Endocrine therapy for prostate cancer has been used for more than 60 years. The current anti-androgen therapy is diverse and its clinical applications are expanding, but the practical implications (benefits) of endocrine therapy have not been established in many cases.
In 1941, Huggins and Hodges published their Nobel Prize-winning study on the role of androgen removal in advanced prostate cancer, which pioneered the endocrine treatment of prostate cancer. Currently, anti-androgen therapy can be achieved by a variety of methods such as debulking (surgery or drugs), estrogens, progestins and non-steroidal anti-androgens (androgen receptor blockers), and the clinical applications are expanding. However, in many cases, the practical significance of endocrine therapy has not been confirmed.
In addition, there are side effects of endocrine therapy for prostate cancer, such as effects on libido, sexual function, anemia, fatigue, flushing, muscle atrophy, weight gain, gynecomastia, depression, cognitive impairment, diarrhea, liver function abnormalities, osteoporosis, and osteoporotic fractures, which significantly affect the quality of life of patients. This article reviews the clinical studies related to endocrine therapy for prostate cancer from the perspectives of study design, survival rate, disease-related symptoms, and quality of life.
1. Endocrine therapy for advanced prostate cancer
Many studies have shown that androgen removal is an effective palliative treatment for symptomatic metastatic prostate cancer. The treatment can reduce bone pain, decrease urinary tract obstruction and bleeding, improve activity status, and lower serum PSA and acid and alkaline phosphatase. However, for asymptomatic metastatic prostate cancer, the best time to start hormone therapy and its effect on survival is controversial.
In 1959, the U.S. Veterans Administration Cooperative Urological Research Group (VACURG) studied stage III (local metastases) and stage IV (distant metastases) prostate cancer. Patients were randomized to a placebo group, a surgical debulking + placebo group, a 5 mg DES group, and a DES + surgical debulking group. The placebo group was to receive hormone therapy at the time of clinical lesion progression. The results showed that the treatment group slowed disease progression but did not improve survival compared to the placebo group. tumor mortality was reduced in the DES group, but mortality from cardiovascular causes was higher than in the placebo group.
Another study of 561 patients with stage III and IV disease compared the effects of 0.2mg, 1mg and 5mg DES on prostate cancer. The results showed that the 1mg DES group improved survival compared to the placebo and delayed treatment groups for stage M1 patients, and cardiovascular mortality was significantly lower in the 1mg DES group compared to 5mg DES.
The British Medical Council study evaluated the effect of immediate or delayed (symptomatic) hormone therapy on prostate cancer in 938 individuals (T2-T4, M0 or asymptomatic M1) randomized to groups. 1997 results showed improved survival in the early treatment group in stage M0 and no change in stage M1; the early treatment group had fewer complications (pathological fractures, extraosseous metastases, urinary tract obstruction). 2000 The results showed no difference in M0 survival between the early treatment group and the delayed treatment group.
The study had the following shortcomings: the original enrollment of 2000 patients and the small number of cases may have led to selection bias; bone scans were not used systematically and there may have been staging errors; 11% of patients in the control group died before starting treatment, accounting for 50% of the difference in tumor-specific deaths between the two groups. For advanced prostate cancer, early endocrine therapy can reduce complications, but the change in survival rate is not exact. The effect of hormone therapy for advanced prostate cancer obviously depends on the extent of the lesion at the time of treatment.
2. Radiotherapy combined with endocrine therapy
In 1998, Granfors et al. studied 39 patients with metastatic pelvic lymph nodes. Patients were randomized to either the radiotherapy group or the orchiectomy + radiotherapy group (which was started a few weeks after debulking). At a median follow-up of 9.3 years, overall survival was high in the combined treatment group (62% vs 39%, P=0.005). The exact value of radiotherapy in this study could not be evaluated, and the volume of specimens was low.
In 1999, Bolla et al. published the results of their study in which 415 patients, 90% with positive T3, T4 or lymph nodes and Gleason score 8-10 if T1-T2, were randomized to radiotherapy group or radiotherapy + goserelin (3.6 mg/4 weeks*3 years) + cyproterone acetate (150 mg/day*1 month). After a median follow-up of 45 months, the overall survival rate (79% vs. 62%, P=0.001) and metastasis-free survival rate were higher in the combination therapy group than in the single radiotherapy group. At a median follow-up of 65 months, the overall survival rate was still higher in the combination group (78% vs. 62%, P=0.001). This study raises questions: Is radiotherapy necessary? What is the most appropriate duration of endocrine therapy? Is it appropriate for patients with non-advanced disease? Three other randomized trials investigated the value of different timing of endocrine therapy in combination with radiotherapy for prostate cancer treatment.
Pilepich et al. studied 471 patients with T2-T4 (tumors >25 cm3) without distant metastases. The patients were randomized to the radiotherapy group (65-72 Gy) or to radiotherapy + 2 months of endocrine therapy (goserelin 3.6 mg/4 weeks + Flutamide 250 mg/dose, 3 times/day) before and after radiotherapy with a median follow-up of 6.7 years. another study by Pilepich et al. enrolled 977 patients with T1-T2(N1), cT3Nx or pT3( After radical prostatectomy), the patients were randomized to receive radiotherapy (65-72 Gy) or radiotherapy + goserelin (3.6 mg/4 weeks starting in the last week of radiotherapy until lesion progression).
With a median follow-up of 5 years, the study by Hanks et al. enrolled 1554 patients, T2-T4, with PSA <150 ng/ml, who received radiotherapy + 4 months of endocrine therapy (goserelin + flutamide, 2 months before and 2 months during radiotherapy) before being randomized to the group with 24 months of goserelin or no further treatment. The median follow-up was 4.8 years.
All three studies showed an improvement in short-term outcomes (disease-free survival, progression-free survival, local progression rate, biochemical recurrence rate, etc.) in the combination treatment group and in the different endocrine treatment durations compared with the radiotherapy alone group, but no significant improvement in survival was observed, and complications and quality of life were not evaluated. The latter 2 groups were found to have improved survival in the combined treatment group for patients with Gleason scores of 8 to 10.
3. Neoadjuvant hormone therapy before radical prostatectomy
Because clinical staging is often lower than pathological staging, many patients with non-limiting lesions undergo radical prostatectomy. Therefore, the recurrence rate after surgery is high, and many studies hope that preoperative hormone therapy will improve the prognosis.
Seven prospective randomized trials compared the effect of radical prostatectomy with androgen removal 6-12 weeks later + radical prostatectomy on the outcome of prostate cancer [11-14]. Each study showed that neoadjuvant treatment significantly reduced the rate of positive margins, reduced prostate volume, and lowered PSA. however, 3-5 years after surgery, there was no difference in overall patient survival, seminal vesicle or lymph node infiltration, or biochemical recurrence-free survival between the neoadjuvant and control groups. possible reasons for this: inadequate duration of neoadjuvant treatment, short follow-up, and difficulty in tumor differentiation after hormone therapy, etc. Gleave et al. The study by Gleave et al. showed that 8 months of neoadjuvant therapy resulted in minimal prostate volume. The results of long-term neoadjuvant therapy are not yet available.
4. Adjuvant hormone therapy after radical prostatectomy
A small study by VACURG evaluated the role of hormone therapy after radical prostatectomy. Patients with stage I and II lesions were randomized to either the radical prostatectomy group or the radical prostatectomy + DES group (5 mg/day). The results showed that the mortality rate (due to excess cardiovascular causes) was high in those treated with DES.
In 1999, Messing et al [16] reported the results of a study of 98 patients with positive lymph nodes after radical prostatectomy. Patients were randomized to observation, delayed treatment group or immediate surgery or drug debulking group. At 7.1 years of follow-up, the immediate postoperative endocrine therapy group had decreased prostate cancer mortality and improved overall survival. Although the results of this study have been widely cited as evidence for early postoperative endocrine therapy in patients with positive lymph nodes, there are a number of problems with this study: more than 50% of the Gleason score of 8-10 was in the observation group (21% vs. 41%); there were differences with the results of other similar studies, and Mayo’s clinical study showed that at 15 years of follow-up, only diploid tumor survival was improved (only 14/790); and there were no significant differences with the results of the study. 14/790); low overall survival, with a 5-year tumor-specific survival rate of 78% compared to 91% in Mayo; and long-term side effects in the treatment group.
In 2001, Wirth et al. published the preliminary results of the Early Prostate Cancer Study (EPCP), in which 8,113 patients with limited or locally advanced disease were enrolled. Patients received either radical prostatectomy, radiation therapy, or watchful waiting and were randomized to receive either a placebo group or bicalutamide (150 mg/day). The results showed that the incidence of metastasis was significantly lower in the treatment group, but the effect on survival was not yet available. Important information on the value of adjuvant endocrine therapy for these patients will be available only when the results of the study are completed.
5. Brachytherapy combined with endocrine therapy
To date, there have been no randomized studies evaluating brachytherapy combined with hormone therapy for prostate cancer related to survival and recurrence. In two non-randomized retrospective studies, D’Amico et al. used I125 seeds and Potter et al. used Pa103 seeds, and no improvement in patient survival was found with the combination of hormone therapy.
6. Single androgen removal for early prostate cancer
Byar et al. published a study on the endocrine treatment of early prostate cancer in 1972. 148 patients with stage I lesions were randomized to placebo, DES (5 mg/day), orchiectomy + placebo, and orchiectomy + DES (5 mg/day). The results showed that the mortality rate was higher in the DES-treated group than in the placebo group, due to the high mortality rate from cardiovascular disease. To date, no other randomized studies have reported androgen removal for early stage prostate cancer.
Hormone therapy is often used clinically for early stage (limited) prostate cancer, especially in patients who are not suitable for local treatment. Although treatment can reduce PSA levels and may delay tumor metastasis, the impact on survival is inconclusive. For such patients, it is up to them to decide whether to take hormone therapy after weighing the risk/efficiency relationship of endocrine therapy.
7.Early antiandrogen therapy for rising PSA after local treatment
Pound et al [18] found that the PSA rose after radical prostatectomy, and after a median time of 8 years, only about 1/3 of patients had metastasis; once metastasis occurred, the median survival was 5 years. There was no correlation between the rise in PSA after radiotherapy and patient survival. Thus, although early anti-androgen therapy resulted in a decrease in PSA in almost all patients, the impact on survival is unclear.
Treatment may not be necessary, and long-term endocrine therapy has considerable side effects. Currently, the choice of anti-androgen therapy for such patients needs to be individualized. Factors affecting the treatment decision include: time to biochemical recurrence, rate of PSA rise, time to PSA multiplication, tumor grade, patient age, physical condition, and the impact of treatment-related side effects on quality of life.
8.Summary
Endocrine therapy for prostate cancer has been used for more than 60 years, but there is a lack of high-quality randomized studies to confirm its role and value in many clinical situations. To date, it is recommended to use anti-androgen therapy in the following cases (to improve survival or tumor-specific survival and to reduce tumor-related complications):
(1) After external radiation radiotherapy or radical prostatectomy for positive lymph nodes, continuous endocrine therapy;
②Patients with local infiltration (T3) or high-grade (poorly differentiated) limited (T2) tumor, after external radiation radiotherapy, 3 years of endocrine therapy;
(iii) Metastatic (M1) lesions. In most cases, there is no clear evidence of benefit from the routine use of endocrine therapy. The clinical use of anti-androgen therapy should be weighed against the benefits, side effects and costs.