The incidence of prostate cancer in the United States is the highest in the world. The incidence of prostate cancer in the United States has surpassed lung cancer as the first tumor that endangers men’s health. The incidence of prostate cancer in the United States has surpassed that of lung cancer as the number one tumor affecting men’s health. In China, endocrine therapy is one of the most important treatments because many patients have already metastasized at the time of consultation, or recurrence and metastasis occur after radical treatment of the primary limited lesion.
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. Endocrine therapy for prostate cancer includes combined endocrine therapy (CAB), debulking alone, neoadjuvant endocrine therapy (NHT), adjuvant endocrine therapy (AHT) and intermittent endocrine therapy (IAD), and the transformation of prostate cancer from hormone-dependent to non-hormone-dependent and eventually to hormone-insensitive tumors after endocrine therapy is the cancer-specific cause of death in prostate cancer patients. cause. Recent studies have shown that complete androgen blockade does not prolong the progression of prostate cancer cells to non-androgen dependence, while complete androgen blockade brings about a decrease in the quality of life of patients, such as low libido, erectile dysfunction, fatigue, decreased intelligence, psychological disorders – mental depression, reduced muscle strength, fat accumulation, reduced physical activity and overall mobility, as well as increased costs associated with patient treatment.
The new concept of IAD treatment proposed by Goldenberg et al. suggests that after interruption of alloandrogen suppression, surviving tumor cells enter the normal differentiation pathway through androgen supplementation, thus restoring apoptosis and delaying the progression into hormone-non-independent cells. Since then there have been numerous reports on the use of the IAD concept in the clinical treatment of prostate cancer. In recent years, it has been shown that intermittent endocrine therapy can delay the transformation of androgen-dependent prostate cancer cells into non-dependent cells, while reducing drug dosage and toxic side effects, significantly improving the quality of life of patients and reducing the cost of treatment.
Biological basis of intermittent endocrine therapy
Huggins et al. found in 1941 that prostate cancer cells require a certain level of androgens to survive and grow. In the absence of androgens, prostate epithelial cells decrease in size and cell number through programmed apoptosis, and the prostate-specific protein PSA decreases. If the prostate epithelial cells are unable to induce apoptosis in the absence of androgens and continue to grow, they are called non-androgen-dependent cells. The end result of complete androgen blockade therapy is almost always a non-hormone-dependent state, and once the tumor exhibits hormone-independent properties, once it progresses to androgen-insensitive cells, it becomes highly resistant to all chemotherapeutic cytotoxic drugs and is ineffective for any further treatment. Some chemotherapeutic agents have a tumor remission rate of approximately 20%, but these tumors have an extremely short regression period, and no cytotoxic therapy has yet significantly prolonged the survival of patients with prostate cancer.
There are several theories for the generation of androgen non-dependent prostate cancer cells.
(1) Clonal selectivity theory: Clonal selection by tumor genetic instability randomly generating anti-apoptotic androgen non-dependent cells.
(2) Adaptive theory: After orchiectomy, 60% of androgens in the prostate are removed, while androgens from the adrenal glands are not cleared, and cancer cells gradually adapt in an environment of low androgen concentration. By androgen suppression adaptation mechanism and upregulation of growth factors, they gradually become androgen insensitive cells.
(3) Anti-apoptotic gene theory: prostate basal cells contain a large number of anti-apoptotic genes, Bcl-2 or mutant p53, all of which have anti-apoptotic functions.
(4) Androgen receptor (AR) mutation and loss of expression, insensitive to androgens, so that anti-androgen therapy loses its effect. 1993 Sher and Kelly found that people who responded well to slow regression tumor treatment, symptoms worsened again after long-term application, PSA increased, after withdrawal of drugs, symptoms improved rapidly, PSA also decreased. This retardation withdrawal syndrome is associated with AR mutations. The incidence of this syndrome is about 44%-75%, mostly occurring 3 years after drug administration. Over the past 15 years, most treatment failures have been attributed to incomplete suppression of androgenic products, so attempts have been made to maximize androgen removal by combining hormones that suppress and block both testicular and adrenal sources. However, this approach increases the side effects and costs associated with treatment and delays progression by only 3-6 months in most patients.
(5) Peptide growth factor and its receptor epidermal growth factor (EGF) acts in the prostate gland in a paracrine manner on prostate stroma and epithelial cells to promote division and regulate the ratio of glandular to stromal cells. In prostate cancer, EGF is converted from a paracrine to an autocrine effect to stimulate cancer cell production without inhibiting growth.
The mechanism of production of androgen-independent prostate cancer is complex, and no single theory can fully rationalize this complex phenomenon, and further studies are needed.
Overall, current evidence suggests that prostate cell carcinomas that survive in an androgen-deficient state can acquire anti-apoptotic potential through androgen supplementation thereby prolonging progression to non-hormone-dependent.
Animal models of intermittent endocrine therapy
LNCaP are PSA-secreting hormone-dependent tumor cells of human body cell origin, and the investigators grew them in nude mice and treated them with intermittent androgen versus continuous androgen blockade, respectively. Compared to the two, the time for LNCaP tumors to develop to non-hormone dependence took 77 days for the intermittent androgen blockade group and 26 days for the continuous androgen blockade group. After castration, all serum PSA values were higher in the continuous androgen blockade group than in the pre-castration group at 28 days, whereas only 75% were higher in the intermittent androgen blockade group after 70 days. This data set suggests that intermittent androgen blockade does have the potential to delay the development to tumor non-dependence in animal models.
Clinical application of intermittent endocrine therapy
Intermittent endocrine therapy means that PSA is less than 0.2 ng/ml after a period of endocrine therapy for prostate cancer, and after 3-6 months of maintenance, the therapy can be stopped for a period of time, and endocrine therapy can be restarted after PSA rebound to a certain threshold, and so on and so forth. The benefits of IAD include improved patient quality of life, possible prolongation of androgen dependency, possible survival benefits, and reduced treatment costs. Significantly improved during off-treatment, such as restoration of sexual desire. IAD is more suitable for patients with limited lesions and local recurrence after treatment.
Issues related to clinical application
Treatment modalities for IAD: MAB approach is mostly used, but pharmacological depot (LHRH-a) such as goserelin, leuprolide and buserelin, or steroidal cyproterone acetate (CPA) is also available.
Criteria for discontinuation of IAD: Theoretically, hormone blockade should be maintained until apoptosis and tumor regression due to maximal depot and discontinued before tumor cells progress to non-hormone dependence. the duration of each cycle of IAD treatment and the criteria for discontinuation of treatment vary, with most scholars agreeing that it should be continued for several months (3-6 months) after PSA <0.2 ng/ml and then discontinued. In China, the recommended discontinuation criterion is 3-6 months after PSA≤0.2ng/ml.
Criteria for restarting therapy after intermittent treatment: The criteria for restarting therapy after IAD treatment also vary greatly. If PSA returns to >4ng/ml, 10-20ng/ml, 20ng/ml and rises to 1/2 of the pre-treatment level, for those whose PSA has fallen by 80% without reaching normal values, treatment is restarted when PSA has risen by 20% of the lowest value. The current domestic recommendation is to start a new round of treatment when PSA > 4ng/m1.
IAD indications: limited prostate cancer, unable to undergo radical surgery or radiotherapy; locally advanced patients (stage T3-T4); positive pathological margins after radical surgery; recurrence after radical surgery or local radiotherapy.
Significance and potential risks of IAD may maintain the hormone dependence of prostate cancer cells, delay the progression of prostate cancer cells to non-hormone dependence, and ultimately may prolong patient survival.
Potential risks of treatment: whether the progression from androgen-dependent to non-hormone-dependent may be accelerated; whether the lesions may progress during the interval of treatment needs to be confirmed or excluded by further studies.