Breast Cancer Research and Treatment 14: 201-206, 1989.
© 1989 Kluwer Academic Publishers. Printed in the Netherlands.
Report
Megestrol acetate versus aminoglutethimide for metastatic breast cancer
S. Lundgren, 1 S. Gundersen, 2 R. Klepp, 3 P.E. L0nning, 1 E. Lund 2 and S. Kvinnsland 1,3
1Department of Medical Oncology and Radiotherapy, University of Bergen, 5021 Haukeland Hospital;
2Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, MontebeUo,
0310 Oslo 3; 3Department of Medical Oncology and Radiotherapy, The Regional and University Hospital
in Trondheim, 7006 Trondheim, Norway
Key words: advanced breast cancer, second-line endocrine therapy, megestrol acetate, aminoglutethimide
Summary
In this prospective, randomized study the clinical response and toxicity of megestrol acetate (MA) and
aminoglutethimide (AG) as second-line treatment in patients with metastatic breast cancer was compared.
176 patients were included, and 150 received treatment > 8 weeks and are evaluable for treatment response.
The two groups did not differ with regard to prognostic factors. Response rate for the AG and MA groups
were 34% and 31% respectively, with duration of response of 13.1 and 13.0 months. Stable disease was
obtained in 33% and 35% respectively. No difference was observed in survival. Side effects occurred more
frequently in the A G group (42%) than in the MA group (18%).
Introduction
The role of endocrine therapy as treatment for
advanced breast cancer is well documented [1, 2]
and the drug of choice as 1. line therapy is the
anti-estrogen tamoxifen, both in postmenopausal
[3] and premenopausal women [4]. There is an
increasing awareness of good results with 2. line
endocrine therapy in many patients [2, 5]. The
question of the best 2. line endocrine therapy has
not been settled, but in postmenopausal patients
both aromatase inhibitors [6] and high dose progestins (HD-GES) [7] have been used.
The aim of the present study was to compare in a
prospective, randomized, multicenter study the
aromatase inhibitor aminoglutethimide (AG) with
the progestin megestrol acetate (MA) as 2. line
endocrine therapy. Patients were evaluated with
regard to response rate and duration, survival, and
side effect profiles of the two different therapies.
Patients and methods
Patient characteristics
176 patients have been included 150 have been
treated > 8 weeks and are evaluable for treatment
response (Table 1). Ten patients had to be excluded due to protocol violation or patient refusal, 12
due to early death and 4 due to side effects (all A G
patients).
The main characteristics of the patients are presented in Table 2. The two groups were well balanced with regard to the most important prognostic
Address for offprints: Dr. Stener Kvinnsland, Department of Medical Oncology and Radiotherapy, The Regional and University
Hospital in Trondheim, 7006 Trondheim, Norway
202
S Lundgren et al.
variables, with the exception of main metastatic
site. There were more patients with bone metastases in the MA group, and more patients with visceral disease in the A G group; the differences are
statistically significant (p < 0.05).
Study design
The study was designed as a prospective randomized trial without stratification. There was no
demand in the protocol to crossover treatment
when progression occurred.
Inclusion criteria were progressive, advanced
breast cancer in patients (< 75 years, Karnofsky
index > 50) previously treated with tamoxifen
either in the advanced or adjuvant situation. The
patients were either previous tamoxifen responders or, if they were previous failures or had been
treated with tamoxifen in the adjuvant situation,
they had clinical characteristics and/or receptor status predicting a response to endocrine therapy.
Single osteoblastic bone metastasis, CNS manifestations only, life expectancy of less than 2 months,
and rapid progression on TAM were exclusion criteria. Previous use of chemotherapy was accepted.
All patients had evaluable disease. No other systemic therapy was allowed simultaneously. Painful
bone metastases, if irradiated, were not used for
evaluation of the endocrine therapy. All patients
gave their verbal informed concent to participate in
the study.
Prior to start of therapy and every 8 weeks patients had a clinical, hematological/biochemical
and radiographical (or ultrasonographical) evaluation. The UICC criteria for response were used
[81.
Previous therapy
Previous systemic therapies for recurrences are reported in Table 4. Most patients had been treated
with 1 or more endocrine therapies in the advanced
situation; 11 in the AG group and 12 patients in the
MA group had been treated with tamoxifen in the
adjuvant situation only, but had recurred either
during the adjuvant therapy or shortly after cessation of this therapy. Some of the patients, 14 and 11
in the two groups respectively, had received chemotherapy in the recurrent situation.
Treatment schedules
The patients were randomized to either megestrol
acetate (MA), (Megace, 160mg) 160mg o.d., or
aminoglutethimide (AG). The treatment schedule
for A G during the first two weeks was AG (Orimiten, 250mg) 250mg b.i.d, and cortisone acetate
(Cortone, 25mg), 50rag b.i.d. Thereafter the
schedule was AG, 250 mg q.i.d, and cortisone acetate 25 mg b.i.d. [9].
Receptor measurements
Steroid receptor levels (estrogen receptor (ER)
and progesterone receptor (PgR)) were known in
Table 2. Patient characteristics, evaluable patients a
Characteristic
AG 1
N = 76
MA z
N = 74
P r e m e n o p a u s a l (n)
Postmenopausal (n)
A g e (mean)
Disease free interval (months)
Time from 1. recurrence to start
of therapy (months)
Main metastatic localization
Soft tissue
Bone*
Viscera**
3
73
62.0
44.3
2
72
62.7
42.8
32.4
28.9
33
11
32
33
23
18
Table 1. Patient material
Total
AG 1
MA z
Total number:
Ineligible; protocol violation,
refused treatment:
176
86
90
10
3
7
Eligible
166
83
83
12
4
3
4
9
0
150
76
74
Early death ( < 2 too):
Side effects withdrawal
Evaluable, treated > 8 weeks
A G a= Aminoglutethimide.
M A 2= Megestrol acetate.
a Treated for > 8 weeks.
A G 1 = Aminoglutethimide.
M A z = Megestrol acetate.
Fischer exact test: * p = 0.01, ** p = 0.02.
203
Endocrine treatment of breast cancer
No differences in objective response rate
( C R + P R ) or response duration were found between the two groups in the study (Table 5). Similarly, no differences were observed between the
two treatment modalities with regard to numbers
and duration of stable diseases. Response related
to receptor ( E R + ) gave C R + P R of 38% and 28%
for AG and MA, respectively, for the patients evaluable after at least 8 weeks of treatment. The
response rate using the total number of patients
included was 30% (26/86) and 26% (23/90), for AG
and MA, respectively. The corresponding results
excluding the ineligible patients (Table 1) were
31% (26/83) and 28% (23/83) respectively.
Side effects were observed in 42% and 18% of
the A G and MA patients, respectively (Table 6).
No serious side effects were observed with MA
treatment. Most of the side effects in the AG group
were transient, but 4 of the patients had to withdraw therapy due to side effects (rash, fever, nausea) for longer than the first few weeks.
The crude survival curves (Fig. 1) showed a small
but insignificant advantage for the AG group (p =
0.20) probably due to the 9 early deaths in the MA
group (only 3 in the AG group), but showed no
difference in the terminal part of the curve. The
corresponding curves for the evaluable patients
were almost superimposable ( p = 0.44) (not
shown). The imbalance in main metastatic sites
(Table 2) had no significant effect on survival assessed by multiple regression analysis either for
bone metastases (~ = 0.0098, S.E. = 0.4383) or
for visceral disease (~ -- - 0.0412, S.E. -- 0.1588).
There were no interactions between main metastatic sites and the two treatments.
The median survival time (75th and 25th quar-
Table 3. Steroid receptor status, evaluable patients"
Table 4. Previous systemic treatment for recurrences"
Receptor
Treatment
98 and 61 of the patients, respectively (Table 4).
For 9 more patients E R were positive, but the
levels were unknown. Both qualitatively and quantitatively the 2 groups are well balanced (p = 0.69).
Steroid receptors were measured as previously reported [10]. Receptor positivity was defined as
10fmol/mg cytosol protein or more for both ER
and PgR.
Statistical methods
Differences in rates between the two groups were
tested with chi square or Fischer's exact test. Survival rates were computed by the life table method,
and possible differences in survival distribution
were tested for by the log-rank test. The effects of
different prognostic factors were analysed by the
Cox regression method. Statistical significance is
indicated by p-<0.05.
Results
E R + n (mean fmol/mg
protein)
E R + , level unknown
ER unknown
PgR+ n (mean fmol/mg
protein)
PgR- n
PgR unknown
AG 1
N = 76
MA 2
N = 74
47 (101.4)
3
26
51 (111.5)
p = 0.69
6
17
27 (155.0)
11
38
34 (115.9)
11
29
AG 1
MA 2
N = 76 N = 74
Endocrine therapy:
Number of different regimens:
Adjuvant only
1 regimen
2 regimens
Best response to therapy
Number of objective responders
(CR+PR)
NC+PD
11
60
5
12
57
5
28
10
20
14
14
11
Chemotherapy:
" Treated for > 8 weeks.
A G I = Aminoglutethimide.
MA 2= Megestrol acetate.
ER = Estradiol receptor.
PgR = Progesterone receptor.
1 regimen (n)
a Treated for > 8 weeks.
AG 1= Aminoglutethimide.
MA 2= Megestrol acetate.
204
S Lundgren et al.
tile) for all patients included were 22.4 months
(8.8, 36.3) and 16.3 months (7.6, 33.3) for AG- and
MA-group, respectively. The corresponding data
for the evaluable patients were 22.9 months (10.2,
37.3) and 18.0 months (11.6, 35.6).
Discussion
Due to the still limited role of chemotherapy in
advanced breast cancer treatment, and the valuable effect and tolerable side effect profile of endocrine therapy, there is still a need of refinement
of existing hormone therapy schedules. Two of the
important questions still to be solved are, firstly, to
define the roles, if any, of combined endocrine
treatments [5] and, secondly, to clarify the right
sequence of endocrine monotherapies [11]. The
importance of different kinds of 2. line endocrine
therapies in advanced breast cancer has been
shown repeatedly [2, 5, 11].
Our study again suggests that 2. line endocrine
therapy will result in about 30% response rate in a
selected population of patients; another 30% will
experience stabilization of their disease for at least
2 months. Stabilization of the disease as response
to endocrine therapy has been shown to be of imTable 5. Treatment response, evaluable patients"
Response
A G 1 N = 76
MA 2 N = 74
Responders (n, C R + P R )
Complete (n, CR)
Partial (n, PR)
Duration of response
(months)
Stable disease (n, SD)
Duration of response
(months)
Progressive disease (n, PD)
Response by site*
Soft tissue
Bone
Viscera
26 (34.2%)
7
19
23 (31.1%)
5
18
13.1
25 (32.9%)
13.0
26 (35.1%)
9.4
25 (32.9%)
11.5
25 (33.8%)
portance [12]. The response rate and duration of
responses obtained in this study are in accordance
with previously obtained results [6, 7]. A randomized study comparing AG and another progestin,
medroxyprogesterone acetate (MPA), gave similar
results as in our study [13], and Wander et al. [14]
showed in a randomized study that the two progestins (MA versus MPA) were equally effective.
Progestins used as 1. line endocrine treatment in
randomized studies comparing progestins (MPA
and MA) and TAM gave higher response rates for
MPA (44%) than for MA (30%) and TAM (31%36%). If patients with no change were included as
responders, progestin treatment (both MPA and
MA) was effective in more than 50% of the patients
in the randomized studies both as 1. line and 2. line
therapy [15-18].
No difference appeared in response rate or duration of response between MA and AG. When effects of the different treatments in relation to metastatic site was evaluated, again no difference was
found (Table 5). AG is effective in patients with
bone metastases [18]; our data indicates better resuits than for MA, as reported for MPA [13]. The
results for patients with soft tissue metastases are in
favor of MA and MPA [13].
These results should be interpreted cautiously
due to low numbers. Fewer side effects were observed with MA treatment. It should be emphasized, however, that most of the AG side effects
Table 6. Side effects, evaluable patients a
15/44 (34.1%) 17/41 (41.5%)
8/27 (29.6%) 6/39 (15.4%)
13/44 (29.5%) 9/27 (33.3%)
* Each patient may have more than one response site.
a Treated for > 8 weeks.
A G 1= Aminoglutethimide.
MA z = Megestrol acetate.
Side effects (number)
A G 1 N = 76
MA 2 N = 74
None
Gastro-intestinal tract
CNS
Rash
Cushingoid
Fever
Dyspnoea
Fatigue
Weight gain
Withdrawal of therapy
due to side effect(s)
44 (57.9%)
5
0
10
2
0
1
9
6
61 (82.4%)
1
0
0
1
0
5
0
8
" Treated for > 8 weeks.
A G 1= Aminoglutethimide.
MA z= Megestrol acetate.
4
0
Endocrine treatment o f breast cancer
205
p=0,20
170 '
078 '
._=
Total
076 '
o.
Dead
AG 86
55
MA 90
63
ga,
074 '
072 •
0~0
i
i
|
20
40
60
Months
Fig. 1. Cumulativeproportion survivingof all patients included. AG- (I) and MA-treatedpatients ([3). The numbers of patients
entered and dead are given.
were transient, and only 4 patients had to withdraw
therapy due to side effects.
The dose of MA chosen, 160mg u.i.d., is the
usual dose reported in literature. However, still the
usual schedule of MA is 40 mg q.i.d. With a half life
of 2-3 days, it is not necessary to administer the
drug more than once daily. This schedule should be
an obvious advantage with regard to patient compliance, and comparable clinical results are reported as for the other progestin, MPA, given in doses
of 1000 mg daily [7, 14].
The AG treatment schedule used in this study
(250 mg q.i.d.), has previously been recommended
by us [9]. It has recently been claimed that a far
lower dose of AG (125 mg b.i.d.) with cortisone
substitution can be used, giving the same results,
and perhaps with a reduced incidence of side effects [19]. The studies using AG without hydrocortisone found lower response rate compared to the
one usually reported with AG 250mg q.i.d. [20].
The issue of the right schedule of AG can only be
decided in a prospective, randomized study corn-
paring the two schedules. We think that the schedule for AG treatment used in this study might still
be the best one, with a well-documented effect and
an acceptable side effect profile, as most side effects subside within a few weeks of treatment.
In conclusion the results of this study add to the
documentation of the relevance of 2. line endocrine therapy in advanced breast cancer. We have
been unable in a fairly large population of patients
to find a difference in efficacy between the aromatase inhibitor aminoglutethimide (AG) and the
progestin megestrol acetate (MA). However, it
should be considered that with the numbers of
patients in the study, the difference of 3% in response rate have a rather large confidence interval
(95% CI, - 12-+ 18). Due to the low frequency of
side effects seen in patients using MA this study
suggests, also due to a simple treatment schedule
(oral administration once daily), that MA might be
the drug of choice as 2. line endocrine monotherapy compared to AG in postmenopausal patients.
A final conclusion on the role of aromatase inhib-
206
S Lundgren et al.
itors as 2. line endocrine therapy awaits further
similar studies using AG, but also similar studies
with new aromatase inhibitors.
References
1. Beatson GT: Oophorectomy in advanced breast cancer in
young women. Lancet II: 104, 1896
2. Macaulay V, Smith IE: Advanced breast cancer. In: ML
Slevin, MJ Staquet (eds) Randomized trials in cancer. A
critical review by sites. Vol 15. Raven Press, New York,
1986, pp 273-357
3. Cole MP, Jones CTA, Todd IDA: A new antioestrogenic
agent in late breast cancer. An early clinical appraisal of ICI
146474. Br J Cancer 25: 270-275, 1971
4. Buchanan RB, Blarney RW, Durrant KR, Howell A, Paterson AG, Preeee PE, Smith DC, Williams CJ, Wilson
RG: A randomized comparison of tamoxifen with surgical
oophorectomy in premenopausal women with advanced
breast cancer. J Clin Oncol 4: 1236-1240, 1986
5. Stoll BA: Combination endocrine therapy - concurrent or
sequential? In: BA StoU (ed) Endocrine management of
cancer. 2. Contemporary therapy. Karger, Basel, pp 80101, 1988
6. Santen RJ, Worgul TJ, Lipton A, Harvey H, Boueher AE:
Aminoglutethimide as treatment of postmenopausal women with advanced breast cancer. Ann Int Med 96: 94-101,
1982
7. Sedlacek SM, Horwitz KB: The role of progestins and
progesterone receptors in the treatment of breast cancer.
Steroids 44: 467-484, 1984
8. Hayward JL, Rubens RD, Carbone PP, Heuson JC, Kumaoka S, Segaloff A: Assessment of response to therapy in
advanced breast cancer. Br J Cancer 35: 292-298, 1977
9. Kvinnsland S, LCnning PE, Dahl O: Treatment of breast
carcinoma with aminoglutethimide. Acta Radiologica Oneologica 23: 421-424, 1984
10. Thorsen T: Occupied and unoccupied nuclear oestradiol
receptor in human breast tumours: Relation to oestradiol
and progesterone cytosol receptors. J Steroid Biochem 10:
661-668, 1979
11. Smith IE: Decision making in palliative therapy. In: BA
Stoll (ed) Breast cancer. Treatment and prognosis. Blackwell Scientific Publications, Oxford, pp 86-97, 1986
12. Paterson AHG: Systemic therapy - prolonged survival or
growth control. Ibid, pp 29--44, 1986
13. Caianey PA, Priestman TJ, Griffiths T, Latief TN, Mould
J J, Spooner D: Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. JNCI 80: 1147-1151,
1988
14. Wander HE, Kleeberg UR, G~irtner E, Hartlapp J,
Scherpe A, B6nisch E, Nagel GA: Megestrolazetat versus
Medroxyprogesteroneazetat in der Behandlung metastasierender Mammakarzinome. Zwischenbereicht einer multizenrischen Phase-III-studie. Onkologie 10, 104-106, 1987
15. Morgan LR: Megestrol acetate v tamoxifen in advanced
breast cancer in postmenopausal patients. Semin Oncol XII
(suppl 1): 43-47, 1985
16. Muss HB, Paschold EH, Black WR, Cooper MR, Capizzi
RL, Christian R, Cruz JM, Jackson DV, Stuart JJ, Richards II F, White DR, Zekan P J, Spurr CL, Pope E, Case
D, Morgan T, Wells B: Megestrol acetate v tamoxifen in
advanced breast cancer: A phase III trial of the Piedmont
Oncology Association (POA). Semin Oneol XII (Suppl 1):
55-61, 1985
17. van Veelen H, Willemse PHB, Tjabbes T, Schweitzer
MJH, Sleijfer DT: Oral high-dose medroxyprogesterone
acetate versus tamoxifen. Cancer 58: 7-13, 1986
18. Smith IE, Harris AL, Morgan M, Ford HT, Gazet JC,
Harmer CL, White H, Parsons CA, Villardo A, Walsh G,
McKinna JA: Tamoxifen versus aminoglutethimide in advanced breast carcinoma: a randomized cross-over trial. Br
Med J 283: 1432-1434, 1981
19. Harris AL, Cantwell BMJ, Sainsbury JR, Needham G,
Evans RGB, Dawes PJDK, Wilson R, Farndon J: Lowdose aminoglutethimide (125 mg twice daily) with hydrocortisone for the treatment of advanced postmenopausal
breast cancer. Breast Cancer Res Treat (Suppl) 7: 41-44,
1986
20. L~nning PE, Kvinnsland S: Mechanisms of action of aminoglutethimide as endocrine therapy of breast cancer.
Drugs 35: 685-710, 1988
Per Lønning
Steinar Lundgren