Primary endocrine therapy for advanced breast cancer: To start with tamoxifen or with medroxyprogesterone acetate?

Annals of Oncology 4: 735-740, 1993. C 1993 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Primary endocrine therapy for advanced breast cancer: To start with tamoxifen or with medroxyprogesterone acetate? M. Castiglione-Gertsch, S. Pampallona, M. Varini, F. Cavalli, K. Brunner, H. J. Senn, A. Goldhirsch & U. Metzger For the Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland

point 'time to progression' have so far been observed: a study of similar size would have a 90% power to detect a hazard Background: The availability of compounds effective against ratio of 1.85. Initial MAP was associated with a significantly metastatic disease and at the same time excellently tolerated higher remission rate (50% versus 30% for tamoxifen; p — even in long-term administration has determined the choice 0.023) and a marginally significantly longer median time to of tamoxifen as primary treatment for palliation in metastatic progression (8.8 versus 5.4 months; p = 0.051). Overall surbreast cancer. Other drugs or other hormonal approaches vival was also longer for the MAP group (28 versus 20 were hardly tested against tamoxifen, especially as first-line months; p - 0.384). The use of MAP was associated with a significantly higher toxicity, mainly hypertension, weight gain treatment Patients and methods: 119 patients with metastatic breast and tremor. cancer and no prior endocrine therapy were randomized to Conclusions: The implications of these results are that receive either tamoxifen (TAM) 20 mg/day orally (64 pa- initial endocrine therapy in postmenopausal patients with tients), or medroxyprogesterone acetate (MAP) lg/day i.m. 5 metastatic disease should be MAP if the patient is willing to days/week for 4 weeks and then 500 mg twice a week (55 pa- accept the side effects of high-dose progestins. Progestins tients). The subsequent endocrine therapy was also prospec- should be tested in the adjuvant setting for postmenopausal tively defined at study entry. women, especially those with no tendency to hypertension or Results: A total of 111 events, contributing to the end- obesity. Summary.

Introduction

Endocrine therapy is the treatment of choice for advanced breast cancer in view of the availability of agents which have a high therapeutic index due to very low toxic side effects [1] especially for patient subsets with features of disease which predict hormone responsiveness. The availability of compounds effective against metastatic disease and which at the same time are well tolerated even in long-term administration has determined the choice of tamoxifen as primary treatment for palliation in metastatic breast cancer [2]. Few other drugs or hormonal approaches have been tested against tamoxifen, especially as first-line treatment. The assumption was always that in an unselected patient population, about one-third of those of postmenopausal age will objectively respond to the treatment. Selection of the patients by estrogen receptor (ER) status permits the allocation of patients to endocrine therapies which provide about a 50% chance of response for women with ER+ tumors and of less than 10% for those with ER-primaries [3,4].

From 1982 to 1985, we conducted a randomized clinical trial of primary TAM versus primary MAP to assess the impact of the choice of endocrine therapy in postmenopausal patients, and the present report is in reference to 111 events which contributed to the endpoint 'time to progression' and 104 deaths in the study population of 119 patients. In a previous trial, our Group (5-7) showed that high-dose MAP is more effective than a lower dose of the drug given by the same route (i.m.). We therefore decided to investigate the impact of primary endocrine treatment on time to progression and overall survival by using the most effective dose of MAP, comparing it with the standard treatment with tamoxifen, and investigating the side effects of both drugs. Materials and methods Trial execution

The trial started in 1982 and was closed to accrual in 1985. A total of 127 patients were entered in the study, contributed by the 7 centers of the Swiss Group for Clinical Cancer Research (Basel, Bern, Lausanne, Geneva, Zurich, St. Gallen, Tessin).

736 Eight ineligible patients, six of whom were randomized to MAPTAM and two to TAM-MAP, were inadvertently entered in the trial. The reasons for ineligibility were: no detectable tumor in 5, central nervous system metastases in 2 and lesions only in previously irradiated fields in 1 patient. These patients were excluded from the subsequent analyses. Sample size

Table 1. Characteristics of 119 eligible patients at study entry. MAP n-55 Age, years median range

62 44-80

61 43-83

9 38 53

11 39 50

40 42 18

38 50 12

Number of involved metastatic sites 1 >2

45 55

42 58

Previous chemotherapy None Adjuvant only Palliative only Both adj. and pall.

56 25 15 4

57 33 8 2

Free interval, years -1 >l-5 >5

29 47 24

31 47 22

80 140

80 140

66

66

IK Sunns The study was. originally designed with a power in excess <>l '>((",, u> Negative detect a hazard ratio of 1.5 between the two primary treatments, in Positive terms of time to progression, with a projected accrual of 150-200 Unknown patients and a follow-up of about 1.5 years. The accrual was discontinued because of low patient entry after 127 patients had been Main localization of metastases randomized. A total of 111 events contributing to the endpoint time Visceral to progression' have been observed thus far a study of similar size Bone would have a 90% power to detect a hazard ratio of 1.85. Soft tissue Randomization Treatment was assigned by telephone call to a central operations office. The minimization method was applied balancing for the following factors: estrogen receptor status (positive, negative, unknown), number of metastatic sites (one versus two or more), previous chemotherapy (none, adjuvant, palliative, both). Patients were assigned to one of the following sequences of primary and secondary treatment: MAP-TAM, MAP-AGT, TAM-MAP, and TAM-AGT; the acronyms stand for treatments defined in Fig. 1. Eligibility criteria Eligible for the study were postmonopausal (last menstruation more than 1 year prior to study entry) non-hormonally pretreated patients with histologically proven advanced or metastatic breast cancer, not amenable to surgery, with measurable or evaluable lesions and a performance status of 0-3 (WHO). Patients with brain metastases or rapidly progressing liver metastases were not eligible.

TAM n-64

Pre-study blood pressure, mm Hg median diastolic median systolic Pre-study weight, kg median

Patient characteristics Since investigation of the primary treatment will be the focus of this report, the characteristics of the patients are detailed in Table 1, according to assigned TAM or MAP. In terms of treatment sequences, within the MAP group, 28 patients were assigned to receive TAM and 27 AGT as secondary therapy. Of the TAM group 32 were assigned to receive MAP and 32 AGT. There appears to be a slight imbalance between the treatment groups in terms of received previous chemotherapy and localization of metastases. Treatment and follow-up Patients received the first hormonal treatment until disease progression (if progression occurred within 12 weeks of study start, see Primary therapy

B. C. D.

R A N D O M 1 Z E

below). Tamoxifen was given orally in a dose of 20 mg/day and Medroxyprogesterone acetate i.m. with a loading period of 28 days whereby the drug was administered daily from Monday through Friday at the dose of 1 g/day. After the first 4 weeks of treatment MAP was given once a week at the dose of 500 mg i.m. At progression the patients were switched to the second treatment of the randomized sequence and continued on this second therapy until new progression. After the second progression patients were considered off-study and were treated individually. In case of progression within 12 weeks of the beginning of the study (primary progression) the patients were treated with MAP if they had received TAM and with Aminoglutethimide (AGT) if they had received MAP.

Secondary therapv

Therapy o*

after CR. PR. NC

primary PD

1 TAM+

MAP*

MAP*

TAJVU

AGT"

MAP*

MAP*

TAiuU

AGT"

MAP*

AGT"

AGT"

Fig. 1. SAKK-Study 24/82: study design. + - TAM (Tamoxifen) 20 mg/day orally; * — MAP (Medroxyprogesterone acetate) dosage: 1 g i.m. per day, except Saturdays and Sundays, for 28 days, then maintenance 0.5 g i jn. per week; ** — AGT (Aminoglutethimide) 500 mg/day orally days 1-3, 750 mg/day orally days 4-6 and 1000 mg/day orally from day 7. In addition 40 mg/day Hydrocortison orally from day 1.

737 The tumor assessments were performed monthly for the first 3 months of treatment and every 3 months thereafter.

Table 2. Response and primary progression according to first treatment of randomized sequence.

Second treatment Eighty-three of 119 patients received a second treatment, but 8 of them did not receive the correct randomized second-line hormone. 36 patients were not switched to the second hormonal therapy for the following reasons: - 5 were still in remission under the first treatment at analysis - 11 received chemotherapy or radiotherapy as they were no longer eligible for endocrine therapy * - 2 refused further therapy - 18 protocol violations (decision of the treating physician).

Response* CR/PR CR PR NC

For the primary treatment the following endpoints were considered: i) time to progression or death (TTP), whichever occurred first, measured from randomization date; ii) response according to the WHO [8] criteria; iii) primary progression defined as progression occurring within the first 12 weeks of treatment. Time to second progression or death and overall survival according to randomized sequence were measured from randomization date.

PD

Where appropriate Pearson chi-squared tests for independence are used for comparing distributions of patients across discrete variables, whereas distributions over continuous factors were compared by means of Kruskal-Wallis tests. Logistic regression was used to simultaneously assess the effect of primary treatment and of selected covariates on the probability of response and of primary progression. Odds ratios (ORs) as approximations to relative risks, and their corresponding 95% confidence intervals (95% Cls) are reported. Statistical analyses were carried out by means of the software package Stata [9|. Progression-free and overall survival percentages over time were calculated by the Kaplan-Meier method [10]. For univanate analyses of time to progression and overall survival the p-values from the logrank test [11] are reported. Hazard ratios (HRs) and their corresponding 95% Cls from a multivariate Cox regression [12] are similarly reported for the analysis of time to progression and overall survival. The variables included in all the regression analysis models were appropriate binary indicators to code the main effects of ER-status (positive, negative, unknown), number of involved sites (1, >2), main localization of metastases (visceral, bone, soft tissue) and free interval (<1 year, 1-5 years, >5 years) at the same levels used in the tables. For treatment evaluation HRs and ORs are expressed with TAM as the reference category, unless otherwise specified.

Results First treatment Response and primary progression Table 2 summarizes the results. With respect to response, though overall statistical significance is not achieved (p = 0.122), when restricting the analysis to complete and partial responses (CR and PR, respectively) together, the therapy with MAP represents a distinct advantage, bringing the percentage of response to 50% as opposed to 30% with TAM (p = 0.023). A multivariate logistic regression on the probability of

TAM

(exact 95%

(exact 95% Cl)c

err

Endpoints

Statistical analysis

MAP

Toxicity" Primary progression yes

50 (37-65)

30 (19-42)

9 (3-21) 41 (28-56) 23 (12-36) 24 (14-38) 2

5 (1-13) 25 (15-37) 31 (20-44) 39 (27-52) 0

15 (9-31)

37 (24-49)

P-value

0.023

0.122

0.013

* Two patients in the MAP group are not reported in this table: one had a major protocol violation, and assessment of response was not possible for the other. b One patient in the MAP group (2%) was not evaluable for response since the therapy was stopped due to toxicity (tremor). c 95% (exact) Confidence Intervals.

CR/PR quantified the advantage of MAP over TAM as more then two-fold (OR - 2.26, 95% Cl: 0.98-5.23). Of the variables included in the regression, none was a statistically significant predictor of response, but free intervals between primary treatment for breast cancer and diagnosis of metastases longer than one year appeared to be positively associated with response. Although not statistically different from the other two groups, the proportion of responders in the soft tissue main metastatic localization was the highest (56%), while visceral and bone main localizations reached similar remission rates (visceral 38%, bone 35%; p — 0.275). The main results regarding primary progression (occurring within 12 weeks after treatment start) are also summarized in Table 2. Consistent with the previous results, MAP has significantly lower percentages of primary progressions than does TAM, 15% and 37%, respectively (p = 0.013). A multivariate logistic regression suggests that MAP significantly reduces the probability of primary progression to one-third of what it is with TAM (OR = 0.31, 95% Cl: 0.11-0.85). None of the other predictor variables considered in the regression was statistically significant, but there was a suggestion that free intervals shorter than one year and negative ER-status were associated with increased probability of primary progression. Time to progression or death, TTP At the time of this analysis only 8 patients (7%) were

738 event-free (neither progressed nor deceased). The median TTP was 8.8 months for MAP and 5.4 months for TAM (logrank test p = 0.049), as shown in Table 3. In terms of hazard ratio, MAP reduced the chances of progression or death by more than 30% with respect to TAM (HR - 0.68, 95% Cl: 0.46-1.00). This result was not greatly affected in magnitude when allowance was made for selected covariates in the regression model (HR - 0.71, 95% Cl: 0.47-1.08). Very consistent results were observed in all subgroup analyses, not reported here, all of which suggested an advantage for MAP over TAM. None of the considered covariates, including estrogen receptor, was of strong prognostic value for TTP. Progression-free survival is represented graphically in Fig. 2.

Table 3. Time to progression (TTP) according to the first treatment of the randomized sequence and overall survival (OS) according to the randomized sequence. N

E

TAM MAP

64 55

61 50

TAM-MAP TAM-AGT MAP-TAM MAP-AGT

32 32 28 27

28 30 23 23

HR

95% Q

P

5.4 8.8

1.00 0.68

reference 0.46-1.00

0.051

22.2 19.7 36.1 21.7

1.00 1.39 0.90 1.07

reference 0.82-2.33 0.52-1.57 0.62-1.87

0.221 0.720 0.801

Md

TTP OS

N - sample size; E — number of events; Md - median time to events, months; HR — hazard ratio from univariate Cox regression; 95% Cl - 95 percent confidence interval for the HR from univariate Cox regression; P — P-value for HR from univariate Cox regression.

Overall survival, OS

Table 3 also details the results for OS. In this case it is more appropriate to assess the relative merits of the four randomized treatment sequences. No distinct pattern appears (logrank test: p - 0.446), but the MAPTAM sequence seems to be associated with a reduction of the chances of death. Allowance for possible prognostic variables suggested a preference for the treatment starting with MAP (taking TAM-MAP as reference, the estimated HR and 95% Cls were: for TAMAGT 1.22, 95% Cl: 0.66-2.25, for MAP-TAM 0.79, 95% Cl: 0.43-1.45 and for MAP-7 0.87,95% Cl: 0.481.57). The survival curves for the 4 treatment sequences are shown in Fig. 3. Toxicity

The toxicity observed with the primary treatments is reported in Table 4. Thromboembolic complications (including thrombophlebitis, thrombosis, embolisms) and

2

3

4

5

8

7

Years sines randomization

— -—• —

TAM-MAP TAM-AGT MAP-TAM MAP-ACT

fig. 3. SAKK 24/82 - overall survival.

3 4 5 Ysars since randomization

MAP TAM

Fig. 2. SAKK 24/82 - time to progression.

cushingoid changes were observed, as expected, more often in the MAP group (p - 0.077 and p - 0.091, respectively) and for tremor and edema the difference between the 2 treatments was significant, both events being more frequent with the MAP treatment (p < 0.001 and p - 0.030 respectively). Special attention was paid to increase in blood pressure and to weight gain. Especially systolic blood pressure showed a significant increase of 20 mm Hg with MAP, whereas the increase with TAM was only 10 mm (median values) (p - 0.022). Patients treated with MAP had a median weight gain of 3.5 kg as compared to 1 kg for TAM-treated women (p < 0.001). Only one patient in the MAP group had to stop therapy due to toxicity (tremor).

739 Table 4. Tenacity of first treatment of randomized sequence.

Thromboembolic episodes Hot flashes Tremor Erythema Edema Vaginal discharge Neurological disturbances Nausea Cushingoid habitus Alopecia Hypercalcemia Local toxicity at injection site

MAP %

TAM %

14 8 24 2 29 8 6 6 10 8 10 8

3 10 0 7 11 5 3 11 2 3 10 0

Blood pressure (median values) Diastolic values, mm Hg Maximum1 100 Difference" 12.5 Systolic values, mm Hg Maximum" 170 Difference11 20

Table 5. Trials comparing high-dose medroxyprogesterone acetate and tamoxifen in advanced breast cancer.

P-value Author (ref.) 0.077 0.753 <0.001 0.774 0.030 0.700 0.658 0.342 0.091 0.409 1.000

v. Veelen [16] Garcia [17] Mattson [18] Muss [13] Pannuti [19] Present study 1

90 10.0

0.013 0.024

N.of pts

RR RR TAM MAP

TTP TTP TAM MAP

OS OS TAM MAP

in months

in months

129 103

35% 54%

44% 44%

23 10

17 10

26 28

20 20

63

55%

70%

184

15%

34%'

33 16 8 7

25+ (CRs) 15 (PRs) 8 (NCs) 8.3 24

32'

41

25%

43%

13

119

30%

50%'

5.4

5 8.8

Difference statistically significant.

megestrol acetate (160 mg/day) or tamoxifen showed no difference in response rates but time to progression was longer with tamoxifen [14]. Weight In our trial the sequence of the endocrine agents was 72 Maximum" 70 0.324 prospectively prescribed. The results all consistently 11 3.5 Difference 1.0 <0.001 favor MAP in our study (response rate, time to pro1 gression and survival). Maximum — maximum value measured during treatment period. b Difference — maximum minus value at beginning of treatment Both sequences including AGT as second-line horperiod. monal therapy showed short times to second progression when compared to sequences including TAM or MAP as second treatment. This observation was alSecond treatment ready made in a previous study of our Group [15]. Toxicity of TAM and MAP was significantly differDue to the incomplete switch to the second treatment ent and MAP was accompanied, as expected, by a and to the high number of protocol violations and the higher weight gain, an increase in blood pressure, and different selection of the patients at time of first pro- frequently tremor. Thromboembolic episodes, although gression we hesitate to give remission rates for the sec- not serious, were also observed more frequently in the ond therapy. Nevertheless, it can be stated that remis- MAP-treated patients. The increased remission rate we sions were observed in all sequential therapies. observed in this trial could promote the study of MAP Noteworthy are the short times to progression ob- in the adjuvant setting, despite its toxicity. This might served in both therapy arms involving AGT as second be particularly interesting in patients who do not pretreatment and the long time to second progression ob- sent the risk factors of toxic effects such as diabetes, served again for the patients treated with MAP-TAM. obesity, hypertension, etc.). For advanced breast cancer, when palliation is needed, it might be wise to start endocrine therapy, if indiDiscussion cated and possible, with MAP, provided there is no underlying clinical situation which will render the atPrimary endocrine treatments for advanced breast can- tempt to palliate a cause of increased discomfort for cer are rarely studied. Reports on the efficacy of pro- the patients. gestins versus tamoxifen are summarized in Table 5. In a recent report of a randomized trial MAP lg/ day orally was tested against tamoxifen in 184 evalu- References able patients [13]. The remission rates were 34% for 1. Goldhirsch A, Gelber RD, Treatment of overt metastatic breast MAP versus 15% for tamoxifen (confidence intervals cancer. In Veronesi U (ed): Bailliere's Clinical Oncology. Inter24%-45% and 8%-24%, respectively). Time to pronational Practice and Research. Breast Cancer 1988; 2: 215— gression was 8.3 versus 7 months and survival 32 ver29. sus 24 months (p < 0.05) in favor of MAP. Conversely, 2. Mouridsen H, Palshof T, Patterson J et al. Tamoxifen in adan investigation performed by the same group vanced breast cancer. Cancer Treat Rev 1978; 5:131—41. in 138 patients randomly allocated to receive either 3. Osborne CK, Yochomowitz MG, Knight WA et al. The value of 155 10

0.004 0.022

740

8.

9. 10. 11. 12. 13.

estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980; 46: 2884-8. Bloom ND, Tobin EH, Schreibman B et al. The role of progesterone receptors in the management of advanced breast cancer. Cancer 1980; 45: 2972-7. Goldhirsch A, Cavalli F, Ganzina F et al. Serum level profile of medroxyprogesterone acetate in breast cancer patients treated intramuscularly with two different dose schedules. Current Chemotherapy and Immunotherapy. Proc 12th International Congress of Chemotherapy 1981; 1471-6. Cavalli F, Goldhirsch A, Jungi WF et al. Low- versus high-dose medroxyprogesterone acetate in the treatment of advanced breast cancer. In Cavalli F, McGuire, WL, Pannuti F (eds): International Symposium on Medroxyprogesterone Acetate. Excerpta Medica 1982; 224-33. Cavalli F, Goldhirsch A, Jungi WF et al. For the Swiss Group for Clinical Cancer Research. Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. JClin Oncol 1984; 2:414-9. WHO Handbook for reporting results of cancer treatment. Geneva 1979; 22-7. Stata. Computing resource center reference manual. Santa Monica: California 1991. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Peto R, Pike M, Armitage P et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Brit J Cancer 1977; 35: 1 -39. Cox DR. Regression models and life tables. J R Stat Soc 1972; B34:187-220. Muss H, Case LD, Fussell R et al. Tamoxifen versus high-dose oral medroxyprogesterone acetate as first line endocrine therapy for metastatic breast cancer A randomized trial of the Piedmont Oncology Association. Proc Am Soc Clin Oncol 1991;11:A38.

14. Muss HB, Wells HB, Paschold EH et al. Megestrol acetate versus tamoxifen in advanced breast cancer 5-year analysis A phase III trial of the Piedmont Oncology Association. J Clin Oncol 1988; 6: 1098-106. 15. Alberto P, Mermillod B, Kaplan E et al. A clinical trial of aminoglutethimide in advanced postmenopausal breast carcinoma: low response in patients previously treated with medroxy-progesterone. Eur J Cancer Clin Oncol 1985; 21: 423-8. 16. van Veelen H, Wiliness PHB, Tjabbers T et al. Oral high-dose medroxyprogesterone acetate versus tamoxifen. A randomized crossover trial in postmenopausal patients with advanced breast cancer. Cancer 1986; 58: 7-13. 17. Garcia-Giralt E, Hurteloup P, Chollet P et al. Breast cancer first line hormonotherapy: A multicenter randomized trial comparing TAM with MAP and their sequential administration. Proc Am Soc Clin Oncol 1987; 6: A236. 18. Mattsson W, Von Eyben F, Hallsten L et al. A trial of tamoxifen vrsus high-dose medroxyprogesterone acetate in advanced postmenopausal breast cancer. A final report. Int Congr Ser 1982; 611: 276-84. 19. Pannuti F, Martoni A, Fruet F et al. Hormone therapy in advanced breast cancer High dose medroxyprogesterone acetate versus tamoxifen. Preliminary results. In Mouridsen HT, Palshof T (eds): Breast Cancer - Experimental and Clinical Aspects. Oxford: Pergamon Press 1980; 93-8.

Received 16 February 1993; accepted 12 May 1993. Correspondence to: M. Castighone-Gertsch MD SAKK/IBCSG Coordinating Center Konsumstrasse 13 3007 Bern, Switzerland