New hormonal approaches to the treatment of breast cancer

Critical Reviews in Oncology/ Hematology, 199 I ; II:294 1 !c 1991 Elsevier Science Publishers B.V. 1040-8428/91/$3.50

ONCHEM

29

00002

New hormonal approaches to the treatment of breast cancer John T. Hamml

and Joseph C. Allegra2

‘Di~~i.~ion of Medical Oncology. James Graham Brown Cancer Center and ‘Department qf Medicine. University

ofLouisville.Louisville. KY,

U.S.A.

Contents I.Introduction

_...........................................................__.._........

29

II.Background

. . . . . . . . . . .._..........................__._...................___........

30

III. Steroid hormone

receptors

IV. Chemohormonal

therapy

V. Sequential

.................

chemohormonal

inhibitors

X. Tamoxifen

in premenopausal

Xl. Tamoxifen

in the adjuvant

XII. Summary

..............................

an M.D. degree from Vanderbilt Hamm

is currently Oncology

ANegra received

Assistant

Medical

Professor

Temple

KY.

and of

Joseph C.

University

in Phila-

delphia, PA and an M.D. degree from Pennsylvania State University in Hershey. PA. Dr. Allegra is currently President, T2 Medical, Atlanta. GA.

Correspondence: cine, Division Center, Kentucky

John T. Hamm, of Medical

529 S. Jackson 40292. U.S.A.

M.D.,

Oncology, Street,

Assistant

James

University

Professor

Graham

of Medi-

Brown

of Louisville,

32

36

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37

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37

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37

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38

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39

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39

1. Introduction

TN. Dr.

in the Division

of Louisville,

from

University

Nashville,

...........

...........

setting

of Medicine

at the University an B.A. degree

School,

31

31

patients

.................................

31

...........

..

...................

John T. Humm received a B.A. degree from Vanderbilt

Medical

....

. ...

.............................

IX.Newagents

References

...........

........................

agonists

VIII. Aromatase

.........

...............

.........

therapy

...................

VI. Clinical trials VII. LHRH

...............

Cancer

Louisville.

Hormonal therapy has been used to treat breast cancer since the turn of the century. The experimental basis for this treatment originated in laboratory observations that some breast cancers were dependent on or stimulated by physiologic levels of estrogen; whereas removal of estrogen stimulation caused regression of these tumors. Established hormonal therapy has consisted of bilateral oophorectomy, bilateral adrenalectomy, hypophysectomy, estrogens, androgens, progestins, and recently the antiestrogen tamoxifen. Although these therapies are all

30

effective, we have not seen a significant

increase

in effi-

glucocorticoid

replacement

and may require

cacy over the original therapies with a response rate of about 30% in unselected patients, 50% in ER-positive tu-

corticoid replacement. Hypophysectomy more endocrinologic deficits necessitating

mors, and up to 80% in tumors

placement of glucocorticoids, mineralocorticoids. A ‘medical

containing

both ER and

PR. Response duration to first line hormone therapy is approx. 12 months. Although a few tumors can respond

mineralo-

causes even lifelong re-

thyroid hormone, and adrenalectomy’ can be

achieved with aminoglutethimide which blocks the conversion of cholesterol to pregnenolone. The standard

for very long periods, it is doubtful that any patient with advanced breast cancer has ever been cured. Because of this ultimately poor outcome new strategies for using

dose is 250 mg four times a day along with hydrocortisone replacement. Side effects include a pruritic skin

hormonal explored.

rash, fever, somnolence, there has been renewed

agents and new hormonal agents The combination of chemotherapy

are being and hor-

ataxia, and lethargy. Recently interest in aminoglutethimide,

monal therapy has been examined and the results are generally disappointing but sequential use of hormonal

with some research concentrating on lower doses which may be as effective but with lower incidence of side ef-

synchronization chemotherapy

fects. This renewed inhibit the enzyme

and stimulation followed by cytotoxic appears effective. There has been re-

newed interest in aminogluthethimide, an aromatase inhibitor useful in breast cancer. A new aromatase inhibitor 4-hyrdoxyandrostene-3,17-dione (4-OHA) may be as effective with fewer side effects. A new antiestrogen, Torimifene, and a new antiprogestin RU486 are being examined, along with new indications for the use of tamoxifen. LHRH analogues which are effective in prostate cancer are under trial in breast cancer. II. Background In the 1890s Beatson [l] first demonstrated that breast cancer is responsive to hormonal manipulation. He performed an oophorectomy in women with advanced breast cancer resulting in tumor regression and even complete remissions in some patients. Therapies such as this which remove a source of endogenous hormone production are called ablative. Other ablative therapies were explored in the late 1940s and 1950s. Huggins and Bergenstal [2, 31 found dramatic responses to bilateral surgical adrenalectomy. Hypophysectomy was also found to be effective. In 1969, Griffith and Hall reported that aminoglutethimide (‘medical adrenalectomy’) was effective in treating breast cancer [4, 51. Later studies by Lipton et al. [6, 71 confirmed its usefulness. All of these surgical ablative therapies and aminoglutethimide have approximately the same response rate. In 3040% of unselected patients a response is seen. In patients with ERpositive tumors S&6096 respond to ablative therapies. While the established ablative therapies are effective, they either are only useful in a minority of patients or are frought with complications. Bilateral oophorectomy, while a relatively minor surgical procedure is only useful in premenopausal estrogen receptor positive patients which is a small portion of breast cancer patients. Bilateral adrenalectomy is only effective in postmenopausal or castrated patients with ER-positive tumors. Following adrenalectomy, patients must be on lifelong

interest is secondary to its ability to aromatase and therefore block the

peripheral conversion of androgen to estrogen. Additive therapies, on the other hand, consist of exogenous administration of hormones. In 1940, Huggins and Hodges [8] found that androgens were effective in breast cancer. Androgens were felt to antagonize the effects of estrogens. Androgens are less effective than other hormonal therapies with approx. 20% of unselected patients responding. They also have poor patient acceptance secondary to their virilizing side effects. Later it was found that the addition of pharmacologic doses of estrogens could control metastatic breast cancer [9-l 11. This was surprising since it was generally accepted that estrogens stimulate breast cancer. Although the mechanism is still not understood, it is felt that the higher doses of estrogen are responsible for the effect since some models demonstrate estrogen stimulation at a low dose and suppression at higher dosages. In the late 1950s progesterone was found to be effective in breast cancer. Again, the response rate was approx. 30% in unselected patients [12-141. Megesterol acetate is the most commonly used agent. It is now most often used as second line hormonal therapy, although its position is changing as more and more patients are receiving antiestrogen in the adjuvant setting. Tamoxifen is a triphenylethylene antiestrogen active in the treatment of breast cancer [15, 161. Tamoxifen binds to the estrogen receptor, then is translocated to the nucleus where it antagonizes many of the actions of estrogen. Tamoxifen does have some estrogenic properties and in certain patients a ‘tumor flare’ is seen during initiation of therapy. The response rate is 30% in unselected patients, 50% in ER-positive tumors and 6&75% in ER-positive and PR-positive tumors. It appears to have a lower response rate in visceral metastasis. Toxicity is relatively minor with the most frequent complaints being hot flashes, nausea, edema, and weight gain. Because of its high tolerance rate and efficacy it is widely used in estrogen receptor positive tumors in post-

31

menopausal

and

premenopausal

patients

(discussed

tin plus cyclophosphamide

later).

tamoxifen

III. Steroid hormone receptors

failure, and the combination ously. The initial response

The discovery of steroid hormone receptors was an important advance in both the understanding of breast cancer and the selection of patients for hormonal therapy. In the 1960s Jensen [ 171 and others [ 18, 191 demonstrated radiolabeled estradiol bound to some breast cancer specimens and correlated this with response to therapy. Subsequently, this work has been greatly expanded upon confirming the usefulness of estrogen and

(Tam),

45%, Tam then AC was no statistical sponse of AC then significantly better

tamoxifen

(AC) followed alone

on failure by

followed

by AC on

of Tam + AC simultanerates were: AC then Tam

22%, and Tam + AC 51.3%. There significance between the initial reTam and AC + Tam but both were than the initial response to Tam

alone. Despite this initial difference there was no statistical difference in overall response or median survival: AC then Tam 18 months, Tam 20 months.

Tam then AC 21 months,

Several trials [28-341 have been conducted

AC +

examining

progesterone receptor assays [20]. As stated before, approx. 30% of unselected patients will respond to hor-

the benefit of adding tamoxifen to adjuvant chemotherapy. The largest such trial is the NSABP B-09 trial [28]

monal therapy, 50% of ER-positive patients respond and approx. 75% of strongly ER- and PR-positive patients respond. On the other hand, only 5-10s of estrogen receptor negative patients will respond to hormonal therapy. Thus, by using receptor status to select patients for hormonal therapy the response rate is increased, while patients with little chance of responding are spared exposure to ineffective treatment.

with 1891 women with stage II breast cancer randomized to receive L-phenylalanine mustard and 5-fluorouracil with or without tamoxifen. There was a 5% increase at 5 years in disease-free survival (DFS) but no survival advantage in the tamoxifen group. This was accounted for almost entirely by improved DFS in the group greater than 50 years of age with four or more positive nodes. This subset also demonstrated improved survival. Other subsets demonstrated no improvement in DFS or survival. The ECOG [29, 301 postmenopausal study showed an improvement in 4-year DFS by adding hormonal therapy to adjuvant chemotherapy. The Ludwig study [3 1, 321 showed improved DFS comparing CMF P + T to P + T alone. These studies suggest a small but significant improvement in DFS by adding tamoxifen to adjuvant chemotherapy. Thus it appears that adding hormonal therapy to chemotherapy in advanced breast cancer is not beneficial to patients over sequential use of hormonal agents followed by cytotoxics at failure. In the adjuvant setting there may be some added benefit to certain subsets of patients in DFS but not survival. Prolonged administration of tamoxifen following adjuvant chemotherapy may be more beneficial, trials of this are underway. Why doesn’t the combination of two modalities of therapy have more effect [26]? Experimental evidence exists which may explain this. Sutherland et al. [35] has found MCF7 mammary cells are arrested in mid to late Gl by tamoxifen. Cells which are rapidly proliferating are most sensitive to chemotherapy, therefore by arresting cells in Gl, tamoxifen may be ‘chemo-protective’. Clarke et al. [36] have shown chemotherapy decreases estrogen receptor content of MCF7 cells in culture. The estrogen receptor is felt necessary for the action of tamoxifen. thus chemotherapy may reduce the susceptibility of cells to hormonal therapy. Hug et al. [37] have directly examined the interaction of chemotherapy and hormonal therapy in two cell

IV. Chemohormonal

therapy

The combination of chemotherapy with hormonal therapy in breast cancer has been a generally disappointing endeavour. Chemotherapy and hormonal therapy are both effective in treating advanced breast cancer. Hormonal therapy is well tolerated with few side effects and can be easily added to chemotherapy regimens with relatively few additional toxicities. Hormonal therapy and chemotherapy are felt to act through different mechanisms; therefore it seemed reasonable to postulate that tumor cells which may be resistant to chemotherapy (slower growing, more differentiated, and possibly more likely to be ER-positive) may be susceptible to hormonal therapy and vice versa. By combining hormonal therapy with chemotherapy it was hoped to eliminate clones resistant to one therapy or the other with little additional toxicity. Many chemohormonal trials [21-251 have been conducted with generally no added survival benefit found, although some did have higher initial response rates [26]. A more important consideration than initial response rate is whether there is added survival benefit by combining chemotherapy with hormonal therapy compared to their sequential use. A few trials have addressed this question. The Australian and New Zealand Breast Cancer Trials Group [27] studied 339 postmenopausal patients with advanced breast cancer. There were three treatment arms each with I 13 patients: Doxorubi-

32

lines, MCF7 and MDA-468. The cell lines were treated with either 5-FU or adriamycin. With increasing dosages of each drug the number of surviving colonies decreased. The addition of tamoxifen to these cultures attenuated the cell killing effect of the cytotoxics. One final consideration is that even though chemotherapy and hormonal

therapy

work

by different

they may be targeting the same population leaving clones resistant to both therapies. V. Sequential chemohormonal

biopsies, prior to treatment, and at 3,6, and 9 days after initiation of treatment. The treatment consisted of estradiol 0.1 mg and progesterone 1 mg i.m. daily beginning

mechanisms

2 days after the initial biopsy. The thymidine labeling index of samples increased significantly from pretreatment to day 3 in seven of ten patients. Three of four ERpositive patients and surprisingly four of six ER-nega-

of cells, still

tive samples

had a significant

increase

in the thymidine

labeling index. The index did not increase any further by the 6th or 9th days.

therapy VI. Clinical trials

Sequential

use of hormonal

agents

prior

to chemo-

therapy may perturb cellular kinetics in such a way as to enhance the efficacy of chemotherapy. Lippman et al. [38] have reported the effects of estrogens and antiestrogens on breast cancer cell cultures. MCF7 cell cultures were treated with either estradiol or tamoxifen. After 14 h the estradiol-treated cells began to proliferate with increased thymidine labeling compared to controls, while tamoxifen-treated cells were inhibited with decreased thymidine labeling. At 36 h estradiol was added to the tamoxifen-treated cells, by 48 h there was a marked increase in thymidine labeling. The labeling exceeded even the cells treated with estradiol alone. This rescue of tamoxifen-treated cells by estradiol suggested that tamoxifen may arrest the cells at a specific point in the cell cycle, either GO or Gl . Estrogen then causes these cells to rapidly enter the S phase in a synchronized fashion. If these synchronized proliferating cells were then treated with cell cycle specific cytotoxic therapy the effect may be a more complete tumor cell kill compared to unstimulated, unsynchronized cells. Sutherland et al. [35, 39, 401 have demonstrated the arrest of MCF7 cells in G&G1 by tamoxifen which was partially blocked by simultaneous administration of estradiol. Their studies suggested tamoxifen effected cells in middle to late Gl stage. Osborne et al. [41] using thymidine labeling and flow cytometry have shown tamoxifen and two other antiestrogens, nafoxidine and trioxifene, cause an accumulation of cells in Gl. In MCF7 cell lines the percentage of cells in G 1 increased from 72% in controls to 92% in cells treated with 1 FM tamoxifen or 72 h. They then treated these cells with estradiol. Even without removing the tamoxifen 6&70% of cells progressed to S phase within 24 h. Tamoxifen and estradiol had no effect on the kinetics of an estrogen receptor negative cell line MDA23 1 suggesting the effect is dependent upon estrogen receptor presence. Dao et al. [42] studied the effect of estrogen and progesterone in vivo. Ten patients with multiple cutaneous nodules of metastatic breast cancer underwent multiple

With

the results

of the cell culture

experiments

of

Lippman as background our group designed a clinical study to test this hypothesis [4345]. Fifty-seven patients with advanced adenocarcinoma of the breast were treated. Patients previously treated with tamoxifen were excluded. Both ER-positive and -negative patients were eligible. The median age was 56 years. Forty-three patients were postmenopausal and fourteen premenopausal. Thirty patients (53%) had ER-positive tumors, twenty (35%) were ER negative, and in seven others * (12%) the ER was unknown. The treatment regimen was as follows. Patients were started on tamoxifen 10 mg orally twice a day for 10 days. The tamoxifen was discontinued, the patients then received premarin (an estrogen) 0.625 mg orally twice a day for 4 days. On the 4th day of premarin therapy the patients received methotrexate 200 mg/m* i.v. followed in 1 h by 5-FU 500 mg/m* i.v. Leucovorin 10 mg orally every 6 h for six doses was started 24 h later. The treatment regimen was repeated every 18 days. The complete response rate was 37~~ partial response 25% for an overall response rate of 62% (Table 1). Twenty-one percent of patients were stable, while 1796 progressed on treatment. Of the ER-positive patients 70% responded, ER unknown 71% responded and ER

TABLE

1

Sequential tamoxifen, premarin, advanced breast cancer

n

methotrexate,

5-FU, and leucovorin

ER positive

ER negative

ER unknown

Total

30

20

20

57

CR

21(37%) 14 (25%)

PR CR + PR Stable

21 (70%)

Progression Allegra et al. [4345]

9 (45%)

5 (71%)

35 (62%) 12 (21%) 10 (17%)

in

33

bined response

rate of 93%. Of the CR patients,

62% of

negative 45% responded. The median duration of remission was 14 months, median survival 24 months.

patients

Lippman et al. [46, 471 have conducted several of sequential chemohormonal therapy. In two 160A and 160B, they examined the effect of tamoxifen followed by premarin to CAMF

main differences between this and the earlier studies were the stage of disease, metastatic vs. only stage III, the dosage escalation schedule, and the use of high-dose MTX with leucovorin rescue. The hormonal priming

therapy.

Cyclophosphamide

studies studies, adding chemo-

750 mg/m* and doxorubi-

tin 30 mg/m* were administered on day 1 and methotrexate 40 mg/m’ on day 8 and 5-FU 500 mg/m* on day 9 in study 160A. In study 160B, 5-FU was administered on day 8, 1 h after MTX on day 8. Randomization in each study was between CAMF alone or CAMF plus tamoxifen 10 mg/m? every day days 2-6 and premarin 0.625 mg/m* every 12 h for three doses starting day 7. The cycle was repeated every 21 days. Data from both studies were combined to compare CAMF to CAMFTP. The complete response rate was 18% with CAMF and 22% with CAMFTP. The partial response rate was 47% with CAMF and 43% with CAMFTP. The combined response rate for both studies was 65%. Although there was no difference observed in the response rate there was a significant improvement @=O.OOl) in time to progression of partial responders; CAMF 11.1 months vs. CAMFTP 17.5 months, with a prolongation in survival from 16.6 months to 22.7 months @ = 0.021). The significance of the prolonged time to progression and survival in the partial response group is unclear. One explanation the authors suggested was that because of study design once a CR was obtained the patients were treated less intensively and all treatment stopped at 1 year, whereas in the PR group intensive therapy continued to failure. Overall, however, the results suggested either no difference or minimal improvement with the addition of hormonal priming. One possible reason for the failure of hormonal priming to increase the response rate is the timing of the therapy. The tamoxifen/premarin sequence was started the day after cyclophosphamide and adriamycin. Even the tumor cells which are not killed by the chemotherapy could be in an altered state of metabolism and have difficulty responding to priming at the time of the peak cytotoxic effect a week after chemotherapy. In another trial, Lippman et al. examined the effect of CAMFTP in stage III breast cancer. The dosages were changed somewhat from the previous studies: day I cyclophosphamide 500 mg/m’ and doxorubicin 30 mg/ m’; tamoxifen 40 mg by mouth days 226; premain 0.625 mg by mouth every 12 h three times beginning day 7; methotrexate 300 mg/m’ i.v. day 8 followed 1 h later by 5-FU 500 mg/m’ and 24 h later by leucovorin rescue, with dosage escalation guided by myelosuppression. Seventy-five of 76 patients were evaluable. The responses were: 49% CR, 44% PR, and 7% NC for a com-

were free of tumor

by multiple

utilizes a higher dose of tamoxifen lar. The high response

and

biopsies.

but is otherwise

pathologic

The

simi-

CR rate of this

study is impressive. It is unclear whether these high rates are due to the increased intensity of the chemotherapy or whether the hormonal priming is contributing to this. Again, in this study the ability of the tumor cells to respond to priming on days 2-8 following cyclophosphamide and adriamycin may be limited thus negating the effect. Cell kinetic studies in vitro and in vivo could establish whether chemotherapy just prior to priming abolishes the priming effect seen with hormonal agents. Bowman et al. [48] repeated the study of Allegra et al. utilizing tamoxifen followed by premarin then methotrexate and 5-FU with leucovorin rescue in metastatic breast cancer. Of 30 patients, one (3%) CR was achieved and one (3%) partial remission with four stable disease (13%) and 24 (80%) progressive disease. The reason for the poor response rate is unclear, although the patients were heavily pretreated and the number of patients is small. The response rate of 6% is significantly worse than even single agent response rates. Benz et al. [49] in a NCOG sponsored study have approached the timing of hormonal stimulation differently than the previously discussed studies. The rationale for this is that tamoxifen has a prolonged half-life, therefore in the other studies when tamoxifen was given for less than 10 days followed by estrogen for less than 4 days steady-state tissue saturation did not occur. Further, the tamoxifen levels during the estrogen priming phase of I4 days should be quite high, perhaps blunting the estrogen effect. The treatment schedule was as follows: tamoxifen 20 mg by mouth twice a day, days O-27 every other month; estrase I mg three times a day, days &20 the alternate months. Chemotherapy consisted of methotrexate 50 mg/m’ orally every 6 h for five doses followed immediately by 5-FU 600 mg/m’ i.v. and leucoThe vorin 10 mg/m2 every 6 h for six doses. chemotherapy was given on days 6 and 20 of each 28 day cycle. Of 18 patients treated five (28%) achieved a complete response and two (11%) a partial response. Additionally, serum levels of tamoxifen. N-desmethyltamoxifen. estradiol, and estrone were obtained during therapy. The estradiol and estrone levels cycled as expected with therapy, very low levels during the tamoxifen administration and high levels while estradiol was being administered. The tamoxifen levels also cycled but

34

because of the prolonged half-life rarely were below 100 mcg/ml during the 4 weeks off tamoxifen. Though these are pharmacologically active levels, the authors felt that the serum molar ratio of tamoxifen and its metabolites to estradiol metabolites was more important. If the ratio was above 1000 they expected antiestrogen effect, below 1000 estrogen effect. By these criteria there was cycling of antiestrogen effect and estrogen stimulation each month. Although the complete response rate of 28% is better than with conventional therapy, the combined response rate of 39% is more in line with standard therapy results. There are several points to consider in this study. First, the number of patients (n = 18) is very small to draw any firm conclusions. Secondly, the monthly alternation of tamoxifen and estradiol only allows for estrogenic priming for the third and fourth chemotherapy administrations, and thereafter two of each four treatments. Further, cell line data indicates maximal synchronization of cells in S-phase 24 h after beginning estrogenic stimulation, not l-3 weeks later as in this study. Finally, although the regimen was designed because of the prolonged half-life of tamoxifen, cell culture studies have shown the effect of synchronization occurs even in the presence of tamoxifen. Two studies have tested the hypothesis of estrogenic stimulation and chemotherapeutic enhancement by blocking endogeneous estrogens rather than using the antiestrogen tamoxifen. This was done by administering an aromatase inhibitor which aminoglutethimide, blocks estrogen synthesis, with simultaneous hydrocortisone replacement. By eliminating endogenous estrogen, a ‘passive’ synchronization of cells in GO/G1 is achieved as compared to the ‘active’ synchronization with tamoxifen. Paridaens et al. [50, 511 reported the results of an EORTC study. They initially studied estrogenic recruitment in a hormone-dependent mouse mammary tumor (MXT model). Increased thymidine labeling following a physiologic dose of estradiol was noted from 12-36 h, with a maximum 3-fold increase at 24 h. Increasing the dose of estradiol to 2.5 mequiv increased the stimulation further but there was no benefit to further dose increase. They then studied oophorectomized mice with the MXT tumor with various doses of estradiol, with and without cyclophosphamide, and changing the time interval between estradiol and cyclophosphamide. Maximal synergism was seen at an estradiol dose IO-times physiologic and with a delay between estradiol and cyclophosphamide of 24 h. If chemotherapy was delayed to 48 h the synergism was lost. With this background they designed a clinical study. Women with advanced breast cancer who had not re-

ceived prior systemic therapy were treated with aminoglutethimide 1 g/day; hydrocortisone 40 mg/day, and the premenopausal patients also underwent oopherectomy. At 2 weeks, the patients were given ethinylestradiol50 mg, 24 h later they were treated with FAC, 5-FU 500 mg/m2, doxorubicin 50 mg/m* and cyclophosphamide 500 mg/m2. The cycle was repeated every 3 weeks. Sixty-seven patients were entered, 57 considered evaluable. Twenty patients (35%) achieved a CR and 23 (40%) a PR for a CR + PR in 43 (75%). It is interesting that responses were roughly equal in both ER-positive and ER-negative patients (less than 30 fmol/mg protein); ER positive 3/B (38%) CR, 7/8 (88%) CR + PR vs. ER negative 5/14 (36%) and 9/14 (64%) CR + PR; and in ER unknown 12/35 (34%) CR and 27/35 (77%) CR + PR. Lipton et al. [52] conducted a randomized study of estrogen stimulation. Thirty-five patients were evaluable, either postmonopausal or surgically castrate, first recurrence 18 or following other therapy 17, ER positive 23 and unknown 12. All patients received aminoglutethimide 1 g/day and hydrocortisone 40 mg/day. The stimulation arm patients received estrase 2 mg sublingually twice a day on days 18-21 of each 3-week cycle, the others received placebo. On the 4th day after receiving estrase or placebo, patients were treated with cyclophosphamide 500 mg/m*, doxorubicin 50 mg/m2, and 5FU 500 mg/m2. In the estrase arm, there were 3/21 CR (14%) and CR + FR 8/21 (38%). In the placebo arm l/l4 CR (7%) and CR + PR 4/14 (29%). With such small numbers it is not possible to draw many conclusions but the results appear worse than the impressive results obtained in the EORTC study. Paridaens et al. postulated that delaying chemotherapy to day 4 following stimulation missed the synergistic effect. Also approximately half of these patients were pretreated, whereas none of the patients in the EORTC study were pretreated. Conte et al. [53] studied the effect of diethylstilbestrol (DES) stimulation prior to chemotherapy. One hundred and seventeen patients were randomized to chemotherapy with or without DES. The chemotherapy alone group received CEF (cyclophosphamide 600 mg/m*, epidoxorubicin 60 mg/m*, and 5-FU 600 mg/m* on day I), every 21 days. The stimulation arm received cyclophosphamide 600 mg/m2 day 1, DES 1 mg on days 5, 6 and 7, and epidoxorubicin 60 mg/m2 and 5-FU 600 mg/m* on day 8. The responses were DES-CEF: 13/54 CR (24%), 29/54 CR + PR (54%) with CEF alone CR 9/56 (16%) and CR + PR 32/56 (57%). There was no statistical difference between these responses. Unfortunately, the chemotherapy in the two study groups was not equal, in the CEF alone arm all the chemotherapy was given on day 1, but in the DES-CEF arm the chemotherapy was divided between day 1 and day 8. One effect

35

of this was that there were more treatment delays and less intensive chemotherapy administered to the DESCEF group. The results of the clinical trials stimulating tumor cells with hormonal therapy to increase the efficacy of chemotherapy are summarized in Table 2. Of the trials utilizing tamoxifen followed by an estrogen there are two studies with impressive responses and one negative study. Allegra et al. [45] and Lippman et al. [47] reported CRs of 37 and 49% and CR + PR of 62 and 93% respectively. The study by Bowman et al. [48] reported a disappointing 6% response rate. The number of patients in the Bowman study is smaller (30 evaluable) and patients were heavily pretreated. Overall, tamoxifen followed by short-term estrogenic stimulation followed closely by chemotherapy appears promising and worthy of further investigation. A similar strategy which also appears promising is using aminoglutethimide with hydrocortisone continuously with brief estrogen priming prior to chemotherapy. This regimen was successfully implemented by Paridaens et al. (EORTC study) with a combined response of 75%. Lipton, Santen et al. conducted a similar randomized study between chemotherapy alone and chemotherapy with estrogenic stimulation. Their study showed no difference, however, the study numbers were very small. The response rate of 39% in the NCOG study by Benz et al. suggests no benefit from the estrogen stimulation schema they employed which was 1 month of tamoxifen followed by 21 days of estradiol. The priming effect would not really be expected to be large in this design since of the first four chemotherapy treatments only the third and fourth would be under the influence of priming, further no synchronization in S-phase would be expected since this occurs for only a short while after beginning estrogen stimulation, not l-3 weeks later as in this study. The study by Conte et al., while commendable for being a randomized trial between DES-CEF and CEF alone, utilizes small numbers of patients and different chemotherapy schedules in the two arms lessening the significance of the finding of no difference with stimulation [53]. We can draw several preliminary conclusions concerning hormonal stimulation. First that cell line and tumor models support the hypothesis that estrogen stimulation either alone or following tamoxifen increases the fraction of cells entering S-phase. Secondly, that this effect is most marked a relatively short time (24 h) after beginning estrogen stimulation. Third, that in tumor models and in some clinical trials this enhances the efficacy of chemotherapy. Finally, this effect occurs in ER-positive and, in some studies, ER-negative patients. Further work needs to be done in this area to bet-

TABLE 2 Sequential

hormone

priming/chemotherapy

Therapy

Study

(see text)

Allegra et al.

Evaluable

CR

CR+PR

51

21 (37%)

35 (62%)

75

37 (49%)

70 (93%)

30

1(3%4

2 (6%;)

18

5 (28%)

7 (39%)

57

20 (35%)

43 (75%)

21

3 (14%)

8 (38%)

14

1 (7%)

4 (29%)

54

13 (24%)

29 (54%)

56

9 (16%)

32 (57%)

312

100 (32%)

194 (62%)

Tam day l-10, Prem

[451

day 11-14 day 14 MTX, 5-FU. day 15 CF Lippman

et al. CTX, Dox day 1

[471

Tam day 26,

Prem

day 778 MTX. 5-FU day 8, CU day 9-10 Bowman

[48]

Tam day l-10. Prem day 1 l-14 MTX. 5-FU day 14. CF day 15516

Benz et al./ NCOG

[49] Tam

x 27 day then

estrase

x 20 day

MTX, 5-FU, CF day 6and20q28day Paridaens

et

al./EORTC 150. 511

AG 1 g/day,

HC 40

mg/day day 14 ethinyl estradiol, 24 h later 5-FU, ADR, CTX, q 3 weeks Lipton et al. 1521

AG + HC, El day 1821 5-FU, ADR, CTX day 21 AG + HC placebo 18-21

day

Conte et al./ Italy [53]

CTX, Epidox.

5-FU

day 1 DES day 5-7, EFD day 8 CTX, Epidox, day 1 only Total

5-FU,

ter delineate the kinetic effects in vivo to determine the optimal schedule of therapy.

36

VII. LHRH agonists

treated

with leuprolide

1 mg subcutaneously

Dosage was escalated depending Leutenizing gonadotropin

hormone hormone

releasing hormone (LHRH, or releasing hormone, GnRH)

when released from the hypothalamus in a pulsatile manner stimulates the pituitary to secrete leuteinizing hormone (LH) and follicle stimulating hormone (FSH). Among other functions these hormones stimulate the ovaries to increase production and release of estrogen. During the early 1970s several analogues of LHRH were synthesized.

When these were clinically

injected

into ani-

mals they were found paradoxically to inhibit the production of LH and FSH and therefore estrogen. It appears that in vivo LHRH is released in a pulsatile manner

which is stimulating,

while continuous

release

or administration is inhibitory. Thus these analogs can be used to inhibit ovarian release of estrogens, a ‘medical castration’. In males, the inhibition of FSH and LH lead to castrate levels of testosterone. LHRH agonists have been extensively tested in males with prostatic cancer and found to be as effective as orchiectomy [55]. The agonists available include leuprolide (D-Leu6-GnRH proethylamide), Buserelin (Zoladex), and Nafarelin. Leuprolide is currently approved for use in men with prostatic carcinoma, it requires daily subcutaneous administration. Buserelin is undergoing clinical trials, it is administered either subcutaneously daily or as a longacting biodegradable compound administered over a month. Nasal administration has been tried with these agents but requires larger doses six times a day. Recently several trials have been conducted to determine their usefulness in treating premenopausal advanced breast cancer, we will review five of these studies (Table 3). Harvey et al. [56] have reported on the Abbott Study Group Trial of leuprolide in advanced breast cancer. Twenty-five evaluable premenopausal patients were

TABLE LHRH

3 agonists

in premenopausal

Study Abbott

patients

Agent

N

leuprolide

25

buserelin

32

zoladex

45

ERf

ER-

CR

CR+PR

Study

Group

[56]

6/14

I l/25(44%)

4/10

Klijn and de Jong 1571 Nicholson WI Mathe et al. [59] Hoffken et al. [60] Total

912309%)

et al. II/20

O/18

D-Trp6LHRH

II

buserelin

I9

3/l 1(27%) 6/11

O/4

23145

4132

5119

g/ 19(42%) 45/123(37%)

on response

once daily. to 5 mg (10

pts) and 10 mg (10 pts) daily. There were no complete remissions, 1 l/25 (44%) had a partial response with a median duration of response of 39 weeks. There was no advantage to administering more than 1 mg/day. Six of 14 ER-positive patients responded, four of ten ER-negative patients

responded.

Minimal

toxicity

was noted,

most

frequently hot flashes, nausea, vomiting, headache, and amenorrhea. In a separate study, 32 postmenopausal women with advanced breast cancer were treated with leuprolide.

The dosage was l-10 mg/day

with escalation

of dose in some non-responders. Two of 20 pts (10%) treated at 1 mg responded, while l/20 responded at 10 mg/day. Thus it appears that leuprolide in a dose of 1 mg subcutaneously is effective in premenopausal breast cancer patients but not in the postmenopausal setting confirming its primary action is to block ovarian estrogen production and not a direct tumor effect. Klijn and de Jong [57] treated 32 premenopausal women with metastatic breast cancer with Buserelin. Patients were all initially treated intravenously then randomized between intranasal and subcutaneous administration. Nine of 23 patients (39%) responded. In the intranasal group 4/12 responded, in the subcutaneous, 5/l 1. Intranasal administration did not give as complete a blockade of estrogen production as the subcutaneous route. Buserelin was also combined with tamoxifen with three of five patients responding and Megace with two or four responding. Nicholson et al. [58] treated 45 premenopausal women for advanced breast cancer with Zoladex. The response rate was 14/45 (31%). Eleven of 20 (55%) of ER-positive patients responded, O/l8 ER-negative patients responded, and 3/7 (40%) ER unknown patients responded. In 22 women who progressed on Zoladex, oophorectomy was performed. Four of 22 responded, of these one had not been fully suppressed to castrate levels by Zoladex, and the other three were only on Zoladex a short time before oophorectomy, 2, 2 and 3 months. Nine postmenopausal women were also treated with Zoladex, two responded, ages 58 and 54 years. Thus they found Zoladex effective in premenopausal ER-positive and unknown patients, and they noted 219 postmenopausal patients tested responded though they were aged 58 and 54 years and pretreatment estrogen levels were not reported. Mathe et al. [59} treated 23 women with breast cancer with D-Trp 6-LHRH. Three of 11 premenopausal patients responded, and 3/ 15 postmenopausal patients responded. These patients were heavily pretreated with 15 having had prior hormonal and/or chemotherapy. Hoffken et al. [60] reported on a phase II study of Bu-

37

serelin

in

19 premenopausal

breast breast cancer. a CR None (55%) tients

patients

Five of 19 patients

with

advanced

(26%) achieved

and 3/19 (16%) a PR for a CR + PR of S/l9 (42%). of the four ER-negative patients responded, 6/l I of ER-positive patients and 2/4 ER unknown paresponded. By 3 weeks after initiation of therapy

serum estradiol

and progesterone

opausal levels. From the preceeding

Side effects included

given i.m. injections,

sterile abtwo allergic

type reactions, and four developed lethargy. Further testing will be required but this appears to be as effective as AG without the problems of complete adrenal blockade and with potentially fewer side effects.

had fallen to postmenIX. New agents

studies

LHRH

agonists

appear

to be active against breast cancer in premenopausal tients. The mechanism of action is by suppressing

paLH

and

Al-

FSH secretion

ly 8123 (35%) responded. cesses in six patients

and thus estrogen

production.

Toremifene [66] is a triphenylethylene antiestrogen currently undergoing clinical trials. Toremifene binds with a high affinity to estrogen receptors in a competi-

though only a few studies evaluated response by estrogen receptor status there was a strong correlation of

tive fashion with estradiol. In the DMBA-induced mammary cancer in rats it inhibited tumor growth. In

ER-positive status to response, as would be expected. With relatively few side effects and efficacy similar to oophorectomy, LHRH agonists may become first line therapy in premenopausal ER-positive patients if an easy method of administration becomes available.

MCF-7 cells Toremifene inhibits cell growth. Clinical trials are currently underway. Several other compounds have been investigated. LY 117018 binds tightly to ER. 4-OH tamoxifen is a metabolite of tamoxifen which in vitro binds ER more tightly. These compounds are not currently in clinical trials. Ru486 (mifepristone) [67] is an antiprogestin and antiglucocorticoid which is undergoing trials in the treatment of breast cancer. In one such trial [68] 12 of 22 patients had a partial response or disease stabilization. Further studies will be needed to define the usefulness of this agent.

VIII. Aromatase inhibitors Although the aromatase inhibitor aminoglutethimide (AG) has been available for over 20 years there has recently been a resurgence in interest in its use for metastatic breast cancer. AG blocks cholesterol side chain cleavage, 1 l/3-hydroxylase, and aromatase, thereby causing a ‘medical adrenalectomy’ and eliminating estrogen production in postmenopausal women [61, 621. AG has approximately the same response rate as tamoxifen in postmenopausal patients but has more side effects including fatigue, dizziness, and a rash. The conventional dosage is 250 mg four times per day with hydrocortisone replacement. In postmenopausal women the major source of estrogen is peripheral conversion of andreostenedione to estrone. This reaction can be blocked by much lower doses of AG than is required for complete adrenal blockade. To examine this, several trials have been conducted to study the effect of lower doses of AG. Dowsett et al. [63] have reported that AG 250 mg/day effectively blocks estrogen production and is effective. Others have confirmed this at 500 mg/day and 250 mg/day. At the dosage of 125 mg/day it may not be as effective. All of these trials were small and more trials need to be conducted to confirm that lower doses are as effective. Brodie et al. [64, 651 have studied the potent aromatase inhibitor 4-hydroxyandrostene-3,17-dionc (4OHA). It is 60-times more potent than AG and more selective. Seventy-five postmenopausal patients were treated with 4-OHA. Effective suppression of estradiol levels was achieved. Fourteen of 52 patients (27%) responded in a group treated i.m., of patients treated oral-

X. Tamoxifen in premenopausal patients Tamoxifen has been widely accepted as a primary treatment for postmenopausal patients with metastatic breast cancer. One reason it is effective in this population is because of the large proportion of ER-positive tumors in these women. A smaller percentage of premenopausal women have ER-positive tumors and therefore less of a chance of responding to tamoxifen used in an unselected fashion. Additionally. oophorectomy has been the standard first line treatment in premenopausal patients with a response of 2437%. With the widespread acceptance and use of ER as a guide to therapy. and increasing experience with tamoxifen there has been increased interest in tamoxifen in premenopausal patients. We will review several recent studies. Buchanan et al. [69] randomized 122 premenopausal women to receive either tamoxifen or undergo oophorectomy. Response rates were similar with 24% of 54 evaluable patients responding to tamoxifen vs. 21% of 53 patients treated with oophorectomy. Although response duration was longer in the tamoxifen group (20 months vs. 7 months) and survival was longer in the oophorectomy group (25 months vs. 15 months), statistical significance was not achieved. Some patients were

38

crossed over after initial failure which may have effected the survival curves, although this data was not reported. ER status was not reported. Ingle et al. [703 also randomized premenopausal ERpositive (greater than 3 fmol/mg) or ER unknown women to tamoxifen treatment or oophorectomy followed by a crossover at failure. The initial response rate was IO/27 (37%) of those treated with oophorectomy, and 7/26 (27%) of those in the tamoxifen group, this did not achieve statistical significance. Of the patients initially responding to tamoxifen, there were 215 responses to oophorectomy, in initial tamoxifen failures crossed over there were 3/10 responders. In patients initially responding to oophorectomy, l/7 responded to tamoxifen, only l/l 1 of oophorectomy failures responded to tamoxifen. Sawaka et al. [71] had 20/74 (27%) postmenopausal women respond to initial tamoxifen therapy. Of nine initial responders who later progressed, five responded to oophorectomy. Of 20 patients who failed to respond to tamoxifen, two patients responded to oophorectomy. Planting et al. [72] conducted a similar study, treating 43 premenopausal patients initially with tamoxifen. Thirteen of 43 patients (30%) responded. At the time of progression, 24 underwent oophorectomy, 3/16 SD or PD patients responded to this second line therapy. Four of eight initial responders later responded to oophorectomy at failure. The majority of these patients were ER unknown. They concluded that there is a significant response to oophorectomy even in tamoxifen non-responders. Hoogstraten et al. [73] reported the results of a

TABLE

SWOG trial of tamoxifen as first line therapy; 22/56 (40%) of premenopausal patients responded. None of 14 initial tamoxifen responders had a response to subsequent oophorectomy and continued tamoxifen. Five of 22 tamoxifen failures responded to oophorectomy + tamoxifen. ER status was unknown in the majority of patients. These results are summarized in Table 4. From these studies it can be concluded that tamoxifen is effective in approx. 30% of ER unselected patients. Presumably the response rate is better in ER and PR receptor positive patients, but insufficient data exists to conclude this currently. The data concerning oophorectomy following tamoxifen response or failure is less clear but it may be reasonable to attempt this in ER-positive patients. XI. Tamoxifen in the adjuvant setting Tamoxifen has been utilized in a number of trials in the adjuvant setting [74]. The Nolvadex Adjuvant Trial Organization (NATO) trial [75] consisted of 1285 women with stage I and II breast cancer randomized to receive tamoxifen or placebo. With a median follow-up of 45 months the relapse free survival was 72.9% in the tamoxifen group and 61.2% in the control group. Overall survival was 80% in the tamoxifen group and 72% in the control arm. Peto has combined the adjuvant studies into an overview. This revealed a 1618% mortality reduction in women greater than 50 years of age treated with tamoxifen. He observed no net effect on survivial in women under 50 years of age. The NIH Consensus Development Conference on Adjuvant Chemotherapy

4

Premenopausal

tamoxifen

studies

Crossover +

_

7126 (27%) IO/27 (37%)

215

3/10

117

l/II

20174 (27%)

519

2120

I3/43 (30%)

418

3116

22156 (40%)

o/14

5122

1l/36 (31%)

13/68 (19%)

Study

ER

Therapy

Response

Ingle et al. [70]

-I/?

Tam Ooph

mixed

Tam

mixed

Tam

13/545 (25%)

Ooph

1l/53 (21%)

mixed

Tam

mixed

Tam

Sawaka

et al. 1711

Buchanan

Planting

et al. [69]

et al. [72]

Hoogstraten Total patients Crossover

et al. [73] treated

Response

Initial:

751253 (30%)

with Tam Tam to Ooph

39

and Endocrine

Therapy

all of the clinical that postmenopausal

for Breast Cancer

trials data available. women

[76] reviewed

They concluded

with positive

hormone

re-

ceptor and stage II breast cancer, in the absence of a clinical trial should be treated with tamoxifen for at least 2 years.

in this direction, the estrogen

towards

achieve more effective hormonal

Summary

I Beatson GW. On the treatment illustrative

tumor response to single agents over the past several decades. By applying knowledge of tumor ER and PR patient populations can be selected which will have a higher response rate to a given hormonal agent. The approach of combining chemotherapy and hormonal therapy does not appear to significantly alter the course of the disease. Sequential use of Tamoxifen, Premarin, and chemotherapy has been shown in cell lines and animal models to synchronize cells thus increasing the efficacy of chemotherapy. Clinical trials of this synchronization generally show higher response rates including significantly higher CR rates than chemotherapy alone. This approach appears promising and is undergoing further trials. LHRH agonists and tamoxifen are effective in premenopausal women with receptor positive tumors and may replace surgical ablative therapy. Aminoglutethimide is gaining wider acceptance as second-line therapy in postmenopausal ER-positive patients. The new agent 4-OHA may be as effective as AG but with fewer side effects. Toremifine a new antiestrogen and RU486 a new antiprogesterone are undergoing trials. While these new agents appear promising with fewer side effects or greater specificity of action, with the exception of sequential hormone priming/chemotherapy they represent ‘the same old approach’. By this we mean manipulation of the hormonal environment of the cell in a continuous fashion acting via the estrogen receptor mechanism to achieve tumor regression. While certain new agents may be more tolerable, it is unlikely that a ‘break through’ will occur with this approach. The problem is the emergence of cells resistant to hormonal therapy. This occurs either through proliferation of a preexisting resistant clone or development under selective pressure of resistant tumors. Some but not ail of these resistant clones have escaped by virtue of not having estrogen receptor present. Others have defects further along the action cascade of estrogen stimulation, such as a defective receptor which cannot bind effectively to the nuclear acceptor sites, or lacking certain other growth factors such as TGF-j?. Whatever the deficit, most patients eventually develop resistant tumors. It is

in

should turn to

therapy.

Suggestions

of inoperable

C. Bergenstal

Assoc 147:101-106, 3 Huggins

cancers

4 Cash R. Brough

of treatment,

DM. Surgery

of the adrenals.

DM.

Inhibition

of human

AJ. Cohen

Satoh PS. Aminoglutethimide

MNP,

trial. J Clin Endocrinol27:1239~1248.

6 Lipton

steroidogenesis:

CT, et al. Preliminary 32:31-37,

A. Santen

adrenalectomy

I Wells SA. Santen RJ. Lipton

9 Council

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in breast

using aminoglutethi-

33:503-512.

A. et al. Medical

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C. Hodges

1:293-297,

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1952.

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J Am Med

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as an inhibitor 5 Griffiths

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1896.

1951.

C. Bergenstal

prostatic

cases of carcinoma

for a new method

cases. Lancet ii:104107,

2 Huggins

From this data we can draw several conclusions. Although many new hormonal agents have been developed, there has not been significant improvement in

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