SAN FRANCISCOThe impact of achieving amenorrhea during
treatment for premenopausal breast cancer is controversial, according to data
from the National Cancer Institute of Canada (NCIC) Clinical Trials Group
(CTG). A common occurrence among premenopausal breast cancer patients,
treatment-induced amenorrhea is often considered a positive prognostic factor.
The NCIC CTG data was unable to demonstrate such an effect.
"Amenorrhea during chemotherapy appeared to have no effect
on disease- free or overall survival in our study," Wendy Parulekar, MD,
of Queens University in Kingston, Ontario, reported. "Surprisingly, the
incidence of amenorrhea was higher with cyclophosphamide (Cytoxan)/epirubicin
(Ellence)/fluorouracil (CEF) than with
cyclophosphamide/methotrexate/fluorouracil (CMF) despite a lower cumulative
dose of cyclophosphamide," she noted. "In receptor-positive patients,
amenorrhea appeared to have a beneficial effect on disease-free survival, but
this disappeared after controlling for treatment, nodal status, and age.
Overall survival appeared unaffected in this group of patients using
unstratified and stratified analyses."
Prognostic Value Analyzed
The NCIC investigators studied the incidence and prognostic
value of drug- induced amenorrhea (DIA) during adjuvant therapy with
anthracycline-containing regimens compared to standard CMF. They analyzed the
database of a randomized phase III NCIC CTG trial conducted in 1989 to 1993
that included premenopausal and perimenopausal patients with node-positive
breast cancer. Patients had been randomized either to:
CMFcyclophosphamide 100 mg/m2 po days 1 to 14,
methotrexate 40 mg/m2 IV days 1 and 8, fluorouracil 600 mg/m2
IV days 1 and 8; or to
CEFcyclophosphamide 75 mg/m2 po days 1-14,
epirubicin 60 mg/m2 IV days 1 and 8, and fluorouracil 500 mg/m2
IV days 1 and 8.
Treatment was given every 28 days for six cycles. According to
Dr. Parulekar, 541 of the 716 patients in the clinical trial had normal
menstruation at randomization and had received six cycles of chemotherapy. Data
from these patients were analyzed for the amenorrhea study.
DIA was defined as cessation of menses for 3 or more months
during treatment. Complete menstrual data during treatment was available for
473 patients234 (89%) treated with CEF and 239 (86%) treated with CMF.
Median ages for both groups were similar: 43.5 years for the CEF group and 43.9
years for the CMF group. Median follow-up for this analysis was 7.7 years.
CEF vs CMF Arm
The incidence of DIA was significantly higher in the CEF arm
compared to the CMF arm. (See Table).
"The incidence of amenorrhea was higher with CEF in all
subgroups and was statistically significant in the subgroup of women younger
than age 35," Dr. Parulekar said.
DIA did not appear to affect relapse free survival (RFS). Dr.
Parulekar reported that the relative risk (RR) was 0.87 (95% CI = 0.66-1.14)
in patients with amenorrhea vs patients without amenorrhea (P = 0.3 by
Adjusting for the variables of T stage, node status, age,
receptor status, and treatment using the stratified log rank test demonstrated
no effect on RFS (P = 0.8).
Amenorrhea appeared to have no effect on overall survival (OS).
In patients with estrogen or progesterone receptor positive tumors (n = 287),
onset of amenorrhea affected RFS in univariate analysis only.
During the discussion period, Dr. Parulekar pointed out that no
tamoxifen (Nolvadex) was not allowed in this study. The authors of this study
agreed that the ability of many of these trials to examine the impact of
amenorrhea is poor. Meta-analytic techniques combining data from a number of
trials or a prospective interventional study designed and powered to answer
this specific question would be the best way to approach this important issue.
Leuprolide Can Prevent Treatment-Related Amenorrhea
"Leuprolide plus adjuvant chemotherapy may preserve
ovarian function in selected breast cancer patients," reported Kevin R.
Fox, MD, of the University of Pennsylvania Cancer Center in Philadelphia.
Younger women with breast cancer are often concerned about maintaining
fertility, he noted.
Permanent amenorrhea is the most common irreversible toxicity
in women given adjuvant chemotherapy for breast cancer. The incidence is 40%
overall and more than 80% in women over age 40 treated with CMF.
Loss of ovarian function is caused by direct toxicity to
developing follicles. Dr. Fox and colleagues reasoned that treatment with
leuprolide might prevent this problem by suppressing follicle growth during the
time chemotherapy was being given.
"This study was done specifically for women wanting to
maintain fertility," Dr. Fox said. "All patients had operable
metastatic breast cancer. Adjuvant chemotherapy was given with curative
Thirteen patients diagnosed between 1994 and 1999 were given
leuprolide during the course of adjuvant therapy as a means of inducing
temporary amenorrhea and thus protecting the ovaries from the cytotoxic effects
of chemotherapy. Patients ranged in age from 26 to 39 years (median age 35).
Five had node-negative disease, and eight had node-positive disease.
Six patients received standard Adriamycin
(doxorubicin)/cyclophosphamide (AC) for four cycles. Five received AC followed
by paclitaxel (Taxol) for four cycles. One received
cyclophosphamide/Adriamycin/fluorouracil (CAF) for 6 months, and one received
doxorubicin/docetaxel (Taxotere) followed by CMF. Median follow-up time was 36
The primary study endpoint was resumption of regular menstrual
cycling after chemotherapy. Secondary endpoints were relapse and survival
rates. Dr. Fox reported on the first 13 patients treated with leuprolide.
Minimum follow-up was 1 year.
In 11 patients, depot leuprolide was given in a dose of 3.75-mg
IM 1 week prior to chemotherapy and repeated every 3 to 4 weeks until
completion of chemotherapy. Two patients received leuprolide 7.5mg on a similar
Dr. Fox said that all patients became amenorrheic by the second
cycle of chemotherapy. Menstrual periods resumed in all leuprolide-treated
patients within 12 months of the completion of chemotherapy, with a mean time
to recovery of 4.9 months (range 2 to 12 months).
Regular Cycles Reported
Dr. Fox said that 12 of 13 patients reported regular cycles,
One reported irregular menses at 16 months from completion of treatment. Four
patients also taking tamoxifen continue regular menses. "Estradiol and
follicle stimulating hormone (FSH) levels are within premenopausal
limits," Dr. Fox reported.
Three patients developed metastatic disease at 19 and 36 months
Dr. Fox said that while this pilot study provides evidence that
leuprolide can be used to maintain menstrual function in women treated with
chemotherapy, questions remain about when leuprolide should be given for
optimal protective effect. Patient selection also needs clarification.
"Patients treated with AC alone have a fairly low risk of
irreversible amenorrhea, but we have seen a 60% rate in patients under age 45
treated with AC plus paclitaxel," he said. The role of leuprolide in
receptor-positive patients also needs further study.