapy No other concurrent hormonal therapy (including estrogen, progesterone, androgens, tamoxifen citrate, SERMs, or aromatase inhibitors) except for the following: Steroids for adrenal failure Hormones for non-disease-related conditions (e.g., insulin for diabetes) Intermittent dexamethasone as an antiemetic No other concurrent investigational agents No concurrent bisphosphonates, except for the treatment of osteoporosis For patients who received prior anthracyclines, the following criteria must be met: Cumulative dose ≤ 240 mg/m² for conventional doxorubicin ≤ 140 mg/m² in case of prior doxorubicin and left chest radiotherapy (LCRT) Cumulative dose ≤ 400 mg/m² for epirubicin ≤ 230 mg/m² in case of prior epirubicin and LCRT

Ages Eligible for Study
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Minimum Age: 66 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CASA-nil PLD<br>Adjuvant pegylated liposomal doxorubicin (PLD) for 16 weeks | Drug: pegylated liposomal doxorubicin hydrochloride<br>* Caelyx (R) (Doxil (R)) 20 mg/m2 iv x 8 doses (delivered every 2 weeks)<br>Procedure: adjuvant therapy<br> <br> Radiation: radiation therapy<br>* Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.<br>|
| Active Comparator: CASA-Nil<br>No adjuvant therapy | Radiation: radiation therapy<br>* Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.<br>|
| Experimental: CASA-CM PLD<br>Adjuvant pegylated liposomal doxorubicin (PLD) for 16 weeks | Drug: pegylated liposomal doxorubicin hydrochloride<br>* Caelyx (R) (Doxil (R)) 20 mg/m2 iv x 8 doses (delivered every 2 weeks)<br>Procedure: adjuvant therapy<br> <br> Radiation: radiation therapy<br>* Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.<br>|
| Active Comparator: CASA-CM CM<br>Low-dose, metronomic cyclophosphamide and methotrexate (CM) for 16 weeks | Drug: cyclophosphamide<br>* cyclophosphamide 50 mg/day orally continuously for 16 weeks<br>Drug: methotrexate<br>* methotrexate 2.5 mg twice a day orally on days 1 and 4 of every week for 16 weeks<br>Procedure: adjuvant therapy<br> <br> Radiation: radiation therapy<br>* Radiation therapy should be used according to institutional accepted guidelines. Radiation therapy to the conserved breast is recommended. Radiation therapy to the chest wall following mastectomy is optional (if given, it may also include nodal fields). Radiation therapy may be given either during operation or after all chemotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast cancer free interval by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events assessed by CTCAE v3.0 every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually after completion of study treatment |  | 5 years after recruitment starts | 
| Quality of life assessed by Casa QL form, Mini-Cog, and VES-13 at baseline and at 2, 6, and 12 months after completion of study treatment |  | 5 years after recruitment starts | 
| Disease-free survival by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 
| Overall survival by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 
| Sites of failure by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 
| Second (non-breast) malignancy by physical examination, laboratory tests, and investigations every 2 weeks for 16 weeks during treatment, every 3-6 months for 5 years, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 
| Causes of death prior to breast cancer recurrence by physical examination, laboratory tests, and investigations every 2 wks for 16 wks during treatment, every 3-6 mo. for 5 yrs, then annually as indicated after completion of study treatment |  | 5 years after recruitment starts | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer