CORRESPONDENCE

THERAPEUTIC OPTIONS IN PATIENTS WITH HORMONE-REFRACTORY PROSTATE CANCER

To the Editor: The study by Dr. Figg and col-

leagues’ was interesting and thought provoking. The authors make a very important clinical observation relating to the role of flutamide withdrawal in hormone refractory prostate cancer. In this regard I would like to highlight some additional data relating to the subject.

Patients who respond to flu- tamide withdrawal can have fur- ther declines in prostate-specific antigen (PSA) values with bicalu- tamide, an oral antiandrogen.” Leibertz and colleagues2 have shown that when bicalutamide was given to 3 patients who re- sponded to flutamide withdrawal, 2 showed PSA declines of 97% and 93% respectively, consistent with in vitro studies showing differen- tial effect of flutamide and bicalu- tamide on androgen receptor transactivation. As bicalutamide is safe and tolerated easily, this lind- ing warrants further investigation.

While a decline in PSA has prog- nostic significance, Eisenberger et al,3 in a study of 1387 stage D2 prostate cancer patients, have shown that the percent decrease in log PSA is the strongest predictor of survival (P = 0.0005), prevailing over all other pretherapy prognos- tic markers.

The authors’ comment on the consistent failure of cytotoxic chemotherapy to demonstrate activity in hormone-refractory prostate cancer. The role of chemo therapeutic agents in the manage- ment of hormone-refractory pros- tate cancer is undergoing signihcant advances. Abel1 and colleagues4 have demonstrated that oral cy- clophosphamide is active in hor- mone-refractory prostate cancer, as evidenced by a decline in pretreat- ment PSA levels of greater than 5@?,

amelioration of symptoms, and ob- jective tumor response.

Prank and colleagues5 in a study of 18 hormone-refractory prostate cancer patients (including 10 patients having histologic and immunohistochemical evidence of neuroendocrine differentiation), observed a response rate of 61% (95% CI 36% to 3%) with carboplatin or cisplatin plus etoposide plus estramustine. Other chemothera- peutic agents shown to be effective in hormone-refractory prostate cancer include doxorubicin plus dose-escalated cyclophosphamide6 and losoxantrone.7

The above data, in conjunction with the authors’ study, suggest that both recent hormonal and chemotherapy regimes hold promise in the management of prostate cancer which has failed androgen deprivation.

Ajay Anund, MD New England Deaconess Hospital

Boston, Massachusetts

1. Figg WD, Sartor 0, Cooper MR, et al. Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med. 1995;98:412-413. 2. Leibertz C, Kelly WK, Theodoulou M, et al. High dose casodex for prostate cancer: PSA declines m patients with flutamide withdrawal responses. Proc Am Sot Clin Oncol. 1995;14:232A. Abstract. 3. Eisenberger M, Crawford ED, McLeod D, et al. The prognostic significance of prostate specific antigen in stage D2 prostate cancer. Proc Am Sot Clin Oncol. 1995;14:235A. Abstract. 4. Abell FL, Wilkes JD, Divers L, et al. Oral cyclophosphamlde (CTX) for hormone refractory prostate cancer (HRPC). Proc Am Sot Clin Oncol. 1995;14:243A. Abstract. 5. Frank SJ, Amsterdam A, Kelly WK, et al. Platinum based chemotherapy for patients with poorly differentiated hormone refractory prostate cancer (HRPC): response and pathologic correlahons. Proc Am Sot Clin Oncol. 1995;14:232A. Abstract. 6. Small SJ, Srinivas S, Madhavan S, et al. Use of doxorubicin fD) and dose-escalated cyclopho- sphamide (0 with granulocyte colony stimulating factor tgCSF) in the treatment of hormone refractory prostate cancer (HRPC). Proc Am Sot Clin Oncal. 1995;14:243A. Abstract. 7. Huan SD, Natale Rl3, Stewart DJ, et al. A phase II mufticenter trial of losoxantrone in patients with meta- static hormonerefractory prostate cancer (HRPC). Proc Am See C/in Oncol. 1995;14:238A. Abstract.

Manuscript submitted May 12, 1995 and accepted August 28, 1995.

The Reply: We appreciate the insightful

comments of Dr. Anand regarding treatment options for patients who have failed initial hormonal ther- apy for metastatic prostate cancer. The first point Dr. Anand refers to is an observation noted bly investi- gators at Memorial Sloan Kettering Cancer Center in which two pa- tients had initially responded to flu- tamide withdrawal and subse- quently responded to bicalutamide (Casodex).’ We (and others) have previously published data demon- strating that bicalutamide inhibits in vitro growth of prostate cancer cells expressing a mutant androgen receptor.2 These same cells are stimulated to grow by hydroxy-flu- tamide, the active metabolite of flu- tamide. If the LNCaP mutation is clinically relevant, then one would hypothesize that some patients re- sponding to flutamide withdrawal might subsequently respond to bi- calutamide.2 As noted above, pre- liminary clinical data suggests that this hypothesis may be correct; thus, these observations warrant further investigation.

The preliminary results of Eisen- berger and colleagues3 may prove to be an important contribution to the prostate cancer literature and we eagerly await a full report of their findings. These results have prompted us to perform a land- mark analysis of our pati’ents un- dergoing flutamide withdrawal and examined the relationship lbetween PSA declines and survival. Our data indicate that PCA declines 50% or greater measured 4 weeks after flu- tamide withdrawal does not predict for enhanced survival in medically or surgically castrated patients un- dergoing flutamide withtdrawal alone.4 In contrast, an analysis of a similar patient population undergo ing flutamide withdrawal in the face of adrenal suppression yielded very different results (Flgnre).5 In these patients, similar PSA (declines were strongly predictive of en- hanced survival (P = 0.0029, Man-

February 1996 The American Journal of Medicine@ Volume 100 243