DIAGNOSIS AND TREATMENT Drugs Five Years Later

Calusterone
RICHARD A. BRODKIN, M.D.; and M. ROBERT COOPER, M.D.; Winston-Salem, North Carolina

Androgens are effective therapeutic agents in postmenopausal women with metastatic breast cancer. Early studies with testosterone propionate showed objective regression rates of slightly more than 20%. Subsequent work with synthetic androgens has failed to show a significant reduction in toxicity or an increase in therapeutic efficacy over testosterone propionate. Calusterone (7y3,17adimethyltestosterone), in early clinical trials, showed both of these qualities and was believed by some to be the "ideal androgen." As with many new drugs, subsequent work failed to confirm these early findings, and most of the later data gathered on calusterone are inconsistent. We conclude from our knowledge at present that calusterone offers no real advantages or disadvantages over other androgens in the treatment of breast cancer.

IN 1896 Beatson (1) demonstrated regression of metastatic breast cancer after oophorectomy. Since this early ciinical observation, our knowledge ofthe hormonal responsiveness of breast cancer has dramatically expanded. The state-of-the-art of present hormonal manipulation in carcinoma of the female breast has recently been reviewed (2). We shall discuss here only the synthetic androgen 7^,17a-dimethyltestosterone (calusterone) and its present position among the ever-expanding number of drugs useful in the treatment of breast cancer.
Background

Interest in synthetic androgens for the treatment of metastatic breast cancer stems from early work demonstrating the effectiveness of testosterone propionate against mammary cancer in the mouse (3, 4) and subsequently in humans (5, 6). Two large cooperative studies (7, 8) confirmed the effectiveness of testosterone propionate to induce objective regression in 21.9% and 21.5%, respectively, of postmenopausal patients with metastatic breast cancer. This drug remained for many years as the prototype in androgen therapy for such patients. Objective response rates in postmenopausai women have been consistently lower with androgens than with estrogens, although there is no substantial difference if one considers only those patients with bone or visceral metastases (7). In fact, higher rates of subjective improvement are
From (he Oiitiikigy Research Center, Bowman Oray -School of Medictiit:. W;ikt Fores! Universiiy, Winsliin-Salem. Niirlh Carolina. Annals of Internal Medicine 89:945-948, 1 978

obtained with androgens in patients with bone involvement (9). Androgens have limited use in premenopausal patients. Ovarian ablation remains the preferred initial therapy in this group of patients with metastatic disease, inducing remissions in 33% to 38% of patients (10, 11), In patients who respond to castration, subsequent androgen therapy is not indicated, since some of the metabolic breakdown products of androgens include estrogenic hormones (9). A search was begun in the late 1950s to find a synthetic testosterone derivative with fewer virilizing qualities than testosterone without sacrificing antitumor efficacy. Segaloff (12), on examining some of these derivatives, observed that structural changes in Ihe testosterone molecule that decreased its androgenicity also diminished its effectiveness in breast cancer. Fluoxymesterone (Halotestin), an orally administered halogenated derivative of testosterone, was found to be equally effective but just as androgenic as testosterone in early clinical trials for metastatic breast cancer (13, 14). Blackburn and Childs (15) and Thomas and associates (16), in separate studies, compared testosterone propionate to a synthetic derivate, 2methyl dihydrotestosterone, in postmenopausal women with progressive metastatic breast cancer and found that the latter drug was at least as effective and less androgenic than testosterone. This was the first suggestion that there might be some separation between the androgenic and antitumor effects ofthe synthetic testosterone derivatives. Subsequent work with synthetic derivatives of testosterone including A'-testololactone and 7a-dimcthyltestosterone furthered our understanding of structure-function relationships of synthetic androgens. No compound, however, with more antitumor efficacy than testosterone propionate could be identified (17-19).
Structure

Calusterone, a synthetic testosterone derivative, was first prepared by Campbell and Babcock (20) in 1959. Structural differences between calusterone and its parent compound testosterone (see Figure 1) include only the presence of a ;3-methyl group at Position 7 and a a-methyl group at Position 17 in calusterone. The addition of the 17a-methyl group to testosterone produces an orally administrable compound with no loss of clinical effectiveness (21); it does, however, confer hepatotoxic qualities
1 97 8 American College ot Physicians

945

--- H

7/3, f7-<-climethyltestD5terori {Calusterone) Figure 1. Structural drflerences between testosterone and one.

Testosterone

not seen with icstosteronc (22). 7-Melhylation in the a position produces a highly anabolic, undrogenic compound (19), whereas a methyl group in the (i position reduces androgenicity signillcanlly (23). Calusterone was. in fact, only one fifth and one twenty-fifth as androgenic as testosterone and f1ut)xymesterone, respectively, in animal studies (23). Mechanism of Action Androgens produce their cfTects on target tissue by receptor binding in a manner analogous to estrogens and other steroids (24), There is little evidence, however, lo support the notion that aiidrogcn-androgen receptor binding plays any direct role in the regression of breast cancer after androgen therapy. There has been some suggestion that androgens reduce the responsiveness of breast cancer to prolactin by either competitive binding to or reduction in the number of available prolactin receptors (25, 26). Peripheral conversion of exogenous androgens to estrogens (24), inhibition of adrenal precursor eonversion to active estrogen (24). and interference with estrogen receptors (27) have all been implicated as pt)ssible mechanisms by which androgens eause regression of hornionally responsive breast caneer. The most popular theory before the "receptor era,"' and one still enjoying strong support, is that androgens deplete endogenous estrogens or interfere wilh their production. Oophoreetomy is the hormoTial treatment of choice in premenopausal women with metastatic breast caneer, although androgens have been shown to produce a 2 0 % response rate (7) probably related to their anligonadotrophic effect. Caluslerone has been shown to decrease endogenous estrogen production by 4 0 % (28) in postmenopausa! women in whom the adrenals are the chief source of estrogens. This therapy has not proved beneficial (29) in women with progressive disease after adrenaleetoniy, implying that once the body's sources of estrogen have been eliminated, androgens have no direct elTcci on lumor growth- This strongly supports the concept that estrogen depletion is the chief mode of action in androgcn-indtiecd regression of metastatic breast eaneer. Clinical Trials Early reports indicated that ciilusleronc might be (he ideal androgen. Twenty-two postmenopausa! women with progressive widely metastatic breast caneer (many of whom failed on previous hormonal therapy) were giv946
DfCfinber I 9/S Annuls of lntern=-!l

en caiusteronc (150 to 3CX) mg/day) in an extended Phase-1 sludy (30). I'ourtecn of 22 patients showed objective regression of funior, including tive of 1 1 with visceral metastases and six o\' I 1 who were less than 5 years postmenopausai (poor prognosis groups). Regression lasted an average of" 7 months (range, 3 to 20 months). Androgenicity, although conmion, was nttt reported to be a major problem, and the drug was well tolerated. The succes.s of this initial study prompted I'lirther evalualion of calusterone. The numbers were almost equally iniprcst;ive after studying 117 patients irealed with calusterone (31). Fiftyone percent of" this group achieved objective regression when given calusterone as primary hormonal therapy. An equal percentage (51%) achieved objective regrcssicin of their tumors when this androgen wa.s used as secondary hormonal therapy. Nineteen percent of those whose disease progressed afler cytotoxic therapy showed evidence of tumor regression when given calusteroncA double-blind cross-over study comparing calusterone to A^-testolo!actone in postmenopausal women wiih progressive metastatic disease showed a 52% (12 of 23 patients) objective response rale with calusterone, whereas A'-testololactone gave a 32% response (31), Three of 12 A'-testololactone failures responded to calusterone after cross-over. Response rales seem high for both drugs, although the 32% response rate obtained with A'-testololactone is especially questionable when one notes the lesser efficacy of this drug when compared to lesiosterone propionale in earlier studies (17, !8). Goldenberg and colleagues <32), in a second controlled trial comparing calusterone with A'-iestololactone. demonstrated objective regression in 30 of lO*^ (28%) patients receiving calusterone, including six of 18 who had received previous chemotherapy. Only 18% of those patients receiving A'-testololactone achieved regression of their tumors. Several additional studies were underlaketi because of the purported efficacy of caiusterone in ihe therapy oi' poslmenopausal metastatic breast cancer. Falkson and CO-workers (33) compared calust crone ph.is cyciophosphamide to fluoxytiiesteroiie plus cyciophosphamide in a group of 59 patients with metastatic breast cancer- They found that 12 of 28 patients in the Ibrnier group experienced some benefit, while 58% in the latter group benefited. They were forced, however, to end their study earlier than anticipated because of intolerable side eftects in the calusterone plus cyciophosphamide group. This study is difficult to interpret because there is no mention of whether the groups were properly inatcheU for age, menopausal status, or sites of metastatic disease, arid criteria for response were no! included- This was the first study to contradict all previous studies thai had claimed caluslerone was well tolerated, with fewer sitle effects than other androgens. Rosso. Porcile, and Brema (34) treated 31 postmenopausai patients with progressive hrcast cancer with calusterone. Two of 27 evaiuable patients achieved a complete remission that lasted 21 and 18 months respectively, and eight patients had ohjeciive regression t>f their tu-

Table 1. Side Effects of Calusterone in Various Clinical Trials Study Fishman and Hdlman i28i Hirsutism Acne Scalp hair loss Hoarsciicss incrtaseJ libido Fluid rclcniion Nausea or gasiruimcsiinal disircs-. Some degree of androgenicily Cliloral cnlaryenicm Osseous Hares Sulfobromophthaicin sodium rcicntion HepaUxcHular dysfunction Hypcrcalceniia Headache and malaise "". % y 22(411 H 22 (36j 4,22 {!8! 4 22 (18)
1/22 (0.51 3 22 (I4t 2 22 i 1 i 15 22 (68. Pioikin and H i n k e s (29)

Gordan
cl al (31)
"O. %

Goldenberg et a I 132)
iu>. %

Falkiion
el III (33f "". %

no.

29 117 (25) 32 117 (27) 7 117 (6: i 5/ ] 1 7 (13) 5117 (4) 12 117 (1(1) 33 117 i28i 117, 117 (MX)) i /117 (li I4M17 (12t ?6 4 0 (90) 0 117 (Oi 1 117 (1)

18/27 (67) 12 27 {44) ()'27 (0) 12 2 (43t Signilicanl 13 28 (461 14 31 (45!

14/44 (32) 12:44 (271 8/44 (18) 12 44 (27) i8 44(41; 7,44(16)

5 28 U8y 7 28 (25) lfi/28 (57)

y 27(33^ 0,27 (0)

11,44 (25) 1/44 (2)

mors. Androgenicily was only moderate, and the drug was well tolerated, in contrast to Falkson's previous report. Aslam and Maxwell (35). in a recent study, noted only a 10% response rate with caluslerone. Eleven of 44 patients treated with the drug had to be withdrawn front the study early (before 4 weeks) because of intolerable side effects. Response rates were lower in this study than in all previous ones, although ofthe 44 patients included, 14 had had oophorectomy, 16 had received estrogens, five had received androgens. and 14 had been treated with chemotherapy.
Side Effects

elevation of liver enzymes was unusual (31). Two later reports, however, demonstrated an 18% (33) and 25% (35) Incidence of elevated liver enzymes with calusterone, Hislologically, this is manifested as cholestasis without bile duct dilatation and with only minima! inflammation and necrosis. Calusterone, unlike other synthetic or endogenous androgens, has no demonstrable erythropoletic effect (36), It is. however, associated with a striking rise in platelet count and a lesser rise in leukocyte count (36, 37). Discussion In view of recent advances in receptor physiology and the introduction of effective antiestrogenetic agents, the role of androgens in the therapy of metastatic breast cancer is unclear. Estrogens offer no advantages over androgens in postmenopausal women with estrogen receptor positivity with bone metastases. and it is in this group that the choice of an androgen as primary therapy may be desirable. Once the decision to use androgens is made, one is confronted with a large number of commercially available products. Many claims have been made for androgens with "increased efficacy" or "less androgenicity"; however, no real breakthroughs have been made. Calusterone, a synthetic analogue of testosterone, was initially studied because of its potential lack of androgenicity. Early clinical trials were indeed impressive, demonstrating not only mild virilizing and toxic effects but also giving response rates unheard of with previous hormonal therapy. As with many new drugs, early enthusiasm has waned, yet many of the studies condemning calusterone as a "poor choice" have been poorly controlled and are under no circumstances conclusive, Calusterone still remains a viable alternative in the treatment of metastatic breast cancer in postmenopausal women but offers no advantages in terms of decreased side effects or increased therapeutic efficacy than other androgens.
* Rcqiii-sis Ibr reprints should be addressed lo Richard A. Hrodkiri, M I),, Dcpiirinienr of MecIieriie/HeiTUilulogy. Bowman Gray SLIIOUI of Mi-ilicnie! -lOO S Hawlhcinif KJ ; Winsniii-Salcm. N f ^7103.
Brodkin and Coopt^r Caluslffone

Hirsutism. acne, deepening ofthe voice, oily skin, k>ss of scalp hair, increasing libido, and ciitorai enlargement arc expected side effects of androgen therapy. The degree of virilization. however, depends on the specific androgen, the dose used, and the duration of therapy. Table 1 gives toxicity data on calusterone in various clinical trials. Significant problems with fluid retention, nausea, osseous flares, and hepatocellular dysfunction have been reported in addition lo masculinizing effects. Conflicting reports on hypercalcemia and headaches have appeared in the literature. Falkson and co-authors (33) reported a 25% incidence of hypercalcemia and a 51% incidence of headache and malaise, whereas no other report with more than a 2% incidence of hypercalcemia attributable to calusterone has appeared. Headache and malaise are not mentioned as side effects in any of the other larger series (30, 31, 34. 35). Early data indicated a relative lack of significant virilizing symptoms associated with calusterono. although most patients who are treated for any length of lime with the drug will show some signs of masculinization. There IS probably no difference in terms of virilizing qualities, in doses presently used, among calusterone, testosterone propionate. or fluoxymesterone. Sulfobromophthalein sodium retention is common with calusterone. but early reports indicated ihat actual

947

Recciyed 2 June !'>78: revision accepted 25 September !'J78.

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December I 978 Annuls of Internal Medicine Voiumf 89 Nun:bei 6