Role Of Androgens In Prostate Cancer
Prostate cancer disease progression is initiated by the formation of prostatic intraepithelial neoplasia , which can progress to high grade PIN , followed by adenocarcinoma and metastasis. The prostate is heavily reliant on androgen for growth and function, and treatments targeting production of androgen or the AR itself are used in every stage of prostate cancer disease progression. Metastatic prostate cancer is the lethal phenotype of the disease and is typically treated with chronic androgen deprivation, usually by pharmacological means. Castration induces involution of the prostate and decreases the size of prostatic carcinoma , which forms the rationale behind androgen deprivation as a therapy. In rodent models, castration induced rapid apoptosis in the rat ventral prostate . Androgen deprivation also induces cellular senescence, a stable cell cycle arrest in response to sub-lethal stress.
Improvement In Pathologic Variables
Treatment with neoadjuvant hormones has been shown to substantially improve local pathologic variables, such as organ-confined rates, pathologic down-staging, and rate of lymph node involvement. With regard to seminal vesical invasion, one study reported a decrease in seminal vesicle invasion rate with neoadjuvant therapy, whereas another study showed no difference.
Advantages And Disadvantages Of Nadt
Neoadjuvant androgen deprivation offers the following potential advantages:
- Rate of positive margins is reduced
- Organ-confined disease is increased
- Serum PSA level is reduced
- Prostate size is reduced.
The following disadvantages of NADT have been identified:
- Clinical trials have not demonstrated unequivocal improvement in disease-free survival rates
- NADT has an unknown therapeutic effect on microscopic local or metastatic disease
- Poorly differentiated areas of tumor are altered minimally
- Tumor is rarely completely eradicated
- Risk of androgen-independent clonal proliferation exists with prolonged NADT
- Ability to evaluate the extent of the tumor at surgical resection may be compromised
- Pathologic interpretation may be obscured
- Increased difficulty occurs at surgery due to periprostatic fibrosis
- Cost of therapy is a disadvantage
- Adverse effects are a potential disadvantage
- Treatment of the tumor is delayed
- Likelihood of requiring blood transfusion during surgery is increased
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Radiation Therapy And Dna Damage
Radiation therapy is known to exert its therapeutic effects through DNA damage, namely double-stranded DNA breaks . Depending on the phase of the cell cycle, DSBs are repaired by one of two pathways in the DNA damage response . Non-homologous end joining is the predominant repair mechanism in G1 phase of the cell cycle, before the mitosis and chromosomal replication has occurred. Whereas homologous recombination is the main repair mechanism in S/G2, after the chromosomes have been replicated and a sister chromatid is available to serve as a complementary template for repair .
Figure 1
Dysregulation of cell-cycle checkpoint proteins or dysfunctional DDR contributes to genomic instability and plays a role in tumorigenesis through the accumulation of unrepaired mutations. On the other hand, it has been shown that in malignancy, enhanced DDR correlates with radioresistance and progression of disease.
Chapter : Early Vs Delayed Adt
The timing of androgen deprivation therapy in the management of recurrent and advanced prostate cancer has been controversial for many years. This is mainly due to a lack of adequate randomized clinical trials comparing early vs delayed ADT in patients with recurrent PSA following failure of local curative treatment. To date the available studies and current guidelines are stating that early use of ADT to be only beneficial in symptomatic patients with recurrent or metastatic disease. The EAU recommends ADT only in symptomatic patients requiring palliative treatment.53 In the following we summarize the current practice guidelines on timing of ADT in patients with recurrent prostate cancer after failing local curative treatment.
Van den Bergh and colleagues performed a systematic literature review to assess the effectiveness of ADT in patients with PSA recurrence following local curative treatment. This meta-analysis found that the benefit of early/immediate ADT for nonmetastatic prostate cancer recurrence remains unproven. The conclusion was that early ADT should be reserved for patients with the highest risk of progression based on PSADT or Gleason Score, but having a long life expectancy. This falls in line with the current standard of care recommendations of the EAU/ESTRO/SIOG and AUA/ASTRO/SUO.58
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Synergy Between Radiation Therapy And Adt
The clinical trial data from the 1980s confirmed that the addition of ADT to radiation therapy for patients with locally advanced disease improves outcomes. Though initially hypothesized to offer benefit from upfront cytoreduction or reduction in disease burden, others began testing the hypothesis that ADT and radiation therapy may indeed behave in a synergistic fashion.
Using a rat prostate cancer model, Zietman quantified the radiation dose required to eradicate 50% of the tumors in tumor-bearing rats, before and after orchiectomy. For rats treated with radiation therapy with intact testes, the TCD 50 was 89 Gy. However, in rats who underwent orchiectomy 24 hours versus 12 days prior to radiation therapy, the TCD 50 was significantly reduced to 60 and 42.1 Gy, respectively. The authors hypothesized that the significant improvement in local control following orchiectomy may indeed be attributed to cytoreduction yielding fewer malignant cells to target with radiation therapy and perhaps improved oxygenation of smaller tumors. On the other hand, the authors proposed that orchiectomy and radiation therapy may behave synergistically by further enhancing cellular apoptosis through re-assortment of cells in the cell cycle for synchronization and optimization of radiation-induced damage . This seminal study lead the way for others to investigate a possible synergistic relationship between ADT and radiation therapy.
Intermittent Versus Continuous Hormone Therapy
Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.
In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.
At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.
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The Role Of Ar Signaling In Crpc
The expression of PSA is mediated by androgen response elements. This suggests that the increasing PSA during ADT reflects activation of AR transcriptional activity. Consistent with this hypothesis, various recent findings have supported the notion that one of the most important mechanisms in CRPC development is the continuous activation of AR in prostate cancer cells. Several cellular and molecular alterations are related to this post-castration activation of the AR, including incomplete blockade of AR-ligand signaling, AR amplifications, AR mutations, aberrant AR co-regulator activities and AR splice-variant expression.
Enzalutamide is a novel AR antagonist that overcomes resistance to conventional anti-androgens by inhibiting nuclear localization and chromatin binding of AR. According to a recent phase I/II study in patients with mCRPC, the use of enzalutamide is safe, elicits PSA and radiographic response, and results in a median time to progression of 47 weeks. The superiority of enzalutamide over placebo was confirmed in a phase III clinical trial that showed increased overall survival and improvement in all secondary end points in patients with mCRPC after chemotherapy. Despite these encouraging results, after a period of remission that is characterized by significant variation in therapeutic response, these tumors eventually progress.
What Is Androgen Deprivation Therapy
Most prostate cancers need testosterone to grow. Testosterone is a male sex hormone that is made by the testes and adrenal glands. One treatment for prostate cancer is to slow or stop the body from making testosterone or block it from working. By depriving your body of androgens, prostate tumors can shrink or grow more slowly. These medications are called androgen deprivation therapy, or ADT. ADT can sometimes be called androgen suppression therapy.
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Changes In Gleason Criteria
Two of the Gleason criteria are altered by NADT. A decrease in gland size and an increase in stroma between glands occur. These findings can lead to a false upgrade of the Gleason score. The use of a modified Gleason system has been proposed to evaluate prostatectomy specimens from patients who have received NADT some physicians have suggested that no Gleason score should be allocated.
Chapter : Intermittent Vs Continuous Adt For Recurrent And Advanced/metastatic Prostate Cancer
Since the 1940s, androgen deprivation therapy has been the foundational treatment for prostate cancer. Bilateral orchiectomy, the original form of ADT, is still used worldwide, in particular in the developing world. Medical ADT options are the standard of care when available. It is well documented in the literature that ADT is associated with numerous significant adverse effects which include hot flashes, loss of libido, erectile dysfunction, loss of muscle mass and strength, fatigue, anemia, breast enlargement and tenderness, mood swings, osteoporosis and bone fractures, obesity, cardiovascular disease, insulin resistance and diabetes. Some studies also see ADT associated with cognitive decline and dementia .
Intermittent androgen deprivation therapy is a cyclic therapy with cessation of ADT allowing serum androgen recovery. The clinical idea is based on animal studies showing that iADT delayed tumor progression.60 Furthermore, the rationale for iADT is based on balancing drug-related toxicity and oncologic benefits. As continuous ADT is associated with substantial side effects, which may increase with duration of therapy, many clinicians consider iADT as an alternative providing reduced morbidity, and thus improved quality of life, with the possible oncological benefit of delaying castration-resistant PCa.
if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. 68
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Adverse Events Of Lhrh Agonists
The adverse events associated with LHRH agonists can be categorized as immediate, acute, and chronic. The optimal use of ADT requires an effort to prevent or treat these adverse events.
One of the limitations of LHRH agonists is the initial flare phenomenon, which is attributed to a surge of serum testosterone levels due to the initial stimulation of LHRH receptors.13 The flare phenomenon may be life threatening if an LHRH agonist is administered to men with high-volume metastatic disease. The clinical consequence of the flare is prevented by pretreatment with an antiandrogen, which inhibits the stimulatory effect of the testosterone surge at the level of the androgen receptor.14
Men with advanced prostate cancer are also predisposed to developing anemia due to hematuria from locally advanced prostate cancer and to bone marrow infiltration by metastatic disease. Testosterone increases production of erythrogenesis-stimulating proteins.22 Therefore, LHRH agonists may cause or exacerbate anemia by indirectly inhibiting erythrogenesis.
Progressive muscle loss has been associated with declining testosterone levels in men.15 Men receiving LHRH agonists for prostate cancer demonstrate significant increases in muscle fatigue.23 Resistance exercises may limit the consequences of LHRH agonists on muscle function.
Metabolic Syndrome And Cardiovascular Disease
Metabolic syndrome is a set of symptoms that increase the risk of stroke, cardiovascular disease, and type II diabetes mellitus . There is an increased risk of developing DM in prostate cancer patients treated with ADT than patients not treated with ADT .103 ADT was also associated with higher risk of complications in patients previously diagnosed with DM. Patients on ADT had a 17% increased risk of developing diabetic retinopathy, 14% higher risk for diabetic neuropathy, and twice as likely to have diabetic amputations.104
In longitudinal cohort study of 190 men undergoing ADT, mean triglycerides , HDL cholesterol , and waist circumference were significantly increased 6 months and 12 months after initiating ADT.105 Although HDL cholesterol is known to improve cardiovascular Health, an increase in overall cholesterol and triglycerides have negative effects as shown in the next two studies. Patients on ADT were at a higher risk of coronary heart disease and myocardial infarctions .106 ADT also increased the risk for ischemic stroke when compared to non ADT users.107
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Insulin Sensitivity And Obesity
Men with prostate cancer being treated with androgen deprivation therapy have an increased risk of osteoporosis and obesity.1-3
To gain more insight on the side effects caused by ADT, researchers from the University of Arizona compared data involving side effects of ADT. The study compared men with prostate cancer who were being treated with ADT and men not being treated with ADT . Obesity developed in 43% of men treated with ADT, compared to only 27% of men in the control group.1
The researchers concluded that patients with prostate cancer treated with ADT are at a higher risk for obesity. Appropriate preventive measures or close monitoring may help to prevent or reduce side effects.
Among men with locally advanced or recurrent prostate cancer, short-term treatment with Lupron Depot® and Casodex® increased body fat and decreased insulin sensitivity according to another study published in the Journal of Clinical Endocrinology and Metabolism.2
Metabolic changes such as insulin resistance could increase the risk of subsequent cardiovascular disease.
To explore whether androgen deprivation therapy reduces insulin sensitivity, researchers in the U.S. conducted a study among 25 men with locally advanced or recurrent prostate cancer. Average patient age was 68 years. The study excluded men who already had diabetes.
These changes also appear to increase the risk of diabetes and cardiovascular disease particularly in older men.
Types Of Androgen Deprivation Therapies Used In The Treatment Of Prostate Cancer
For patients with localized prostate cancer, definitive extirpative therapy includes radical prostatectomy and/or radiation therapy , delivered with or without adjuvant androgen deprivation. Despite initial success with these treatments, up to a third of patients will have a biochemical recurrence that is characterized by rising serum PSA . Patients with biochemical recurrence can then undergo androgen deprivation therapy, or remain in surveillance. With evidence of metastatic prostate cancer, patients are treated with androgen deprivation with or without docetaxel chemotherapy , or with or without abiraterone , with the androgen deprivation continued indefinitely. At this stage, androgen deprivation therapy can include approaches that decrease serum androgen levels by orchiectomy or by targeting gonadotrophin releasing hormone , with or without blockade of the androgen receptor with nonsteroidal anti-androgens .
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What Are The Advantages And Disadvantages Of Hormone Therapy
What may be important to one person might be less important to someone else. So speak to your doctor or nurse about your own situation.
- Its an effective way to control prostate cancer, even if it has spread to other parts of your body.
- It can be used alongside other treatments to make them more effective.
- It can help to reduce some of the symptoms of advanced prostate cancer, such as urinary symptoms and bone pain.
- It can cause side effects that might have a big impact on your daily life.
- It cant cure your cancer when its used by itself, but it can help to keep the cancer under control, sometimes for many years.
Surgical Implications Of Nadt
Neoadjuvant androgen deprivation therapy has been demonstrated to decrease prostate volume by 20-50%. The initial hope was that shrinking the gland would make radical prostatectomy technically easier, with less blood loss. The findings in this regard have been inconsistent.
In the multicenter, randomized T2bN0M0 trial, surgeons rated the difficulty of dissection, presence of seminal vesicle adherence, and extent of blood loss and found that seminal vesicle adherence to the periprostatic tissues was more common in patients pretreated with NADT than in those treated with surgery alone . They also recorded the operating time and amount of blood transfused. Surgical dissection was more difficult in pretreated patients. No significant difference in operating time, blood loss, or transfusion requirement occurred.
Although more dissections that were difficult were reported with NADT in this study, no operative complications occurred in the NADT group, whereas 6 intraoperative injuries were reported in patients who underwent surgery alone.
The authors believe that interference with apical dissection is potentially the most difficult problem caused by NADT. Also of serious concern is the fact that NADT-induced fibrosis can make intraoperative evaluation of the extent of the tumor more difficult, which in turn may compromise the extent of resection if the surgeon relies on intraoperative findings to determine performance of a nerve-sparing operation.
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Adt: What You Really Need To Know
The only people who really like androgen deprivation therapy are the drug companies that make billions of dollars a year selling the drugs. Doctors dont like it, and men dont like being on these drugs.
So why do it?
There are very few specific situations when ADT therapy is the right thing to do. These are the most common:
* Intermediate-risk men who are given six months of ADT plus external-beam radiation
* High-risk men who are getting radiation therapy. This is a finite course of ADT, and this combination two or three years of ADT plus external-beam radiation has been proven to cure cancer in many men.
* Men with metastatic prostate cancer. ADT can make a big difference in these men, in relieving their symptoms and dramatically improving their quality of life. It can also extend life some men have been on ADT for 20 years and are still going strong.
Chapter : Combination Of Adt With Radiation Therapy In The Management Of Prostate Cancer
Radiation Therapy and its part in prostate cancer management has continued to evolve as this Technology has improved over time, and research has led to a better understanding of the oncologic disease dynamics. Radiation therapy for prostate cancer consists of targeted energy beams such as External Beam Radiation Therapy or implantable radioactive seeds such as Brachytherapy, which destroy and thus eliminate neoplastic cells. While there are diverse subcategories of radiation-based therapies , the risk and benefits of each as well as other factors such as the patients preference ultimately guide the decision of the selected type of therapy. There are varying degrees of early and late mainly gastrointestinal and genitourinary complications caused by RT which underscore the need for shared decision making between treating physicians and PCa patients.56,69
The current AUA/ASTRO/SUO guidelines for management of advanced prostate cancer recommend primary radiotherapy in combination with ADT as a treatment option for selected patients with hormone sensitive prostate cancer and low volume metastatic disease . This is only a conditional recommendation with Grade C level evidence and is mainly based on two preliminary Phase III trials showing some benefit of combined therapy in these patients.56 These studies are still ongoing and may provide additional information to guide clinical practice in the upcoming years.
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