Chemotherapy Adjuvant Study for women at advanced Age (CASA); 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*

The appropriate use of adjuvant chemotherapy for elderly women with breast
carcinoma remains controversial. Efficacy data in women aged > 70 years are
scarce, resulting in a lack of clear guidelines for patients in this age group.
Several studies have demonstrated decreasing use of chemotherapy with age, with
no age-related differences in either the drug regimens recommended or patient
acceptance rates for adjuvant therapy. In the 1998 Overview Analysis conducted
by the Early Breast Cancer Trialists* Collaborative Group (EBCTCG), few women
aged 70 or over had been studied. No clinical trials have been specifically
conducted in elderly women with an endocrine nonresponsive early breast cancer
in order to define the best adjuvant treatment in this subpopulation.
Thus, a therapeutic dilemma exists when a woman at advanced age presents with
an endocrine nonresponsive early breast cancer. Relapses of breast cancer may
occur earlier in patients with endocrine nonresponsive disease compared to
those with hormone receptor-expressing tumors, even when axillary nodes are
negative at presentation. This provides a rationale for reducing the risk of
relapse even when life expectancy is less than decades.
Such dilemma does not exist if the patient is biologically (and functionally)
young, and a *standard* chemotherapy regimen may be offered with no concern.
The physician may decide not to offer a relatively frail patient any treatment,
for fear of possible subjective or severe toxic effects of chemotherapy.
Typically, however, these patients are treated in a rather heterogeneous way by
arbitrarily reducing doses or modifying schedules of adjuvant chemotherapy
regimens that were studied in younger women. This trial is therefore important
because it is designed to test a reasonably tolerated cytotoxic regimen for a
patient subpopulation uniformly treated within a randomized trial.
The choice of the population (endocrine nonresponsive) is advantageous because
the magnitude of chemotherapy effect for this postmenopausal cohort is likely
to be quite large, similar to the effect observed for premenopausal patients
with similar biological tumor characteristics. Avoiding dilution with patients
having endocrine responsive tumors (even those with high number of axillary
lymph nodes involved) maximizes the chance to observe a benefit in the shortest
time with the lowest number of patients.

The overall aim of the CASA trial is to investigate the role of PLD as adjuvant
chemotherapy for older postmenopausal women for whom chemotherapy is indicated,
but standard regimens, derived from trials in younger women, are assumed to be
too toxic or inconvenient. The stratified analysis combining the results of
both randomization options will provide the primary evidence on the
effectiveness of PLD. This analysis will assess PLD versus non-PLD-containing
control groups (either nil or CM). In addition, analyses will be conducted
separately for each of the two randomization options (adjusted for multiple
comparisons) to
assess each of the individual pair-wise contributions to the overall result.

Some of the investigators are likely to choose no adjuvant cytotoxic therapy as
a standard for frail patients at advanced age, while others will prefer to
offer some treatment for all patients with endocrine nonresponsive disease. In
order to take into consideration both attitudes towards the same problem, the
International Breast Cancer Study Group (IBCSG) has designed a randomized
trial, the CASA trial, with two individual complementary options, in order to
investigate the role of adjuvant cytotoxic chemotherapy for postmenopausal
women at advanced age with endocrine nonresponsive early breast cancer. Caelyx®
(Doxil®), a pegylated liposomal doxorubicin (PLD), was chosen as the
experimental treatment because it has been shown to be active in advanced
breast cancer and is well tolerated.
These two complementary randomization options are tailored to the
investigator's decision and/or the patient*s preference about what would
constitute an appropriate control treatment group for the individual patient,
thus enabling the physician to express his or her own attitude and/or belief
towards adjuvant treatments in this subpopulation. Because of the separate
designs, at the time of
randomization the investigator will be asked to select one of the two
andomization Options.
This trial requires a rather large number of patients from a rather small
subpopulation of breast cancer patients. Although the incidence of breast
cancer in elderly women is quite high, it is estimated that only 15% will have
a receptor negative (no expression of estrogen receptor [ER] and progesterone
receptor [PgR]) disease. Thus, a satisfactory accrual can only be reached with
an international collaboration and participation around the world.

Pegylated Liposomal Doxorubicin versus nil, is designed for patients who,
according to the treating physician and/or to the patient's preferences, are
candidates to receive no adjuvant therapy.

Pegylated Liposomal Doxorubicin versus low dose, metronomic cyclophosphamide
and methotrexate (CM), is designed for patients who, according to the treating
physician and/or to the patient's preferences, should receive some adjuvant
treatment.

minimal risc, based on standard treatment