Intermittent Endocrine Therapy for Prostate Cancer
The incidence of prostate cancer is currently on the rise worldwide. The incidence of prostate cancer in black Americans is the highest in the world, and currently 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 endocrine therapy for prostate cancer [1]. 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 death of 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. suggested that after interruption of alloandrogen suppression, surviving tumor cells enter into normal differentiation pathways through androgen supplementation, thus restoring apoptotic capacity and delaying the progression into hormone-non-independent cells [2, 3]. Since then there have been numerous reports of the use of the IAD concept in the clinical treatment of prostate cancer [4, 5]. 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 patients’ quality of life and reducing treatment costs.
Biological basis of intermittent endocrine therapy
Huggins et al. discovered 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. Once the tumor exhibits hormone-non-dependent properties, it becomes highly resistant to all chemotherapeutic cytotoxic drugs once it has progressed to androgen-insensitive cells and is poorly resistant to 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:The prostate basal cells contain a large number of anti-apoptotic genes, Bcl-2 or mutant p53, all of which have anti-apoptotic function.
(4) Androgen receptor (AR) mutations and loss of expression, insensitivity 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 [6].
(5) Peptide growth factor and its receptor epidermal growth factor (EGF) acts in a paracrine manner in the prostate gland to promote division and regulate the ratio of glandular to stromal cells in the prostate stroma and epithelial cells. In prostate cancer, EGF is converted from paracrine to autocrine action to stimulate cancer cell production without inhibiting growth.
An analysis of 113 prostate cancer puncture specimens treated with intermittent endocrine therapy showed a significant decrease in cell proliferation activity, no significant change in apoptosis rate, and no trend toward a significant increase in Gleason score during the first six months. Continuation of intermittent endocrine therapy showed no significant changes in proliferative activity, apoptosis rate, or Gleason score. Androgen receptors were consistently expressed at a high level in all specimens. This suggests that androgen withdrawal inhibits tumor growth mainly by suppressing cell proliferation activity and that intermittent endocrine therapy may not delay the emergence of non-androgen-dependent cells. Neither the proliferative activity of the cells nor the Gleason score increased during continued treatment, suggesting that the malignancy of the tumor was determined early in the pathogenesis. The expression profile of androgen receptors suggests that the androgen signaling system remains active after androgen withdrawal. Another study showed that androgen receptors were low relative to androgen-sensitive cells, grew rapidly in the absence of hormones in vivo and in vitro, Stat3 expression remained active, and down-regulation of Stat3 activation inhibited the growth of non-androgen-dependent prostate cancer cells in vitro, as shown by the assay of cell culture-induced non-androgen-dependent prostate cancer cells.
These aforementioned studies suggest that the mechanism of androgen non-dependent prostate cancer production is complex, and no single theory can fully rationalize this complex phenomenon, and further studies are needed.
Overall, the 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. The time for LNCaP tumors to develop to non-hormone-dependent compared to the two took 77 days for the intermittent androgen blockade group versus 26 days for the continuous androgen blockade group. After castration, all serum PSA values were higher in the continuous androgen blockade group than before castration at 28 days, whereas only 75% were higher in the intermittent androgen blockade group than before castration at 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 [9].
Goldenberg et al. investigated the relationship between intermittent androgen blockade on tumor stem cell composition and expression of the apoptosis-related gene TRPM-2 using a shionogi tumor model. They grew tumor cells in nude rats and castrated the rats when the tumors grew to 3 g. When the tumors degenerated to 40% or less of the original tumor volume, they were transplanted into another uncastrated rat and counted for 1 cycle. after 4 cycles (151±25 days), the tumors developed to hormone non-dependence and were at least 3-fold longer compared to the continuous androgen blockade group (51±25 days). Subsequent studies of tumor stem cell numbers with LimitingDilutionAssays revealed that the numbers remained stable during the first 3 cycles, but the tumor stem cells increased 15-fold in the 4th cycle. Before androgen blockade (0.8% of all stem cells were hormone-independent), the ratio increased to 47% after 4 cycles of intermittent hormone therapy [10].
Akakura et al. reported that normal prostate cells can be subjected to repeated androgen-induced growth and depot-induced degeneration multiple times through androgen supplementation and withdrawal of androgens. These animal experiments suggest that IAD treatment delays the development of non-hormone-dependent prostate cancer [11].
Clinical application of intermittent endocrine therapy
Goldenberg et al. proposed a new concept of intermittent androgen suppression, suggesting that tumor cells surviving intermittent androgen suppression are forced to enter the normal differentiation pathway by androgen supplementation, thus restoring apoptosis and possibly delaying progression to androgen non-dependence. Since 1992, the concept of IAD has been tested in clinical trials.
Intermittent endocrine therapy means that after a period of endocrine therapy for prostate cancer with PSA <0.2ng/ml, the treatment can be stopped for a period of 3-6 months and then restarted after the PSA rebounded 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.
Oliver et al. conducted a retrospective study of 20 patients with prostate cancer who opted for cessation of therapy. 45% were progression-free at 9-42 months of follow-up, and 75% of those who recurred (mean time to recurrence 9 months) demonstrated a second PSA remission with an overall survival rate of 85% at 3 years, comparable to continuous therapy [12]. estradiol (DES) to intermittently regulate serum testosterone levels in 19 patients with advanced prostate cancer. After treatment discontinuation, 60% of patients relapsed during a mean of 8 months (1-24 months), but all patients remained effective with the drug again. With the use of anti-androgen drugs, such as chlormadinone acetate and flutamide, luteinizing hormone-releasing hormone (LHRH) analogs, such as Inhibitors,research,lifescience,medical and Norelide, the androgen suppression became reversible. Unlike earlier studies, serial measurement of PSA allows for proper monitoring of lesion activity and can be used as an indicator for starting and interrupting treatment [13].Goldenberg et al. treated 47 prostate cancer patients with IAD and followed them for a mean of 29 months. Treatment with combined androgen blockade was started and continued for a mean of 9 months, with the exception of those whose PSA did not reach normal (<4.0 ng/ml), which were considered as primary resistant. patients whose PSA dropped to normal interrupted drug therapy until the PSA rose to a mean value of 10-20 ng/ml, when slow regression of the tumor was applied. This treatment and no treatment is repeated until PSA regulation becomes androgen non-dependent (PSA rises continuously despite androgen suppression therapy). Patient health improved during each cycle of discontinued treatment, and libido and erectile function were restored. The results suggest that IAD can delay tumor cell dependence on androgens by at least 3-fold without major negative effects on lesion progression or survival time, both similar to continuous suppressive therapy [3]. Therefore, a phase III randomized clinical study is necessary to properly evaluate the role of intermittent therapy.
Clinical trials performed by Panl et al. have also shown that IAD therapy can take patients off treatment for a certain period of time (7-15 months); that discontinuation time is shortened with increasing restart cycles; and that patients’ quality of life is significantly improved during the period of discontinuation.IAD therapy can prolong the duration of androgen dependence of tumor cells without major negative effects on lesion progression or survival time. However, serum testosterone levels do not return to normal in all patients during the interval between treatments [14]. IAD is more suitable for patients with limited lesions and local recurrence after treatment.
Zerbid and Conquy studied studied 68 patients (1/3 with metastases and 2/3 patients with PSA recurrence after radical prostate cancer resection). Androgen blockade therapy was stopped 6 months after PSA stabilization and restarted when PSA was greater than 4ng/ml. The average duration of the 1st treatment cycle was 12 months (ranging from 3-36 months), and the average time off treatment in the 1st treatment cycle was 8 months (ranging from 3-24 months). There was a mean of 6 months on treatment and 6 months off treatment in treatment cycle 2. Those with an active libido prior to treatment regained it during the intertreatment period, and all patients had an improvement in quality of life at the time of discharge from treatment [15].
Bruchovsky et al. performed intermittent endocrine therapy in 103 patients with biochemical recurrence after radiotherapy and the study was conducted over 6 years with a mean follow-up of 3.7 years. the PSA response rate was 95% and the time off treatment was 53% of the total time, with the time off treatment decreasing as the cycle was extended, 63.7 weeks in the first cycle and 25.6 weeks in the fifth cycle. Prostate volume was reduced by 40% in the first cycle, 34% in the second cycle, and no reduction in the third and fourth cycles. At the end of the study, 38.5% of the patients remained on treatment, 23.9% failed and 15.6% died. Tumor-specific death was 2%. The results suggest that patients with biochemical recurrence after radiotherapy can still receive intermittent endocrine therapy and still maintain a high response rate [16].
Relevant issues in clinical application
Treatment modalities for IAD: mostly MAB approach, but also pharmacological depot (LHRH-a), such as goserelin, leuprolide and buserelin, or steroidal cyproterone acetate (CPA) [2,3,14].
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 develop non-hormone dependence.The duration of each cycle of IAD treatment and the criteria for discontinuation of treatment vary, with most authors agreeing that it should be continued for several months (3-6 months) after PSA <0.2 ng/ml and then discontinued. A few reported the discontinuation criteria as PSA <4.0 ng/ml. the recommended discontinuation criteria in China is after PSA ≤0.2 ng/ml for 3-6 months [17].
Criteria for restarting therapy after intermittent treatment: the criteria for restarting therapy after IAD treatment also vary widely. If PSA returns to >4ng/ml, 10-20ng/ml, 20ng/ml and rises to 1/2 of the pre-treatment value, 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 [17].
Indications for IAD: limited prostate cancer that cannot be treated with radical surgery or radiotherapy; patients with locally advanced disease (stage T3 to 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 it may accelerate the progression from androgen-dependent to non-hormone-dependent; whether the lesions may progress in the interval of treatment need to be confirmed or excluded by further studies [17,18].
The results of a recent Meta-analysis study of 1382 patients treated with intermittent endocrine therapy and continuous endocrine therapy showed that there was insufficient information to suggest differences in overall survival, tumor-specific survival, or disease progression. Limited information suggests that intermittent endocrine therapy has relatively few side effects. Intermittent endocrine therapy is as effective as continuous endocrine therapy and remains more effective during the off-treatment period [19]. Due to the limited sample size, the effectiveness and advantages of intermittent endocrine therapy are yet to be validated by further studies in the clinic by means of evidence-based medicine.