Endocrine therapy for prostate cancer
Back in 1941, Huggins and Hodges discovered that surgical debulking and estrogen slowed the progression of metastatic prostate cancer and first demonstrated the responsiveness of prostate cancer to androgen removal. Prostate cells will undergo apoptosis in the absence of androgenic stimulation. Any treatment that inhibits androgenic activity can be referred to as androgen removal therapy. Androgen removal is achieved mainly through the following strategies.
① Inhibition of testosterone production: surgical debridement or pharmacological debridement (luteinizing hormone-releasing hormone analog, LHRH-A).
② Blocking androgen-receptor binding: application of anti-androgen drugs to competitively block the binding of androgens to androgen receptors on prostate cells. The combination of the two can be used to achieve maximum androgen blockade. Other strategies include inhibition of synthesis of adrenal-derived androgens and inhibition of the conversion of testosterone to dihydrotestosterone.
The goal of endocrine therapy is to reduce the concentration of androgens in the body, inhibit the synthesis of adrenal-derived androgens, inhibit the conversion of testosterone to dihydrotestosterone, or block the binding of androgens to their receptors in order to inhibit or control the growth of prostate cancer cells.
Endocrine therapy approaches include denervation and antiandrogen (blocking the binding of androgens to their receptors) therapy. Endocrine treatment options.
① simple denervation (surgical or pharmacological denervation).
(ii) maximal androgen blockade.
(iii) intermittent endocrine therapy.
④ neoadjuvant endocrine therapy prior to radical treatment.
⑤ adjuvant endocrine therapy, etc.
1.Indications
(1) Metastatic prostate cancer, including N1 and M1 stage (debulking, maximal androgen blockade, intermittent endocrine therapy).
(2) Localized early stage prostate cancer or locally progressive prostate cancer that cannot be treated with radical prostatectomy or radiation therapy (debulking, maximum androgen blockade, intermittent endocrine therapy).
(3) Neoadjuvant endocrine therapy (debulking, maximal androgen blockade) prior to radical prostatectomy or radical radiotherapy
(4) Adjuvant endocrine therapy (depot, maximal androgen blockade) in conjunction with radiation therapy
(5) Local recurrence after curative treatment, but no further local treatment is possible (depot, maximal androgen blockade, intermittent endocrine therapy)
(6) Distant metastasis after curative treatment (debulking, maximal androgen blockade, intermittent endocrine therapy)
(7) Persistent androgen suppression in the androgen non-dependent phase (depot)
2.Destructive treatment (castration)
(1) Surgical depot: Surgical depot can cause a rapid and sustained decrease in testosterone to very low levels (depot level). The main adverse effect is the psychological impact on the patient. Because surgical depot may cause psychological problems and the inability to flexibly adjust the regimen during treatment, pharmacological depot should be considered first if available.
(2) Drug depot: Luteinizing hormone-releasing hormone analog (LHRH-a) is a synthetic luteinizing hormone-releasing hormone, and the products that have been marketed are: leuprorelin, goserelin, and triptorelin. The extended-release formulations are injected once every 1, 2, 3 or 6 months. After LHRH-a injections, testosterone levels gradually increase, reaching a peak at 1 week (a transient increase in testosterone), and then gradually decline to reach depot levels by 3 to 4 weeks, although 10% of patients treated with LHRH-a do not reach depot levels. lHRH-a has become one of the standard treatments for androgen removal.
Since there is a transient increase in testosterone when LHRH-a is first injected, anti-androgen drugs should be given 2 weeks before or on the day of injection until 2 weeks after the injection to counteract the flare-up caused by the transient increase in testosterone (flare-up). LHRH-a should be used with caution in patients with existing spinal cord compression from bone metastases, and surgical debridement with rapid reduction of testosterone levels may be an option.
(3) Estrogens: The mechanisms by which estrogens act on the prostate include inhibition of LHRH secretion, inhibition of androgenic activity, direct inhibition of testicular Leydig cell function, and direct toxicity to prostate cells.
The most common estrogen is hexestrol, which can achieve the same effects as denervation, but has a higher incidence of cardiovascular adverse effects and should therefore be applied with caution.
The tumor-related survival and progression-free survival rates of patients treated with surgical debulking, pharmacological debulking, or estrogen are basically the same for all three treatment modalities.
3.Single anti-androgen therapy (AAM)
(1) Purpose: Single application of higher dose of androgen receptor antagonist inhibits the stimulatory effect of androgens on prostate cancer and the growth of androgen-dependent prostate cancer cells, and hardly affects the serum testosterone and luteinizing hormone levels of patients.
(2) Indications: It is suitable for the treatment of patients with locally advanced prostate cancer without distant metastases, i.e. T3 to 4NxM0 stage.
(3) Methods: Non-steroidal anti-androgen drugs, such as bicalutamide 150 mg orally once daily, are recommended.
(4) Result: There was no significant difference in overall survival compared with drug or surgical debulking; patients’ sexual performance and physical performance were significantly improved and the incidence of cardiovascular disease and osteoporosis was reduced during the drug administration.
4.Maximum androgen blockade (MAB)
(1) Objective: To remove or block both testicular-derived and adrenal-derived androgens.
(2) Method: The commonly used method is depot plus anti-androgen drugs. There are two main categories of anti-androgen drugs: one is steroidal drugs, represented by megestrol acetate; the other is non-steroidal drugs, mainly bicalutamide and flutamide.
(3) Results: The combination of MAB with non-steroidal anti-androgen drugs prolonged the overall survival by 3-6 months compared with depot alone, and the mean 5-year survival rate increased by 2.9%. For limited prostate cancer, the longer the application of MAB treatment, the lower the PSA recurrence rate. The combination of MAB treatment with bicalutamide reduced the risk of death by 20% compared to debulking alone, and prolonged progression-free survival accordingly.
5. Neoadjuvant endocrine therapy (NHT) before radical surgery
(1) Objective: To provide endocrine therapy for a certain period of time before radical prostatectomy for prostate cancer patients in order to reduce tumor volume, clinical stage, and positive prostate margin tumor rate, and thus improve survival rate.
(2) Indications: Suitable for T2 and T3a stage.
(3) Method: The MAB method of LHRH-a combined with anti-androgen drugs is used, or LHRH-a or anti-androgen drugs alone can be used, but the MAB method has more reliable efficacy. The duration of neoadjuvant treatment was 3 to 9 months.
(4) Results: Neoadjuvant therapy may reduce the clinical stage of the tumor, may reduce the rate of positive surgical margins and lymph node infiltration, reduce the rate of local recurrence, and treatment longer than 3 months may prolong survival without PSA recurrence, while there is no significant improvement on overall survival.
6. Intermittent endocrine therapy (IHT)
In the absence or low level of androgens, prostate cancer cells that are able to survive continue to grow through the anti-apoptotic potential of supplemented androgens, thereby prolonging tumor progression to a hormone-non-dependent stage. the advantages of IHT include improved patient quality of life, reduced treatment costs, possible prolongation of tumor dependence on androgens, and a possible survival advantage over conventional endocrine therapy . clinical studies of IHT Studies have shown a significant improvement in the quality of life of patients in the interval between treatments (e.g., libido recovery). IHT is more suitable for patients with limited lesions and local recurrence after treatment.
(1) Treatment modalities of IHT: Mostly MAB methods are used, and pharmacological depot (LHRH-a), such as leuprolide, goserelin, treprostinil, or cyproterone acetate (CPA), is also available.
(2) Criteria for discontinuation of IHT treatment: There are different reports, but the recommended discontinuation criteria in China is after PSA ≤ 0.2ng/ml for 3-6 months.
(3) Criteria for restarting therapy after intermittent treatment: reports vary and a unified standard has not been reached. The criteria for restarting treatment reported in different literature are as follows: after PSA>4ng/ml; when PSA rises to 10-20ng/ml; after PSA>20ng/ml;; PSA rises to 1/2 of the pre-treatment level;;; Currently, a new round of treatment is recommended in China when PSA>4ng/ml.
(4) IHT indications: limited prostate cancer, unable to undergo radical surgery or radiotherapy; locally advanced patients (T3 to T4 stage); metastatic prostate cancer; positive pathological margins after radical surgery; recurrence after radical surgery or local radiotherapy. Those who are sensitive to endocrine therapy and whose PSA reduction can meet the discontinuation criteria after a certain period of endocrine therapy.
(5) Significance and potential risks of IHT.
(1) Significance of treatment: It may maintain the hormone dependence of prostate cancer cells and delay the progression of prostate cancer cells to non-hormone dependence, thus possibly prolonging the survival of patients.
②Potential risks of treatment: whether the progression from androgen-dependent to non-hormone-dependent can be accelerated; whether the tumor will progress during the interval of treatment.
7.Adjuvant endocrine therapy (AHT) for prostate cancer
AHT refers to adjuvant endocrine therapy after radical resection or radical radiotherapy for prostate cancer. The purpose is to treat residual lesions at the cut edge, residual positive lymph nodes, and micro metastatic lesions to improve long-term survival rate.
(1) Indications.
① Positive pathological cut margins after radical surgery.
② Positive postoperative pathological lymph nodes (pN+).
③ Postoperative pathology confirmed as stage T3 (pT3) or ≤ stage T2 but with high risk factors (Gleason > 7, PSA > 20ng/ml).
④ Locally advanced prostate cancer with the following high-risk factors (Gleason > 7, PSA > 20ng/ml) may undergo AHT after radical radiotherapy.
⑤ AHT can be performed after radiotherapy for locally advanced prostate cancer.
(2) Modalities.
① maximal androgen blockade (MAB).
(ii) pharmacological or surgical debulking.
(3) Anti-androgen therapy (anti-androgens): including steroids and non-steroids.
(3) Timing: most advocate starting immediately after surgery or radiotherapy to be .
In conclusion, AHT treatment is mainly aimed at patients with positive cut margins, pT3, pN+ and ≤pT2 stage with high-risk factors, and most of the literature reports that it can slow down the disease progression, but there is no consistent conclusion whether it can improve the survival rate of patients. The choice of treatment timing and limits should take into account the patient’s pathological stage, treatment side effects and costs, which are still inconclusive.
Follow-up of prostate cancer
Follow-up after curative treatment of prostate cancer
Curative treatment of prostate cancer refers to radical prostatectomy and radiation therapy, including external irradiation or brachytherapy, or a combination of these treatments.
Indicators of follow-up after curative treatment.
Changes in serum PSA levels: Monitoring changes in serum PSA levels is an essential part of the follow-up of prostate cancer.
(1) Monitoring of PSA after radical prostatectomy: PSA should not be detectable three weeks after successful radical prostatectomy. persistent elevation of PSA indicates the presence of PSA-producing tissue in the body, i.e. residual prostate cancer lesions. Two consecutive serum PSA levels above 0.2 ng/ml after radical prostatectomy suggest biochemical recurrence of prostate cancer.
Because there is a clearance period for PSA, the first PSA test after radical prostatectomy should be performed between 6 weeks and 3 months postoperatively, and should be repeated when PSA is found to be elevated to rule out laboratory errors. value can improve specificity. For example, defining 2 consecutive serum PSA levels ≥0.4 ng/ml as biochemical relapse, this criterion correlates best with clinical progression.
(2), monitoring of PSA after radiation therapy: the gland is still present after radiation therapy and PSA level decreases slowly. The lowest PSA value after radiotherapy is a sign of biochemical cure and an important prognostic judgment factor. In general, the lower the value, the higher the cure rate, and it is generally believed that the prognosis of those with a minimum PSA level of 1 ng/m1 within 3-5 years is better, and 80% of the 10-year survivors after radiotherapy have a PSA level of less than l ng/ml. biochemical recurrence, and the time of biochemical recurrence is the time when this occurs. This criterion is more sensitive and specific for predicting clinical recurrence than the older criteria for biochemical recurrence after radiotherapy, and is a good predictor of distant metastases, etiology-specific mortality, and overall mortality.
The previous biochemical recurrence criteria after radiotherapy required retrospective biochemical recurrence, resulting in artifacts of early decline and late flattening of the Kaplan-Meier curve, and it was not closely related to clinical prognosis. Since there is a natural increase in PSA levels after recovery of androgen secretion, the previous criteria would result in an increase in pseudo-biochemical relapse in these patients and would not explain the common PSA rebound in radiotherapy patients. Biochemical relapse is only a definition and does not imply the need to initiate remedial therapy. The application of adjuvant or remedial therapy should be individualized according to the overall risk factors of the patient and needs to be judged based on a combination of benefits and risks of treatment.