Through the work of Huggins et al. [1] in 1941, it was shown that metastatic prostate cancer responds positively to an orchiectomy (surgical castration). We now know that there isn’t any other therapy which produces a more reliable regression of both distant and local disease than androgen withdrawal (ADT).
Animal models of castrate sensitive tumors indicate that androgen deprivation (ADT), through both surgical and chemically induced methods decreases the proportion of tumorigenic stem cells and induces apoptosis in differentiated tumor cells [2]. Androgen deprivation produces a reduction in both primary tumor bulk and the delay in the development of metastatic disease.
Gomez et al. [3] used flutamide (Casodex) plus a luteinizing hormone-releasing hormone (LHRH) agonist (like Lupron) to treat 115 men with T3 tumors and observed a 68% 10-year actuarial cancer-specific survival, with 53.4% of surviving men remaining clinically progression free. Having similar findings, Rana et al. [4] reported a series of 199 men with T3-T4 disease treated with early or delayed HT. They found a 70% 5-year actuarial cause-specific survival. In this series of men, 85% of them required a TURP and 26% underwent orchiectomy at diagnosis. After a median follow-up of 4.2 years, a further 26% required surgery for local symptoms, and 46% had developed metastatic disease.
The Medical Research Council (MRC) of the United Kingdom conducted a prospective randomized trial comparing immediate ADT (orchiectomy or LHRH agonist) versus deferred ADT in 938 men with T2-T4 M0, MX, or asymptomatic M1 men. In the men with no evidence of metastases, 169 (69%) of 244 men assigned to delayed therapy eventually required treatment, in most cases for symptomatic progression. Immediate ADT produced better 5-year overall survival and cancer-specific survival rates than deferred ADT in men with T2-T4 M0 disease [5].
Approximately 40 to 50% of men with clinical T3-T4 tumors will be found to have pathologically involved pelvic lymph nodes [11, 6]. In this group of men who have a high risk of experiencing a metastatic recurrence where there is no evidence that local treatment with radiation or surgery favorably impacts survival. Zagars et al. [7] reported a 5-year clinical progression-free survival of 45% and metastasis-free survival of 78% in 179 pN1-3 men (78% T3) treated with early androgen ablation. These results are similar to the outcome of pN+ patients treated with both ADT and radiation therapy (RT) in the Radiation Therapy Oncology Group (RTOG) 85-31 (55% progression-free survival with PSA < 1.5; 73% 5-year metastatic free survival), suggesting that local radiation may not substantially improve relapse rates in these men [8]. Moreover, Schmeller and Lubos [9] performed a retrospective study of 76 men with T1-3 pN1-2 men treated with either combined RP and ADT or ADT alone and found no benefit to adding RP.
Not only does ADT produce disease-free survival rates that are comparable to or better than those seen with local treatment alone, it also may be as effective in preventing symptomatic local progression [9, 10]. The MRC conducted a multicenter randomized trial of orchiectomy alone versus radiotherapy alone versus orchiectomy plus radiotherapy in 277 clinically staged men with T2-T4 N0M0 prostate cancer. The trial was not adequately powered to detect small differences in outcomes, and the radiation treatment was not standardized. Nevertheless, it showed that there were no significant differences in overall survival or symptomatic local progression between the three treatment groups. After a minimum follow-up of 4 years, using radiation did not influence the need for treatment (usually TURP) for local symptoms, which was required in 64% of men].
Hormone therapy (ADT) has a positive effect on disease progression of localized prostate cancer when compared to localized treatment alone.
(1) - Huggins, C. and Hodges, CV Studies on prostatic cancer (the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic cancer of the prostate), Cancer Res. 1941; 1:293-297
(2)- Bruchovsky, N., Snoek, R., Rennie, P.S., Akakura, K., Goldenberg, S.L., and Gleave, M. Control of tumor progression by the maintenance of apoptosis. Prostate Suppl. 1996; 6: 13–21
(3)- Gomez, J.L., Cusan, L., Diamond, P., Candas, B., and Labrie, F. Long-term treatment of clinical stage C/T3 prostate cancer with flutamide and castration (6-year median follow-up) . (abstract 1080)Br J Urol. 1997; 80: 275
(4)- Rana, A., Chisholm, G.D., Khan, M., Rashwan, H.M., and Elton, R.A. Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate. Br J Urol. 1994; 74: 637–641
(5)- The Medical Research Council Prostate Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer (initial results of the Medical Research Council Trial). Br J Urol. 1997; 79: 235–246
(6)- Zincke, H., Utz, D.C., and Taylor, W.F. Bilateral pelvic lymphadenectomy and radical prostatectomy for clinical stage C prostatic cancer (role of adjuvant treatment for residual cancer and in disease progression). J Urol. 1986; 135: 1199–1205
(7)- Zagars, G.K., Sands, M.E., Pollack, A., and von Eschenbach, A.C. Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer (prognostic variables and outcome). J Urol. 1994; 151: 1330–1333
(8)- Lawton, C.A., Winter, K., Byhardt, R. et al. Androgen suppression plus radiation versus radiation alone for patients with D1 (pN+) adenocarcinoma of the prostate (results based on a national prospective randomized trial, RTOG 85-31). Int J Rad Onc Biol Phys. 1997; 38: 931–939
(9)- Schmeller, N. and Lubos, W. Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer. Br J Urol. 1997; 79: 226–234
(10)- Fellows, G.J., Clark, P.B., Beynon, L.L., et al. Treatment of advanced localized prostatic cancer by orchiectomy, radiotherapy, or combined treatment. Br J Urol. 1992; 70: 304–309
(11) - Van den Ouden, D., Davidson, P.J.T., Hop, W., and Schroder, F.H. Radical prostatectomy as monotherapy for locally advanced (stage T3) prostate cancer. J Urol. 1994; 151: 646–651
Joel T. Nowak, MA, MSW wrote this Post. Joel is the CEO/Executive Director of Cancer ABCs. He is a Cancer Thriver diagnosed with five primary cancers - Thyroid, Metastatic Prostate, Renal, Melanoma, and the rare cancer Appendiceal cancer.
