Clinical trial NCT00296010: Liposomal Doxorubicin Compared With Observation or Cyclophosphamide and Methotrexate in Treating Older Women Who Have Undergone Surgery for Breast Cancer
Official title: 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"
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
First posted: 2006-02-24
Enrollment: 77
Sex: FEMALE
Minimum age (years): 66
Maximum age (years): 120
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 5 years after recruitment starts
Secondary outcomes:
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
measure: 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
timeFrame: 5 years after recruitment starts
Other outcomes:
Locations:
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Cancer Care Centre at Nepean Hospital
state: New South Wales
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Centre Hospitalier Etterbeek Ixelles
city: Kortrijk
country: Belgium
facility: AZ Groeninge - Oncologisch Centrum
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Liege
country: Belgium
facility: CHU Liege - Domaine Universitaire du Sart Tilman
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico - Aviano
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Biella
country: Italy
facility: Ospedale degli Infermi - ASL 12
city: Carpi
country: Italy
facility: Ospedale Civile Ramazzini
city: Fano
country: Italy
facility: Ospedale Civile S. Croce
city: Milano
country: Italy
facility: European Institute of Oncology
city: Rimini
country: Italy
facility: Ospedale Civile Rimini
city: Rome
country: Italy
facility: Ospedale Sant' Eugenio
city: Treste
country: Italy
facility: Centro Sociale Oncologico
city: Udine
country: Italy
facility: Policlinico Universitario Udine
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic - Universitatea de Medicina
city: Ljubljana
country: Slovenia
facility: Institute of Oncology - Ljubljana
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Skovde
country: Sweden
facility: Skaraborgs Hospital
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Bern
country: Switzerland
facility: Oncocare Sonnenhof-Klinik Engeriedspital
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Mendrisio
country: Switzerland
facility: Ospedale Beata Vergine
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: Regionalspital
Study officials:
affiliation: Centro di Riferimento Oncologico, Aviano (Italy)
name: Diana Crivellari, MD
role: STUDY_CHAIR
affiliation: European Institute of Oncology, Milano (Italy)
name: Silvia Dellapasqua, MD
role: STUDY_CHAIR
affiliation: Royal Prince Alfred Hospital, Camperdown (Australia)
name: Anne Hamilton, MD
role: STUDY_CHAIR
References: