CLINICAL TRIAL OF NAFOXIDINE* IN ADRENALECTOMIZED PATIENTS WITH ADVANCED

BREAST CANCER <JITENDERJAIN, MD, BOHUMIL SAMAL, MD, AMNUAY SINCHAKOWINTA, MD, FACP, AND V. K.

VAITKEVICIUS, MD, FACP

Antiestrogen compounds are relatively new in the treatment of breast cancer. A clinical trial of Nafoxidine therapy is being pursued in our institution. In a selected group of patients with metastatic breast cancer who had, in the past, undergone adrenalectomy, Nafoxidine therapy produced objective tumor re- gression in six out of ten patients. Of the six patients whose tumors contained demonstrable estrogen receptors, four showed regression (67%), one patient had stable disease, and one showed tumor progression. Of the four patients in whom estrogen receptor estimation was not done, two had, in the past, shown regression after endocrine therapy and they also showed regression of tumor with Nafoxidine therapy. In patients with metastatic breast carcinoma, who have undergone adrenalectomy in the past, a therapeutic trial with Nafoxidine may be worthwhile particularly in patients who have demonstrable estrogen receptor in the tumor or those who have in the past shown regression of tumor after endocrine therapy.

Cancer 40:2063-2066, 1977.

ECENT REPORTS ATTEST TO T H E EFFICACY OF R antiestrogen compounds in the treatment of breast cancer as well as in other neoplasms known to be influenced by hormone ther- apy. 2.6.9.10 The mechanism of action of these so- called antiestrogen compounds remains some- what controversial.' In uitro experiments suggest that these compounds compete with estrogens for cytoplasmic estrogen receptors (ER). ''

Clinical trials in Europe have already estab- lished the effectiveness of Nafoxidine in ad- vanced breast cancer in postmenopausal pa- tients with the objective tumor remissions occurring in 35% of the patients.'" We, in the

From the Department of Oncology, Wayne State Univer- sity School of Medicine, and the Milton A. Darling Memo- rial Center of the Michigan Cancer Foundation at Harper- Grace Hospitals, Detroit, Michigan.

Supported in part by Clinical Cancer Research Center grant No. CA-07177 and grant No. IR25-CA17952 from the National Cancer Institute, United States Public Health Ser- vice.

Address for reprints: Jitender Jain, MD, Wayne State University School of Medicine, Department of Oncology, 540 E. Canfield, Detroit, MI 48201.

Accepted for publication March 29, 1977. * Nafoxidine hydrochloride = 1-(2-[p-(3,4-dihydro-6-me-

thoxy-2-phenyl-l-naphtyl)phenoxyl]-ethyl)-pyrrolidine hy- drochloride. Supplied through Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland.

Department of Oncology, Wayne State Univer- sity, have been involved in the clinical trial of Nafoxidine for the past several months. The re- sults observed in adrenalectomized patients with advanced active breast cancer seem to be partic- ularly interesting and are reported here in brief.

CLINICAL DATA

Ten adrenalectomized patients with advanced breast cancer have been treated with Nafoxi- dine. The prerequisite for the admission of pa- tients into the study was objective evidence of progressive metastatic breast carcinoma refrac- tory to conventional endocrine or chemotherapy and expected survival of at least 8 weeks. Fur- thermore, at least 6 weeks must have passed after the discontinuation of any previous therapy before patients became eligible for entry in this study. All these patients were either post- menopausal or had undergone bilateral oopho- rectomy in the past as part of the treatment for breast cancer.

A profile of the previous treatments in all these patients and the type of tumor response to each one of them is presented in Table 1. We shall not try to analyze the table in detail; how- ever, we point out the rebound regression of the tumor, which we observed rather frequently in our small selected group of patients. In patients

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2064 CANCER flovember 1977 Vol. 40

TABLE 1. Pertinent Data of the Patients Treated with Nafoxidine

Previous response to endocrine treatment

Duration Addi- Sex Previous Response of

Dominant tive hormone chemo- to remis- Patient site of Estrogen Oophor- sex with- Adrenal- therapy nafoxi- sion* Present

No. initials metastasis receptor ectomy hormone drawal ectomy (response) dine (mos) status

1 2

3 4 5 6

7

8

9 10

W.S. J.S.

M.B. M.B. V.T. E.M.

E.B.

L.R.

B.C. W.E.

Skin Viscera

Bone Skin Skin Skin

Bone

Skin

Bone Bone

(Lung)

+ N D ND F

ND P + N D + N D + F

+ N D

+ '8

ND F** ND ND

?' N D

N D F F ND

P

F"

ND F

?' F N D F

N D P P F F P ND P

P P

ND P

ND F P P

Yes (F) Yes (P)

Yes (P) Yes ( P ) Yes (P) Yes (F)

No

N o

No No

P F

P P F P

S D

C

S D P

3 Failure

4 3

Failure 7+

7

7+

3 b

Chemotherapy Died

Died' Chemotherapy Chemotherapy Continued on

Nafoxidine Died on chemotherapy

Continued on Nafoxidine

Chemotherapy In relapse but

no therapy at present

* Counted from the day remission was documented. ' Data not available about the type of response. f Died in remission. Cause of death: adrenal insufficiency. 5 Oophorectomy and radical mastectomy was done at the same time as primary treatment. " Estrogen induced hypercalcemia. ** Oophorectomy and adrenalectomy done at the same time. ND = Not done. F = Failed. P = Partial remission. C = Complete remission. SD = Stable disease.

4 and 10 (Table 1) treated with additive hor- mone therapy, tumor continued to show pro- gression. A definite objective regression was ob- served in both these patients following discontinuation of additive hormone therapy. Occurrence of rebound regression (regression of tumor following discontinuation of additive hor- mone therapy) in patients who have not shown regression with previous additive hormone ther- apy, although uncommon, is sometimes seen in selected patients, This has been our experi- ence'.'' and has been reported by others also.' Precise underlying mechanism for such rebound regression remains obscure. Speculation is that it represents either a relief of exacerbation of tumor by estrogen' or an effect similar to castra- tion effect in premenopausal patients.

Skin was the dominant site of metastases in five patients; in four others it was the bones while in one patient it was lungs. When tumor tisse was accessible for biopsy, in addition to histopathological confirmation of metastasis, es- trogen receptor estimation was also carried out by gel-filtration analysis and/or dextran-coated charcoal. As shown in Table 1, estrogen recep-

tor was assayed in the tumors of six of these ten patients and in all of them it was present. Na- foxidine was administered orally as 60 mg T.I.D. daily for at least 6 weeks and was contin- ued until there was objective evidence of increas- ing disease (F).

The criteria of response were as follows:

1. Complete remission ( C R ) : Dis- appearance of all clinical evidence of tumor for a minimum of 3 months. All lytic lesions must show reossification.

2. Partial remission (PR): 50% or greater decrease in the sum of the products of the diameters of measured lesions persisting for a minimum of 3 months. No simultaneous increase in the size of any lesion or appear- ance pf any new lesions may occur.

3. Stable disease (SD): Steady state or re- gression less than partial remission. No new lesions or no worsening of symptoms.

4 . Increasing Disease (F): Unequivocal in-

No. 5 NAFOXIDINE IN BREAST CANCER Jain et al. 2065

crease of at least 25% in the size of any pre- existing measurable lesion, or appearance of new lesions or clearly progressive skeletal involvement such as manifested by increas- ing number of lytic lesions or mixed lytic or blastic lesions.

RESULTS

No serious side effects were observed. Because of the known light sensitizing effect of Nafoxi- dine, all patients were advised to avoid sunlight exposure; two patients developed moderate de- gree of ichthyosis. Fluid retention and pedal edema were observed in two other patients. Tu- mor regression was observed in six of the ten patients so treated (60%). In addition, two pa- tients' symptoms improved while objective mea- surements were stable and the other two pa- tients showed definite progression of the disease (Table 1). Of the six patients whose tumors contained demonstrable estrogen receptors, four showed regression (67%), one patient had stable disease, and one showed tumor progression. This agrees with the reported hormone therapy response rate of 55-60% in patients with estro- gen receptor in the tumor.

Although the number of patients in this series is small, it appears that the type of tumor re- sponse after adrenalectomy did not necessarily correlate with the type of response to Nafoxidine therapy (Table 1). All of the six patients who responded to Nafoxidine either had estrogen re- ceptor present or had in the past demonstrated tumor regression after endocrine therapy (Table 1). Complete data regarding duration of remis- sion and survival are not yet available; the pre- sent status of all these patients is given in Table 1.

DISCUSSION

In recent years, antiestrogen compounds like Nafoxidine and Tamoxifen have been proven to be effective in the management of disseminated breast carcinoma.','' The purpose of this brief communication is to report the effectiveness of Nafoxidine in those patients with disseminated breast cancer who had in the past undergone bilateral adrenalectomy. Controversy still exists as to the precise mechanism of action of these so-called antiestrogen compounds. In uiuo ex- periments on the rat uterus have shown that Nafoxidine has antiestrogenic as well as slight estrogenic activity. l5 The mechanism of anti-

estrogenic effects has been suggested to re- side in its ability to compete for cytoplasmic estrogen receptors, thereby reducing the forma- tion of estrogen and estrogen receptor com- plexes. However, Clark et al. demonstrated that Nafoxidine causes depletion of the estrogen receptors because it lacks the property ot re- plenishment of cytoplasmic receptor, which is an intrinsic property of estradiol.'

As mentioned before, these compounds also have slight estrogenic activity. Whether they ex- ert estrogenic activity or antiestrogenic activity seems to be a matter of dose, according to Te- renius, l5 who did experiments on mouse uterus zn uztro and observed estrogenic activity with low doses of Nafoxidine and antiestrogenic activity with higher doses. In the clinical trial of Nafoxi- dine carried out by EORTC Breast Cancer Group,' in 11 out of 14 patients vaginal cytology examination disclosed a transformation from an atrophic or nonspecific picture to an estrogenic picture; the Breast Cancer Group believed that Nafoxidine action was more like an estrogen.

We have reported here a tumor regression rate of 60% with Nafoxidine in patients who had in the past undergone bilateral adrenalectomy. Admittedly, this is a small and selected group of patients. What role the previous adrenalectomy had in these patients is difficult to speculate. There is evidence to suggest that endogenous production of estrogens is not completely elimi- nated even after oophorectomy and adrenal- ectomy or hypophysectomy.' Furthermore, Sto- nesifer et al. have demonstrated conversion of hydrocortisone to 11P-hydroxy estradiol in a pa- tient with carcinoma of the breast after oopho- rectomy and adrenalectomy. I' In light of this, it is possible that metabolic transformation of maintenance adrenocortical hormones to estro- gens by extra-endocrine tissues could sustain the growth of mammary carcinoma. Blocking the action of metabolically transformed estrogen from replacement corticosteroid might explain the effectiveness of Nafoxidine in adrenal- ectomized patients, or else there is yet another mechanism by which Nafoxidine can affect breast cancer growth. Studies are needed to clarify further the mechanism of action of anti- estrogen compounds in breast cancer. We be- lieve that in patients with metastatic breast car- cinoma, who have undergone adrenalectomy in the past a therapeutic trial with Nafoxidine may be worthwhile, particularly in patients who have demonstrable estrogen receptor in the tumor or those who have in the past shown regression of tumor after endocrine therapy.

2066 CANCER November 1977

REFERENCES

Vol. 40

1. Baker, L. H., and Vaitkevicius, V. K.: Re-evaluation of rebound regression in disseminated carcinoma of the breast. Cancer 29:1268-1271, 1972.

2. Carbone, P. P.: Antiestrogens and breast cancer treat- ment. Ann. Intern. Med. 83:730-731, 1975.

3. Clark, J. H., Peck, E. J. Jr . , and Anderson, J. N.: Oestrogen receptors antagonism of steroid hormone action. Nafure 251 :446-448, 1974.

4. Diczfalusy, E., Birke, G., Franksson, C., Hellstrom, J.. Hultberg, S., Plantin, L-O., and Westman, A.: Remarks on the nature of Kober chromogens excreted by some oopho- rectomized-adrenalectomized patients. In Endocrine As- pects of Breast Cancer, A. R. Currie, Ed. Edinburgh, E & S Livingstone, 1958; pp. 186-196.

5. Duncan, G. W., Lyster, S. C., Clark, J. J., and Ledni- cer, D.: Antifertility activities of two diphenyl-dihydro- naphthalene derivatives. Proc. Sac. Exp. Bzol. 112:439, 1963.

6. EORTC Breast Cancer Group: Clinical trial of nafoxi- dine, a n oestrogen antagonist in advanced breast cancer. Eur. 5. Cancer 8:387-389, 1972.

7. Heuson, J. C., Engelsman, E., Blonk-Van der Wijst, J., Maass, H. , Drochmans, A., Michel, J., Nowakowski, H., and Gorins. A . : Comparative trial of nafoxidine and ethiny- loestradiol in advanced breast cancer-An E.O.R.T.C. study. Br. Med. .7 2:711-713, 1975.

8. Kaufman, R. ,J., and Escher, G.: Rebound regression in advanced mammary carcinoma. Surg. Gynecol. Obstet. 113:635-640, 1961.

9. Legha, S. S., Slavik, M., and Carter, S. K.: Nafoxi- dine-An antiestrogen for the treatment of breast cancer. Cancer 38: 1535-1 541, 1976.

10. Lerner, H., Band, P., and Israel, L.: Treatment of advanced breast cancer with tamoxifen-10 mg b.i.d.: Pre- liminary report. Proc. Am. Soc. Clin. Oncol. 17:237, 1976 (Astr.).

11. Rochefort, H., and Capony, F.: Binding properties of an antiestrogen to the estradiol receptor of uterine cytosol. 1;EBS Lellers 20: 1 1-1 5, 1972.

12. Singhakowinta, A., Henderson, M. D., and Vaitke- vicius, V. K. : Bilateral adrenalectomy in selected patients with carcinoma of the breast. Surg. Gynecol. Obsfef. 138:689-692, 1974.

13. Singhakowinta, A., Mohindra, R., Brooks, S. C., Vaitkevicius, V. K., and Brennan, M. J.: Clinical correlation of endocrine therapy and estrogen receptor. In Estrogen Receptors in Human Breast Cancer, W. L. McGuire, P. P. Carbone, and E. P. Vollmer, Eds. New York, Raven Press, 1975; Chapter 10, pp. 131-155.

14. Stonesifer, G. L. Jr . , Lowe, R. H., Cameron, J. L., and Ganis, F. M.: Conversion of hydrocortisone to estrogen in carcinoma of the breast after oophorectomy and adrenal- ectomy. Ann. Surg. 178:563-564, 1973.

15. Terenius, L.: Two modes of interaction between oestrogen and anti-oestrogen. Acfa Endocrinol. 64:47-58, 1970.