|
Home:
Educational Supplement: Appendix
Hormonal
Ablation
Nancy
E. Davidson, M.D.
Ovarian ablation
was the first form of adjuvant systemic therapy used in premenopausal
women with early-stage breast cancer. A 1995 meta-analysis summarized
results from 12 of the 13 randomized studies that assessed ovarian
ablation by irradiation or surgery; these trials all began before
1980 (EBCTCG, 1996). Because menopausal status was not uniform across
these studies, analysis was directed at the 2,102 women in the studies
under the age of 50, most of whom were likely to be premenopausal.
Ovarian ablation led to a 25 ± 7 percent reduction in the
annual odds of recurrence, and a 24 ± 7 percent reduction
in the annual odds of death, for women who underwent ovarian ablation
in the absence of chemotherapy. The benefit appeared significant
for both node-negative and node-positive women. There was a trend
for greater efficacy of ablation in women with estrogen receptor-positive
tumors, although this was only assessed in 4 of the 12 trials, all
of which included chemotherapy. The benefit was less pronounced
for women who were randomized to ovarian ablation in the presence
of chemotherapy (10 ± 9 percent and 8 ± 10 percent,
respectively). It is expected that this analysis will be updated
and expanded with 20 years of followup later this year.
More recent
trials have expanded and refined our knowledge in this field. They
have focused largely on two questions: What are the relative effects
of adjuvant chemotherapy and ovarian ablation with or without tamoxifen
in premenopausal women? Does ovarian ablation have additional benefit
in young women who have received adjuvant chemotherapy? Key features
of some of these newer trials are careful (but variable) definition
of premenopausal status, enrollment of women with steroid receptor-positive
tumors, and the use of luteinizing hormone-releasing hormone (LH-RH)
agonists to effect a temporary chemical castration.
Two trials have
compared adjuvant ovarian ablation to cyclophosphamide, methotrexate,
fluorouracil (CMF) chemotherapy. The Scottish/ICRF trial of 332
premenopausal women with node-positive breast cancer showed no difference
in event-free or overall survival after a maximum followup of 12
years (SCTBG, 1993). Estrogen receptor (ER) assays were available
for 270 tumors; retrospective analyses suggested that oophorectomy
was associated with improved survival in patients with ER concentrations
>= 20 fmol/mg protein, while six months of oral CMF was more beneficial
for patients with ER <= 20 fmol/mg protein. A second trial assessed
ovarian ablation and nine cycles of IV CMF in 732 women with hormone
receptor-positive breast cancer that involved lymph nodes or that
measured more than 5 cm (Ejlertsen, Dombernowsky, Mouridsen, et
al., 1999). The 5-year disease-free survival (DFS) rate was 67 percent
with ovarian ablation and 66 percent with CMF; corresponding survival
rates were 78 percent and 82 percent respectively (nonsignificant).
Amenorrhea occurred in 68 percent of the patients receiving CMF.
Together, these trials suggest that oophorectomy and CMF chemotherapy
have similar effects in women with node-positive breast cancer.
Results of a third trial (ZEBRA) that compared CMF with goserelin,
a LH-RH agonist, in women with early-stage breast cancer of any
receptor type should be available at the time of the consensus conference.
If part by its ability to ablate ovarian function, leading to a
state of estrogen withdrawal.
The concept
of combined endocrine therapy has also been tested in two trials
using CMF. The GROCTA 02 study compared oral CMF with 2 years of
goserelin and 5 years of tamoxifen in 244 women with node-positive
ER-positive breast cancer (Boccardo, Rubagotti, Amoroso, et al.,
1998). Five-year disease-free survival was 69 percent for CMF and
72 percent for goserelin-tamoxifen (not significant), and survival
was identical at 87 percent.
A larger trial
of similar design was conducted by the Austrian Breast Cancer Study
Group [ABCSG] (Jakesz, Hausmaninger, Samonigg, et al., 1999). ABCSG
compared IV CMF for six cycles with goserelin for 3 years, and tamoxifen
for 5 years, in 1,045 women with stage I and II steroid receptor-positive
breast cancer. At a median followup of 42 months, combination endocrine
therapy showed a significantly improved recurrence-free survival
(RFS) compared with CMF ( p=0.02), without an impact on survival.
In the CMF group, those women who developed amenorrhea had significantly
better RFS and survival than those who did not. A third trial compared
six cycles of IV FEC (an anthracycline-containing regimen) with
3 years of tamoxifen and triptoreline (another LH-RH agonist) in
333 premenopausal women with hormone receptor-positive breast cancer
involving 1 to 3 nodes (Roche, Kerbrat, Bonneterre, et al., 2000).
With median followup of 54 months, disease-free survival and overall
survival were 92 percent and 97 percent, respectively, for endocrine
therapy, and 81 percent and 93 percent for FEC; these differences
are not significant. FEC induced amenorrhea in 42 percent of patients.
Thus, these three trials suggest that combined endocrine therapy
has effects similar to those of adjuvant chemotherapy, although
it is not likely that any of these trials had the statistical power
to document true equivalence.
Adjuvant chemotherapy
is a routine part of care for many women with node-positive breast
cancer. Thus, a second question is whether the use of ovarian ablation
adds to the benefits of adjuvant chemotherapy. This question was
addressed in INT 0101, a trial of chemohormonal therapy in 1,503
premenopausal women with node-positive, receptor-positive breast
cancer (Davidson, ONeill, Vukov, et al., 1999). The trial
compared three treatment arms: six cycles of oral CAF, six cycles
of CAF followed by 5 years of goserelin (CAF->Z),
and six cycles of oral CAF followed by 5 years of goserelin and
tamoxifen (CAF->ZT).
The 7-year disease-free survival rates were 58 percent for CAF,
64 percent for CAF->Z,
and 73 percent for CAF->ZT.
Comparison of CAF->ZT
with CAF->Z showed
a significant disease-free survival rate advantage with the addition
of tamoxifen (p =0.0025), while comparison of CAFZ with CAF
showed no disease-free survival rate advantage for the addition
of goserelin (p =0.0955). Survival at 7 years was similar
for all three arms: 77 percent for CAF, 78 percent for CAF->Z,
and 80 percent for CAF_ZT. Final analysis of the impact of amenorrhea,
patient age, and serum hormone levels on clinical outcome is in
progress.
The ZIPP trial
also permitted assessment of the effects of ovarian ablation in
the context of other adjuvant therapy (Baum, 1999). That study combined
results from four trial groups that used a common 2x2 design to
evaluate tamoxifen for 2 years, goserelin for 2 years, tamoxifen
and goserelin for 2 years, and no endocrine therapy, in 2,631 premenopausal
women with early-stage breast cancer of any steroid receptor type
(56 percent node-negative). Elective adjuvant chemotherapy was permitted
in selected patients according to predetermined plans and was given
to 43 percent of the participants. At a median followup of 4.2 years,
there was a statistically significant 23 percent reduction in first
events in women who received goserelin (first events in 20 percent
of patients with goserelin and 25 percent of patients without goserelin,
(p=0.001). The benefit was less pronounced in patients who received
concurrent adjuvant tamoxifen or chemotherapy. There is no significant
effect on survival at the present time ( p=0.12).
Available data
suggest that both adjuvant ovarian ablation with or without tamoxifen
and CMF chemotherapy have similar benefits for premenopausal women
with early-stage breast cancer. Thus, ovarian ablation (±
tamoxifen) appears to be a reasonable alternative to CMF chemotherapy
for selected women with receptor-positive breast cancer. It appears
unlikely, however, that ovarian ablation has a benefit for women
with receptor-negative tumors.
A number of
questions remain to be answered. These include (1) the importance
of amenorrhea as a determinant of outcome for premenopausal women
with early-stage breast cancer; (2) the optimal duration of ovarian
ablation if an LH-RH agonist is employed; (3) the relative efficacy
of ovarian ablation and other types of adjuvant chemotherapy (e.g.
CAF, AC, or AC followed by paclitaxel); (4) the additional value
of ovarian ablation after chemotherapy, particularly for women who
remain premenopausal after adjuvant chemotherapy; and (5) the value
of combined hormone therapy.
References
Baum M. Adjuvant
treatment of premenopausal breast cancer with Zoladex and tamoxifen.
[abstract]. Breast Cancer Res Treat 1999;57:30. No Abstract Available.
Boccardo F,
Rubagotti A, Amoroso D, Mesiti M, Minutoli N, Aldrighetti D, et
al. CMF versus tamoxifen (tam) plus goserelin (gos) as adjuvant
treatment of ER positive (ER+) pre-perimenopausal breast cancer
(ca) patients (pts). Preliminary results of the GROCTA 02 study.
[abstract]. Proc Am Soc Clin Oncol 1998;17:99a. Abstract.
Davidson NE,
ONeill A, Vukov A, Osborne CK, Martino S, White D, et al.
Effect of chemohormonal therapy in premenopausal node (+) receptor
(+) breast cancer: an Eastern Early Breast Cancer Trialists
Collaborative Group (EBCTCG). Ovarian ablation in early breast cancer:
overview of the randomised trials. Lancet 1996;348:1189-96. Abstract.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Ovarian
ablation in early breast cancer: overview of the randomised trials.
Lancet 1996;348:1189-96. Abstract.
Ejlertsen B,
Dombernowsky P, Mouridsen HT, Kamby C, Kjaer M, Rose C., et al.
Comparable effect of ovarian ablation (OA) and CMF chemotherapy
in premenopausal hormone receptor positive breast cancer patients.
[abstract]. Proc Am Soc Clin Oncol 1999;18:66a. Abstract.
Jakesz R, Hausmaninger
H, Samonigg H, Kubista E, Depisch D, Fridrik M, et al. Comparison
of adjuvant therapy with tamoxifen and goserelin vs CMF in premenopausal
stage I and II hormone-responsive breast cancer patients: four-year
results of Austrian Breast Cancer Study Group (ABCSG) Trial 5. [abstract].
Proc Am Soc Clin Oncol 1999;18:67a. Abstract.
Roche HH, Kerbrat
P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, et al. Complete
hormonal blockade versus chemotherapy in premenopausal early-stage
breast cancer patients with positive hormone-receptor (HR+) and
1-3 node-positive (N+) tumor: results of the FASG 06 trial. [abstract].
Proc Am Soc Clin Oncol 2000;19:72a. Abstract.
Scottish Cancer
Trials Breast Group (SCTBG) and ICRF Breast Unit, Guys Hospital,
London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal
women with pathological stage II breast carcinoma: the Scottish
trial. Lancet 1993;341:1293-9. Abstract.
|
|