.

(iii) Risk grouping of patients with localized or locally advanced prostate.

Currently, the European Society of Urology’s risk grading system for locally or locally advanced prostate cancer is widely used internationally and is based primarily on the D’Amico classification system. This type of risk classification is based primarily on the degree of risk of biochemical recurrence in patients who have undergone radical prostatectomy or external radiotherapy treatment.

Low risk group: PSA <10ng/ml and Gleason score < 7 (ISUP 1 grade) and clinical staging cT1 to T2a.

Mid-risk group: PSA 10 to 20ng /ml, or Gleason score 7 score (ISUP 2/3

level), or cT2b.

High risk group: PSA> 20ng/ ml, or Gleason score > 7 score (ISUP 4/5

level), or cT2c.

High-risk locally advanced: any PSA, any Gleason score, cT3 to T4, or clinical diagnosis of lymph node metastasis.

In addition, the National Comprehensive Cancer Network guidelines for prostate cancer have similar risk grading criteria that are more detailed and graded, also with the goal of improving the risk of prostate cancer by being more

A detailed stratification of patients for different treatment options.

Very low risk: T1c, Gleason score ≤ 6/

Very low risk: T1c, Gleason score ≤6/ Gleason 1 level, PSA <10 ng/ml, less than 3 positive prostate biopsies with ≤ 3 cancer foci per needle :Times New Roman”>50%, PSA density < 0.15ng/(ml–g).

Low risk: T1 to T2a, Gleason score ≤ 6/ Gleason 1 level, 1 level, PSA <10 ng/ml.

Moderate preference: T2b to T2c, or Gleason scale 3+4=7/ Gleason 2 scale, or PSA 10 to 20 ng/ml but a positive prostate biopsy stitch count of less than 50%.

Moderate deviation: T2b to T2c, or Gleason score 3+4=7/ Gleason Grade 2, or Gleason score 4+3=7/ Gleason 3 grade, or PSA 10 New Roman”>PSA 10 to 20ng/ml.

High risk: T3a, or Gleason score 8 / Gleason 4 grade, or Gleason score 9 to 10/ Gleason 5 grade, or PSA> 20ng/ml.

Very high risk: T3b to T4, or major graded area Gleason 5, or puncture biopsy with a Gleason score of 4 stitches or more 8 to 10/ Gleason 10/ Gleason 4 or 5 levels.

IV. Diagnostic evaluation

(a) Monitoring screening and early diagnosis.

Screening for prostate cancer has been widely performed in Europe and the United States. For example, prostate cancer mortality in the United States has declined in recent years, in part due to a broad and rigorous prostate cancer screening policy. Of course, as more advanced prostate cancers are detected and treated, the proportion of early-stage prostate cancers is increasing, and there may be a small amount of overdiagnosis and overtreatment. As a result, there is considerable debate in Europe and the United States about population-based prostate cancer screening, and some policy guidelines may be diametrically opposed. However, in our country, where mass prostate cancer screening has not been initiated, there should be a significant number of people in the population who have been screened for prostate cancer.

of highly aggressive or advanced prostate cancer cases. Therefore, screening for prostate cancer is essential at this stage in our country.

Recommended for people 50 years of age and older, or those with a family history of prostate cancer 45 years of age or older, prostate cancer screening based on PSA testing with adequate information about screening risks.

PSA is a serine protease activated single-chain glycoprotein synthesized and secreted by prostate alveoli and ductal epithelial cells. PSA is a single-chain glycoprotein with serine protease activity that is synthesized and secreted by prostatic vesicles and ductal epithelial cells and is mainly present in semen, participating in the process of semen liquefaction. Under normal physiological conditions, PSA is mainly confined to the prostate tissue, and serum PSA is maintained at low concentrations. Serum PSA is present in two forms, with a fraction (10% to 40%) as free PSA; a fraction ( 60% to 90%) bound to α1- anti-chymotrypsin, a small amount to α-2-macroglobulin and others, called complex PSA. The sum of free PSA and complex PSA is usually referred to as total serum PSA. -family:Times New Roman”>PSA. When the prostate gland becomes cancerous, the normal tissue is destroyed and a large amount of PSA enters the body’s blood circulation causing the serum PSA >elevated. The half-life of PSA is 2 to 3 days.

Determination of PSA results: total serum PSA > 4ng/ml is abnormal and the initial PSA abnormalities need to be retested. Patient serum PSA levels are affected by factors such as age and prostate size.

Total serum PSA levels in 4 to 10ng/ml, free PSA has some diagnostic value as an aid. Because patients’ serum free PSA levels are negatively correlated with the development of prostate cancer, when free PSA/total PSA <0.1, the probability of developing prostate cancer was 56%, and when the free PSA/ total PSA >> 0.25, with a probability of only 8%. Our recommended free PSA/Total PSA> 0.16 as a normal reference value. If the patient’s total PSA

levels in the range of 4 to 10ng/ml, while the free PSA/ total PSA <0.16 should be recommended for prostate puncture biopsy.

In addition, measurement of prostate volume by ultrasound or other methods, followed by calculation of PSA density,< span style="font-family:Times New Roman">the greater the PSA density, the greater the likelihood of clinically significant prostate cancer. The PSA rate can also be calculated from different time PSA values as well as PSA multiplication time, which are 2 indicators that are useful in determining prognosis, but are relatively less significant at the beginning of the diagnosis due to the number of confounding factors.

Because the tumor specificity of PSA is not high, scholars have been searching for new prostate cancer-specific tumor markers. In recent years, PSA homologue 2 (p2PSA) and its derivative prostate health index (prostate health index, PHI) are gaining attention. The findings suggest that p2PSA is associated with high-grade prostate cancer, particularly for patients with a total PSA of 4 to 1.5. span style=”font-family:Times New Roman”>10ng/ml, PHI is more effective than total PHI in diagnosing prostate cancer. “font-family:Times New Roman”>PSA, which can reduce unnecessary prostate puncture biopsies. By using total PSA, free PSA and p2PSA were calculated for PHI with the following equations.

PHI = p2PSA / free PSA×

In addition, 4 kind of kininase release enzyme fractions were measured by combined determination of total PSA, free PSA/ total PSA, intact PSA, and intact PSA and kininase-releasing enzyme-like peptidase, and was derived by considering the patient’s age, DRE and previous puncture results, with the The goal is to reduce unnecessary prostate puncture biopsies.

(ii) Genetic testing.

There is a growing body of evidence supporting the importance of genetic testing in the early diagnosis of prostate cancer and in the comprehensive treatment of advanced tumors. In a comprehensive

Based on the consensus of the latest domestic and international guidelines, there is a consensus among experts in China to further standardize and guide the target, content, technology, data processing and interpretation of genetic testing for prostate cancer. In addition, the genetic test is recommended for patients who wish to undergo genetic testing to guide treatment decisions or for the purpose of genetic counseling. The genetic mutation profile of prostate cancer patients at different stages of disease and treatment varies, and second-generation sequencing for genetic counseling and treatment decision making is recommended based on the current state of prostate cancer clinical practice and drug development.

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• Providing genetic counseling
  

The assessment of the need for genetic testing is based on the family history, clinical and pathologic features of the patient with prostate cancer. The family history includes consideration of (1) whether an immediate family member such as a brother, father, or other family member was diagnosed with prostate cancer before the age of 60 years.

Prostate cancer or death from prostate cancer; (2) whether there is a same-line family member with style=”font-family:Times New Roman”>3 and above including bile duct cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, kidney cancer, melanoma, small intestine cancer and uroepithelial cancer, especially if their age of diagnosis is ≤ 3. family:Times New Roman”>50 years; (3) whether the patient has a personal history of male breast or pancreatic cancer; (4) whether the family is known to carry the relevant germline pathogenic mutation. Carriers of deleterious mutations in the BRCA1/2 gene are at increased risk of developing prostate cancer by 65 years of age, especially Patients with BRCA2 germline mutations have a higher risk of early-onset prostate cancer and prostate cancer death.

For patients at very low to intermediate risk of prostate cancer without risk assessment at initial diagnosis, obtaining a family history and genetic counseling is a necessary step before testing: For patients with a clear relevant family history and known family members carrying germline causative mutations, the following tests are recommended For patients at these risk levels with a clear relevant family history and known family members carrying germline pathogenic mutations, DNA damage repair-related genes are recommended.

(especially BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1,

MSH2, DNA repair genes (especially BRCA2, , and ) is recommended. BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, the

MSH2, MSH6, PMS2) for germline variant detection.

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• Treatment decision
  

For all metastatic castration-resistant prostate cancer (metastatic castration- resistant prostate cancer, mCRPC) patients, it is recommended to perform at least one study that includes HRR. Roman”>HRR gene germline and systemic variants, and testing for microsatellite instability and DNA mismatch repair defects may be considered. In patients with prostate cancer whose tumor tissue testing has identified mutations associated with risk of tumor development and lack of germline variant verification, genetic counseling is recommended before considering testing.

Distinguish germ line (germ line, a variant derived from parental germ cells, depending on the purpose of the test (which can be passed on to offspring through germ cells) or system

(somatic, an acquired genetic variation in the cells of the body) mutation test. Germline variants can be detected using blood (preferred), saliva, oral swabs, etc., while tumor tissue (e.g., fresh tumor tissue, paraffin-embedded tissue sections, etc.) or circulating tumor DNA (DNA) can be detected. “font-family:Times New Roman”>circulating tumor DNA, ctDNA), then embryonic DNA can be performed. family:Times New Roman”>+ systemic variant testing, germline gene variant validation is required if necessary on the basis of tumor tissue or ctDNA testing (or simultaneous germline gene variant testing ). Because of the systemic mutations in prostate cancer

exists (especially for the HRR gene), germline mutations alone are not sufficient to reflect the actual gene mutation in the tumor. The test is not sufficient to reflect the actual mutational status of the tumor.

(iii) Clinical diagnostic methods.

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• DRE
  

Prostate cancer mostly occurs in the peripheral zone of the prostate, and DRE is an important reference for early diagnosis and staging of prostate cancer. It is an important reference value for the early diagnosis and staging of prostate cancer. The typical presentation of prostate cancer is a hard nodule of the prostate with poorly defined borders and no pressure pain. If the nodules are not palpable, prostate cancer cannot be ruled out and needs to be considered in conjunction with PSA and imaging. DRE compression of the prostate can lead to PSA into the bloodstream, affecting serum PSA values are accurate, therefore DRE should be performed when the patient has blood drawn for laboratory examination PSA afterwards.

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• Prostate MRI
  

MRI is one of the most important methods to diagnose prostate cancer and to clarify the clinical stage. It relies mainly on T2 weighted images and enhancement features, and the characteristic presentation of prostate cancer is a low signal lesion in the peripheral zone of the prostate T2 weighted image. There is a low signal lesion, which is distinct from the normal high signal peripheral zone. In addition, tumor areas tend to show early enhancement. Prostate MRI can show the integrity of the peripheral envelope of prostate cancer and whether it invades the prostate surrounding adipose tissue, bladder and seminal vesicles; the accuracy of predicting peri- or extra-peri-peri-peri-peri invasion is 70% to 90%, and 90% for the presence or absence of seminal vesicle invasion; 90%; 90%; 90%. ; MRI can show invasion of pelvic lymph nodes and bone metastases, which is important for clinical staging of prostate cancer.

multiparameter MRI () multiparameter megnetic resonance imaging, mpMRI) is increasingly used in the diagnosis and staging of prostate cancer. mpMRI imaging should include T2--weighted images, diffusion-weighted imaging, and dynamic contrast-enhanced images.

In addition, high-quality mpMRI requires 3.0T field strength. The need for an endorectal coil at the time of examination remains controversial.

The mpMRI can be applied at different stages of prostate cancer diagnosis and treatment. First, mpMRI is useful to detect larger hypofractionated cancers (i.e., Gleason score ≥ 7/Gleason Grade 2 and above). mpMRI has been incorporated into the MRI – ultrasound fusion-targeted biopsy protocol, which achieves more biopsies with fewer punctures biopsy needle count, while reducing the detection of low-grade and clinically nonsignificant cancers. Second, mpMRI provides assistance in terms of extraperitoneal invasion (T staging), with a higher negative predictive value in low-risk patients. with high negative predictive values, and the results can inform decisions about preserving nerve surgery. Again, mpMRI is comparable to CT in terms of pelvic lymph node assessment. Finally, for the detection of bone metastases, mpMRI is superior to bone scan, with 98% to 100% sensitivity and 98%-100% specificity.

Magnetic resonance spectroscopy is based on the metabolism of citrate, choline, and creatinine in prostate cancer tissue showing different spectral lines from those in prostate hyperplasia and normal tissue to reflect the metabolic changes of cells in the body, which can compensate for the conventional MRI is also useful for early diagnosis of prostate cancer.

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• PET-CTApplication
  

Carbon -11 Choline positron emission computed tomography (positron emission tomography-computed tomography, PET-CT) has been used to detect and differentiate prostate cancer from benign lesions. The sensitivity and specificity of this technique in patients with biochemical failure to restage were 85% and 88%, respectively. Carbon -11 choline PET-CT may be helpful in detecting distant metastases in these patients.

Prostate-specific membrane antigen (prostate-specific Prostate-specific membrane antigen, PSMA, is highly expressed specifically on the surface of prostate cancer cells, making it extremely important for research in the field of molecular imaging and targeted therapy of prostate cancer, especially for nucleotide labeling PSMA. span style=”font-family:Times New Roman”>PSMA small molecule inhibitors have shown promising clinical applications in the molecular imaging diagnosis of prostate cancer. Gallium -68 (68Ga (/span>)-PSMA PET-CT imaging has a sensitivity of 86% for the diagnosis of patients with prostate cancer. The specificity was 86%; for prostate cancer lesions the sensitivity was 80% and the specificity was 97%.

68Ga-PSMA PET-CT is much more accurate than conventional imaging for prostate cancer, for example MRI, CT and prostate ultrasound.

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• Prostate puncture biopsy
  

• Indications and contraindications for initial prostate puncture: Indications for prostate puncture include: ①DRE (1) suspicious nodules in the prostate with any PSA value; (2) suspicious lesions on transrectal ultrasound or MRI with any PSA value; (3) PSA >10ng/ml; (4) PSA 4-10ng/ml, suspicious free PSA/total PSA ratio or suspicious PSA density value.
  

  Contraindications to prostate puncture include: ① being in a period of acute infection, fever.

  ②Hypertensive crisis; ③Cardiac insufficiency in the decompensated phase; ④Severe bleeding tendency disease; ⑤Diabetes mellitus with unstable blood glucose; ⑥Severe internal or external hemorrhoids, perianal or rectal lesions.

• Performing a prostate puncture biopsy: Routine examination before puncture: Because prostate puncture biopsy can cause changes in local MRI images of the prostate gland, it is important to perform an MRI biopsy of the prostate gland. The prostate biopsy is usually recommended before the prostate puncture biopsy if clinical staging is to be assessed by MRI.
  

Prophylactic antimicrobial drug use: transrectal ultrasound-guided prostate puncture biopsy should be routinely administered orally or intravenously before the procedure. The antimicrobial agents should be routinely administered orally or intravenously prior to transrectal ultrasound-guided prostate puncture biopsy, with quinolones being preferred.

Gut preparation: Bowel cleansing prior to transrectal prostate puncture biopsy is routine, and cecropan can be used instead of enemas.

Perioperative anticoagulation and antiplatelet agents: For patients with a history of cardiovascular or cerebrovascular disease or stent implantation who have been taking oral anticoagulation or antiplatelet agents for a long time, the risk of bleeding and cardiovascular disease should be evaluated perioperatively and the decision to use them should be made carefully. The use of relevant medications should be carefully assessed in the perioperative period.

Number of puncture needles and sites: A prostate volume of 30 to 40ml of prostate volume, no less than 8 needles are recommended for puncture biopsy, and 10 to 12 needle systematic puncture as a baseline (initial) prostate puncture strategy. The increase in the number of puncture needles did not significantly increase the incidence of complications. Saturation puncture may be used as a puncture strategy.

• Repeat puncture: Consider repeat prostate puncture when the results of the first prostate puncture are negative but the DRE, repeat PSA, or other derivative levels suggest suspicion of prostate cancer. Repeat puncture is required if: (1) atypical hyperplasia or high-grade prostatic intraepithelial neoplasia is found in the pathology of the first puncture, especially if the pathological results of multiple needles are as above; (2) PSA > 10ng/ml on recheck; (3) PSA 4-10ng/ml, free PSA percentage, PSA density value, DRE or abnormal imaging performance on recheck, such as transrectal ultrasound or MRI suggesting suspicious If the cancer foci are suspected by rectal ultrasound or MRI, targeted puncture of the point of interest can be performed under the image fusion technique; ④ If PSA 4 to 10ng/ml, free PSA percentage, PSA density value, DRE, and imaging performance are normal, every
  

3 monthly review of PSA. If PSA continuous 2 times> 10ng/ml, or PSA rate >

0.75ng/ml, requiring repeat puncture.

Repeat puncture is recommended in addition to the routine examination before mpMRI based on mpMRI targeted puncture significantly increases the rate of positive repeat punctures and avoids missing high-risk prostate cancer. The timing of repeat punctures is controversial, with recommendations of 3 months or longer, pending complete recovery of tissue architecture.

If suspicious foci are identified on imaging before repeat puncture, targeted puncture of the suspicious foci should be performed.

Puncture.

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• Limitations and new strategies of prostate system puncture: transrectal or trans-synovial
  

The major limitations of negative systemic prostate puncture biopsy are false negatives, missed high-risk prostate cancers, and overdiagnosis. The challenge of improving the positive puncture rate while avoiding overdiagnosis is a major challenge in the early diagnosis of prostate cancer. In recent years, targeted prostate puncture biopsy based on ultrasound-enhanced imaging, ultrasound elastography, and mpMRI has shown significant advantages in detecting clinically significant prostate cancer and avoiding overdiagnosis.

MRI guided targeted puncture can be performed in MRI guided direct extraction of the suspicious foci with the highest accuracy. Several studies have shown that MRI guided prostate puncture biopsy can improve the detection rate of high-grade prostate cancer at repeat punctures. However, the procedure is relatively complex and expensive, making it difficult to promote.

MRI/ transrectal ultrasound fusion technique combines MRI localization accuracy and the convenience of transrectal ultrasound-guided puncture, significantly increasing the rate of positive puncture while increasing the proportion of clinically significant prostate cancers detected and avoiding detection of non-clinically significant prostate cancers, in contrast to MRI is more convenient than puncture.

V. Treatment of prostate cancer

(a) Watchful waiting and active surveillance.

Watchful waiting includes monitoring the course of prostate cancer to provide timely palliative care when symptoms appear, test results change, or PSA indicates impending symptoms. Thus, observation is different from active surveillance. The aim of observation is to maintain the quality of life of patients by avoiding noncurative treatment when prostate cancer is unlikely to cause death or significant morbidity. The main advantage of observation is the avoidance of unnecessary treatment [such as androgen deprivation therapy (androgen deprivation therapy, ADT)] may cause side effects. It is generally indicated for patients with a life expectancy of less than 10 years at all stages.

Proactive monitoring includes active dynamic monitoring of the disease process to detect tumor progression with the aim of timely intervention for curative purposes and is primarily indicated for patients with a life expectancy of 10 years or more for patients with low-risk prostate cancer, with the aim of delaying potentially curative treatment and thus reducing the potential side effects of treatment without compromising overall survival. Because these patients have a longer life expectancy, they should be followed closely, including DRE, PSA >, mpMRI and repeat punctures, etc. Once tumor progression is detected, treatment should be started immediately to avoid missed opportunities for healing.

Inclusion criteria for patients on active surveillance include life expectancy 10 years or more, tumor stage cT1 or cT2, cT2, PSA ≤ 10ng/ml, biopsy Gleason score ≤ 6, positive number of needles ≤ 2 and the proportion of tumors per puncture specimen ≤ 50%. Before implementing active surveillance in such patients, radical surgery and radical radiotherapy should be fully communicated to the patient, and the patient should be informed that he or she may have to undergo radical surgery or radiotherapy at some point in the future. The follow-up process should be performed DRE (at least 1 time per year), the

PSA (at least every 6 months 1 ), mpMRI, and repeat punctures (at least every 3 to 5 years and repeat punctures (at least every 1 1 times) and other checks.

When pathology changes after repeat biopsy, such as Gleason score, number of positive stitches, or volume occupied by tumor, and Tstaging progression, then active surveillance should be adjusted to active treatment.

Before choosing watchful waiting and active monitoring, the patient and family should be fully informed of the possible benefits and risks and should understand and cooperate.

(ii) Radical prostatectomy.

The goal of radical prostatectomy is to completely remove the tumor while preserving urinary control and, if possible, erectile function. The procedure can be performed open, laparoscopically, or robot-assisted laparoscopically. Robotic-assisted laparoscopic radical prostatectomy can shorten the operative time and reduce intraoperative blood loss. Regardless of the surgical approach, hospitals with a high number of surgeries per year and experienced surgeons have a lower rate of positive postoperative margins and better control of the tumor. Preoperative pelvic floor exercise is helpful for recovery of urinary control 3 months postoperatively.

The choice of treatment modality should be based on a thorough multidisciplinary consultation with the patient, including urology, radiotherapy, medical oncology, and imaging, and should include the benefits and possible complications of each treatment modality.

The role of preoperative endocrine neoadjuvant therapy before radical surgery is typically applied for 3 months, and there are some randomized controlled studies examining its role. Preoperative endocrine neoadjuvant therapy reduces the incidence of pT3 , reduces the incidence of positive cut margins, and reduces the incidence of positive lymph nodes. The above benefits were more pronounced the longer the treatment duration (up to 8 months). However, because of the absence of PSA recurrence survival and tumor specificity

survival is not improved, preoperative neoadjuvant endocrine therapy is not currently standard clinical practice and can be performed in certain populations.

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• Low-risk prostate cancer
  

Due to the potential for complications in the perioperative period of radical prostatectomy, radical prostatectomy should be used for patients with a life expectancy of 10 years. span>year or more. There are studies

studies have shown that the 15 year prostate cancer-specific mortality rate for patients undergoing radical prostatectomy is as low as 15 years. span style=”font-family:Times New Roman”>12% and only 5% in low-risk patients.

A study in 695 patients with early-stage prostate cancer (mostly stage T2 ), comparing radical prostatectomy with watchful waiting. After a median follow-up of 12.8 years, patients in the radical prostatectomy group showed significant improvements in tumor-specific survival, overall survival, and risk of metastasis and local progression. Mortality was significantly lower at 23 years of follow-up, with an absolute difference of 11%. Overall 8 patients needed to be treated to prevent 1 death; and for 65 years of age or younger, it was necessary to treat 4 patients

and prevented 1 fatality. The results of this study support radical prostatectomy as a treatment option for clinically limited prostate cancer.

Low-risk prostate cancer with a positive pathological pelvic lymph node rate of less than 5% is not routinely recommended for pelvic lymph node dissection.

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• Intermediate risk prostate cancer
  

A SPCG-4 study showed that in intermediate-risk limited prostate cancer, radical prostatectomy can be used for postoperative 18 years to reduce overall mortality, tumor-specific mortality, and distant metastasis rates. And another PIVOT study showed that radical

Prostatectomy can be performed after 10 years but does not reduce tumor-specific mortality.

The rate of lymph node positivity in intermediate-risk prostate cancer ranged from 3.7% to 20.1%. If the assessed risk of positive lymph nodes exceeds 5%, expanded lymph node dissection should be performed at the same time as radical prostatectomy, otherwise it can be left out.

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• High-risk prostate cancer
  

While not all patients with high-risk prostate cancer have a poor prognosis after radical prostatectomy, such patients have a poor postoperative PSA recurrence, need for a second prostatectomy, or need for a second prostatectomy. span>Recurrence, the need for a second treatment option, progression of metastatic disease, and the risk of death are high. There is no standard protocol for the treatment of high-risk prostate cancer. Radical prostatectomy remains a reasonable option for patients whose tumors do not anchor the pelvic wall, or whose tumors do not invade the urethral sphincter. Since the likelihood of positive pelvic lymph nodes in high-risk prostate cancer is 15% to 40%, radical surgery should be performed in all patients. Radical surgery should be accompanied by concomitant expanded lymph node dissection in all such patients.

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• Indications for Nerve Preservation Surgery
  

Most limited prostate cancers can be treated with radical prostatectomy with preservation of the nerve, with clear contraindications for surgery in patients at high risk of extraperitoneal invasion, such as cT2c or cT3 stage prostate cancer, or a biopsy Gleason score 7 or higher for prostate cancer. Preoperative mpMRI may be helpful in patient selection, and if intraoperative findings reveal possible residual tumor, the operator should remove the vascular nerve bundle, and intraoperative freezing may be helpful in these decisions.

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• Lymph node dissection
  

There is insufficient evidence to confirm the oncologic benefit of concomitant lymph node dissection during radical prostatectomy. However, it is generally accepted that lymph node dissection provides definitive pathologic staging and prognostic data that cannot be replaced by any other available method. The panel recommends the use of line graphs developed at Memorial Sloan -Kettering Cancer Center to predict the risk of lymph node metastasis, including pretreatment PSA, clinical staging, and Gleason score. The decision to perform lymph node dissection should be based on the probability of lymph node metastasis, either 2% or 5% as the threshold for lymph node dissection. the threshold for lymph node dissection.

Lymph node dissection should be performed with an extended pelvic lymph node dissection that includes the external iliac vein superiorly, the pelvic wall laterally, the bladder wall medially, the pelvic floor inferiorly, the Cooper’s ligament distally, and the internal iliac artery proximally. Several studies have supported the survival benefit of expanded lymph node dissection, possibly due to the removal of small metastatic lesions. Lymph node dissection can be done laparoscopically, robotically assisted laparoscopically, or open surgery, and complication rates are similar for all three procedures.

It has been shown that lymph node dissection during radical prostatectomy for cN0 has been shown to be a significant complication for cN0. span style=”font-family:Times New Roman”>pN1 patients with ,15 year tumor-specific survival and overall survival rates were 45% and 42%, respectively.

The number of lymph nodes dissected, the number of positive lymph nodes, the volume of tumor in the lymph nodes, and whether the tumor invaded the lymph node tegument were The number of positive lymph nodes, the volume of tumor in the lymph nodes, and whether the tumor invades the lymph node tegument are predictors of early recurrence after radical prostatectomy in patients. A density of positive lymph nodes greater than 20% suggests a poor prognosis.

One study using intraoperative indocyanine green injection to show lymph nodes showed that more positive lymph nodes could be removed, however, follow-up < span style="font-family:Times New Roman">22 months showed no difference in biochemical recurrence. There is insufficient evidence to support an association between sentinel lymph nodes and tumor control, and sentinel lymph node biopsy is still in the pilot phase.

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• Adjunctive therapy after radical prostatectomy
  

For extraperitoneal invasion pT3, Gleason score > 7 score, and a positive cut edge

(R1) in patients with postoperative 5 year probability of local recurrence is as high as 50%. There are 3 main RCT studies worldwide addressing the issue of postoperative adjuvant radiotherapy in this group of patients. The current conclusion is that for pT3 pN0 patients, postoperative PSA levels <0.1 ng/ml, with a higher risk of local recurrence due to positive incision margins (the most important factor), extraperitoneal invasion and / or invasion of the seminal vesicles. There are currently 2 options to communicate with the patient: (1) adjuvant to the surgical area immediately after the return of voiding function Radiotherapy.

• Clinically close follow-up in PSA is above 0.1ng/ml when salvage radiotherapy is initiated.
  

  For patients with pN1 , early post-radical surgery combined with adjuvant endocrine therapy after =This improved tumor-specific survival and overall survival has been demonstrated in prospective randomized controlled clinical studies. This improvement in tumor-specific survival and overall survival has been demonstrated in prospective randomized controlled clinical studies.

  For patients with pN1, there may be benefit from postoperative adjuvant radiotherapy. However, the degree of benefit depends largely on the characteristics of the tumor, such as 3 to 4 positive lymph nodes, Gleason score < span style="font-family:Times New Roman">7 to 10 scores, pT3 to 4 stages, and positive cut margins. A retrospective study of the SEER database noted an improved overall survival time with adjuvant radiotherapy after radical surgery

Trend of adjuvant radiotherapy after radical surgery with no statistically significant prolongation of tumor-specific survival. There is no consensus on the extent of radiation for adjuvant radiotherapy, with most taking the entire pelvic radiotherapy.

After expanded lymph node dissection, for 1 to Patients with 2 microscopic lymph node metastases, PSA <0.1ng/ml and no extra-nodal invasion, we can temporarily observe and wait.

Adjuvant chemotherapy after radical surgery is inconclusive and still in clinical trials.

The period of adjuvant chemotherapy after radical surgery is still in clinical trials.

(iii) External radiation therapy.

Radical external radiation therapy (external beam radiotherapy, EBRT)

Similar to radical prostatectomy, it is one of the most important curative treatments for prostate cancer patients. The main treatments are three-dimensional conformal radiotherapy (three-dimensional conformal radiotherapy, 3D-CRT Roman”>3D-CRT) and intensity-modulated conformal radiotherapy (intensity modulated radiotherapy, IMRT), graphically guided radiation therapy(image-guided radiation therepy, IGRT) and other techniques, which are now the mainstream technology for radiation therapy. EBRT has the advantages of good efficacy, broad indications, and low complications and adverse effects. It can achieve similar efficacy to radical surgery for patients with low-risk prostate cancer. Depending on the purpose of radiotherapy treatment, EBRT is divided into three categories: radical radiotherapy as one of the radical treatments for patients with limited and locally progressive prostate cancer; postoperative adjuvant and postoperative salvage radiotherapy; and palliative radiotherapy to reduce symptoms and improve quality of life. palliative radiotherapy for metastatic cancer.

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• Indications for Radical EBRT
  

Limited prostate cancer: low-risk patients (T1 to 2a, Gleason score 2 to 6

min, PSA < 10ng/ml), EBRT and radical prostatectomy were the first

The method of choice, with radical EBRT and radical prostatectomy preferred in elderly patients. Roman”>EBRT. Intermediate-risk patients (T2b or Gleason score 7 score or PSA 10 to 20ng/ml), both radiotherapy and surgery are the preferred methods, with radical EBRT, with the option of combining short-course neoadjuvant

/Simultaneous / adjuvant endocrine therapy (4 to 6 months). High-risk patients (≥ T2c or Gleason score ≥ 8 score or PSA > 20ng/ml), EBRT, requiring combined long-course neoadjuvant /concomitant /adjuvant endocrine therapy (2 to 3 years), but surgery is still an option for some patients.

Locally progressive prostate cancer (T3 to 4N0M0): radical EBRT combined with long-course neoadjuvant / Roman”>/ concurrent / adjuvant endocrine therapy (2 to 3 years). Surgery, radiotherapy, and endocrine therapy are different means of treatment for locally progressive prostate cancer in a combination of approaches, and the choice needs to be made based on the patient’s condition.

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• EBRT Complications
  

Adverse effects associated with radiotherapy are related to the single and total dose, the radiotherapy regimen and the volume of irradiation. In the acute phase, common adverse effects include urinary frequency, hematuria, diarrhea, and blood in the stool, which largely resolve several weeks after the end of radiotherapy. Late stage adverse effects include rectal bleeding and radiation cystitis bleeding. The incidence of these complications is significantly lower with conformal and intensity-modulated radiotherapy, but pelvic radiotherapy may increase the risk of developing a second primary tumor, such as rectal or bladder cancer.

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• Surgical treatment of biochemical recurrence after radiotherapy
  

Radical prostatectomy is a salvage treatment for patients with biochemical recurrence of prostate cancer after external radiotherapy. The incidence of complications, including urinary incontinence, erectile dysfunction, and bladder neck contracture, is higher with radical prostatectomy than with radical prostatectomy as initial treatment. The 10 year overall survival and tumor-specific survival rates are

54% to 89% and 70%~83%. Patient selection is very important. Salvage prostatectomy should be performed by an experienced surgeon.

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• Status and development of radiotherapy techniques
  

With the development of radiotherapy technology over the past few decades, it has become possible to safely treat with higher radiation doses. 3D-CRT using computer software, combined with the internal anatomy of the treatment site CT images, enables the application of higher doses with a lower risk of delayed response risk, and apply a higher cumulative dose. The second-generation 3D technique, IMRT, is increasingly used in practice because in some but not all studies, IMRT is more comparable to IMRT. span>reduces the risk of gastrointestinal toxicity compared to 3D-CRT. For 3D-CRT or IMRT , daily use of IMRT is mandatory. family:Times New Roman”>IGRT for prostate positioning to achieve narrow target area boundaries and treatment precision. The previously routinely used 70Gy dose may be slightly lower. A total dose of 75.6 to 79.2Gy is appropriate for low-risk patients, with routine fractionated irradiation of the prostate (with or excluding the seminal vesicles). Intermediate-risk and high-risk patients may receive up to 81.0Gy of radiation therapy.

Large split image-guided IMRT regimens (per 2.4 to 4Gy, total 4 to 6 weeks) with similar efficacy and toxicity to conventionally divided IMRT . These radiotherapy techniques can be considered in place of conventional segmentation regimens, and results from randomized clinical trials have shown a correlation between dose boosts and improved biochemical outcomes.

Stereotactic body radiation therapy (STEREOTACTIC BODY RADIATION THERAPY , SBRT) is an emerging treatment technique that delivers highly conformal, high-dose radiation in five or fewer segmentation sessions that are safe only when guided by precise imaging. Compared to standard radiotherapy techniques, SBRT has a better

biochemically progression-free survival and similar early toxicity (bladder, rectum, and quality of life). However, IMRT may have relatively more severe adverse effects compared to SBRT .

(iv) Brachytherapy.

Radiation brachytherapy is a technique for treating limited prostate cancer by accurately targeting radioactive particles into the prostate through a 3-dimensional treatment planning system, increasing the local dose to the prostate and reducing the radiation dose to the rectum and bladder. The efficacy is certain, less invasive, and particularly suitable for elderly prostate cancer patients who cannot tolerate radical prostatectomy.

Traditionally brachytherapy has been used in low-risk cases because early studies found that brachytherapy was less effective than EBRT in high-risk patients. However, a growing body of evidence suggests that with technological advances in brachytherapy, there is a role for brachytherapy in high-risk limited and locally advanced prostate cancer. There are two main approaches to prostate brachytherapy: low-dose and high-dose brachytherapy.

Low-dose brachytherapy involves the placement of permanent granulation source implants in the prostate. The small area of radiation emitted from these low-energy field sources allows sufficient radiation dose to be applied to the lesions within the prostate, avoiding over-irradiation of the bladder and rectum.

Permanent brachytherapy is suitable as a monotherapy for the treatment of low-risk patients (cT1c to T2a, Gleason score of 6 score and below, PSA <10ng/ml. For intermediate-risk prostate cancer, brachytherapy can be combined with EBRT (45 Gy), and with or without neo adjuvant ADT. High-risk patients are often considered unsuitable for permanent brachytherapy alone.

Patients with large or small prostates, symptoms of bladder outlet obstruction (high International Prostate Symptom Score), and prior transurethral prostate surgery are not ideal candidates for brachytherapy. In these patients, implantation of radioactive particles may be more difficult and there is an increased risk of side effects.

High-dose brachytherapy, which is the temporary insertion of a radiation source, is a new dose enhancement for high-risk prostate cancer patients treated with EBRT. A new method of dose enhancement in the treatment of The combination of EBRT (40 to 50 Gy) and high-dose brachytherapy can increase radiation dose while minimizing acute or late toxicity in patients with high-risk limited or locally advanced prostate cancer.

Short-range radiotherapy combined with EBRT, along with the addition of ADT (2 or 3 years) is a common regimen for treating high-risk patients. The combination of the three treatments is effective, with studies showing 9 year progression-free survival and disease-specific survival rates of 87% and 87%, respectively. span>and 91%.

(v) Proton therapy.

Early in the 20th century The use of proton beam radiotherapy to treat cancer patients began in the 50s. Proponents of proton therapy believe that this form of radiation therapy may be superior to X--ray (photon)-based radiation therapy in some clinical situations. Proton therapy can deliver a highly conformal dose of radiation to the prostate. Proton beam-based therapy delivers a much lower dose to the normal tissues surrounding the prostate. However, these tissues are not routinely responsible for the adverse effects of prostate radiation therapy, so the benefits of lowering the dose to these non-critical tissues are not obvious. American Society for Radiation Oncology

(American Society for Radiation Oncology, ASTRO) concluded that the efficacy of proton beam therapy compared with other prostate cancer treatments is inconclusive. Because

The role of proton beam therapy for limited prostate cancer is unclear among the currently available treatment options. Although proton beam therapy is not a new technology, its use in the treatment of prostate cancer will continue to evolve. ASTRO strongly supports the development of patient data from clinical trials that are necessary to reach consensus on proton therapy for prostate cancer, especially for comparing proton therapy with other radiotherapy modalities such as IMRT and brachytherapy) is critical.

(vi) Other treatments for limited prostate cancer.

For limited prostate cancer, there are a number of alternative treatments that have emerged in addition to those mentioned above. The most established and well-documented method is cryoablation of the prostate (focal cryosurgical ablation of the prostate, a method that has been used to treat prostate cancer. -family:Times New Roman”>CSAP) and high-energy focused ultrasound (high-intensity focused ultrasound, HIFU).

CSAP is the destruction of tumor tissue by local freezing. One study noted that low-risk patients with cryotherapy had a 5 year biochemical-free recurrence rate of 65% to 92%. Cryosurgery and radical prostatectomy have similar oncologic outcomes for prostate cancer. One study compared cryotherapy with T2 or T3 stage prostate cancer patients to EBRT . All patients received neoadjuvant ADT. The results showed no statistical difference in 3 year overall survival or disease-free survival, and patients who received cryotherapy had poorer post-treatment sexual function. However, it has also been found that despite similar tumor-specific and overall survival times, CSAP compared to EBRT >Lower biochemical progression-free survival.

Potential patients for CSAP include those with limited prostate cancer, PSA <

20ng/ml, Gleason score < 7 score, low-risk prostate cancer or intermediate-risk prostate

Patients with cancer but physically unfit for radiotherapy or surgery, prostate volume <

40 ml. There are no long-term data on the efficacy of tumor treatment beyond 10 years, as

This should be fully informed for patients with a life expectancy of 10 years or more.

HIFU is a treatment that uses ultrasound to damage tumor tissue through mechanical and thermal effects. The treatment of tumors is achieved through mechanical and thermal effects. HIFU is now used for the initial treatment of prostate cancer and for recurrence after radiation therapy. In a prospective study, 111 patients with limited prostate cancer were treated with HIFU, 2 year survival without other radical treatment was 89% and 12 months, the percentage of patients retaining urinary control and erectile function was 97% and 78%, respectively. Roman”>78%. After a median follow-up of 64 months, 48% of patients were exempt from the application of ADT.

HIFU can also be used in patients who have relapsed after radiation therapy. The study noted a median biochemical relapse-free survival time of 63 months after HIFU treatment and 5 year overall survival rate 88% and tumor-specific survival rate 94%. After a median follow-up of 64 months, 48% of patients were exempt from the application of ADT.

Other emerging local therapies, such as vascular targeting photodynamics (vascular targeting photodynamics, VTP) therapy and irreversible electroporation of the prostate

etc., warrant further refinement of long-term follow-up data. A multicenter, open, III

Phase I randomized controlled trial in which 413 patients with low-risk prostate cancer were randomized to receive VTP treatment (intravenous paliperfin, fiber optic insertion into the prostate, followed by laser activation) or active surveillance. After a median follow-up of 24 months, VTP in the VTP group :Times New Roman”>28% of patients had disease progression compared with 58% in the active monitoring group. Negative prostate re-biopsy results were more common in the VTP group. The most common serious adverse effect in the VTP group was urinary retention, which resolved within 2 months. Irreversible electroporation of the prostate is achieved by generating short, intense electric field pulses in the tissue to kill cells, and changes in the electric field

causes the formation of nanopores in the cell membrane, which ultimately leads to cell instability and death through apoptosis. Studies have shown that the tumor detection rate 16%-25% in the ablated area at 6 months after irreversible electroporation.

It should be noted that due to the lack of long-term follow-up and controlled study results for the above-limited treatments for limited prostate cancer, they should be adopted with relative caution in clinical practice. It is recommended that this be done as a clinical trial after full communication with patients and families and after a rigorous medical ethics review.

6. Treatment of metastatic prostate cancer

Metastatic prostate cancer is an important stage of the disease that severely affects the patient’s prognosis. In Europe and the United States, metastatic prostate cancer accounts for only 5% to 6% of new prostate cancers, while in China, the rate is as high as 54%. .

ADT is the primary systemic primary therapy for patients with advanced metastatic prostate cancer and is the basis for a variety of novel combination therapy options. ADT includes multiple delivery options, with debulking alone (surgical or pharmacologic) being the most widely accepted core treatment modality. In recent years, there have been a number of breakthroughs, notably ADT in combination with novel endocrine therapies or chemotherapeutic agents, that have improved the overall outcome of metastatic prostate cancer. Nevertheless, the associated drug toxicities and economic burden associated with various novel combination regimens need to be taken into account and serve as an important reference for clinical selection.

The number of metastatic lesions and tumor burden in patients with metastatic prostate cancer are associated with treatment prognosis. The results of several large clinical studies in recent years have led to the gradual clinical application of a stratified approach to the assessment of patients with metastatic disease.

High versus low metastatic load:CHAARTED study defined high metastatic load as visceral metastases, or ≥ 4 bone metastases with at least 1 was outside the spine or pelvis. Low metastatic load was defined as no visceral metastases and ≤ 3 bone metastases.

The definition of high-risk versus low-risk disease was also derived from large clinical studies. LATITUDE study defined high-risk disease as meeting 3 of the following risk factors style=”font-family:Times New Roman”>2 of the following: Gleason score ≥ 8 score, bone metastases ≥ 3 sites, and the presence of visceral metastases. Low-risk disease was defined as having no more than 1 of the above risk factors.

(i) ADT.

ADT can be treated with surgical debulking (bilateral orchiectomy) or pharmacological debulking. Surgical debridement is achieved by bilateral orchiectomy to block testicular androgen production. The surgery is relatively simple, low cost and has few adverse effects. After surgery, serum testosterone levels drop rapidly, and patients can usually reach depot levels within 12 hours. Bilateral orchiectomy is a reasonable option when the patient’s condition requires a rapid reduction in testosterone, such as bone metastases to the spinal cord. However, surgical denervation may have a negative psychological impact on the patient compared to pharmacologic denervation.

The rationale for pharmacologic debulking is to affect the hypothalamic –pituitary -pituitary – gonadal axis to reduce androgen production in the testes, commonly used drugs include luteinizing hormone releasing hormone, LHRH) agonists, or LHRH antagonists. At the start of LHRH agonist therapy, LHRH agonist binding to the receptor can cause luteinizing hormone and This causes a sudden increase in testosterone levels, resulting in a “scintillation response” that may stimulate prostate cancer growth and cause bone pain, bladder outlet obstruction, or spinal nerve damage.

The symptoms of compression are exacerbated. For patients with significant metastases and the potential for symptoms associated with a dramatic increase in testosterone from initial LHRH agonist therapy alone, it is important to start 1 with the application of Roman”>1 week, classical NSAIDs can be used until 4 weeks, after which the combination can be used for about 4 weeks. In contrast, LHRH antagonists are able to reduce luteinizing hormone and follicle-stimulating hormone release by rapidly binding to LHRH receptors. release, which subsequently suppresses testosterone levels and avoids exacerbation of disease due to elevated testosterone, and does not have to be administered in conjunction with an anti-androgen.

The current internationally accepted definition of a depot level is testosterone < 50ng/dl

(1.735 nmol/L), but this standard was actually developed many years ago developed and was limited by the level of detection technology at that time. Available methods confirm that the average level of testosterone after surgical debulking is 15 ng/dl, so testosterone <20 ng/dl (20 ng/dl). span> (0.694 nmol/L) should be a more reasonable level of depot. A decrease in testosterone to lower levels during ADT (deep depot ketosis) is associated with better disease prognosis and regression. Testosterone management across the spectrum of prostate cancer diagnosis, assessment, treatment, and prognostic evaluation is clinically important for patients at all stages of disease. Transient or persistent failure to achieve depot levels of testosterone during treatment is known as testosterone escape and can be caused by a variety of factors, such as dietary structure, metabolic status, poor adherence to treatment, or injection errors. Testosterone is measured as a baseline value at important disease stage initiation (diagnosis, relapse, neo-onset, metastasis, etc.) and treatment transition points (curative treatment, change in ADT approach, initiation of other treatments such as chemotherapy, etc.) to provide a reference for subsequent treatment. During prostate cancer ADT and at diagnosis of destructive-resistant prostate cancer (castration- resistant prostate cancer, CRPC), still at testosterone levels <50 ng/dl

(1.735 nmol/L) as a criterion for depot; however, deep descending ketones during ADT i.e., testosterone

suppression to <20 ng/dl (0.694 nmol/L) at lower levels, which should be used as a reference indicator for better clinical treatment prognosis and adjustment of therapy.

(ii) Combination therapy of ADT with other drugs.

style=”margin-left: 61pt”>
• Combination chemotherapy
  

Multiple randomized controlled studies of debulking combined with docetaxel chemotherapy have compared the clinical efficacy of debulking alone and combined chemotherapy for the treatment of metastatic prostate cancer. The results of the CHAARTED trial and the STAMPEDE trial showed that compared to depot alone, combination chemotherapy could significantly improve the overall prognosis of patients with high tumor load. Therefore, depot combined with docetaxel chemotherapy is one of the standard treatment options for patients with high tumor load.

style=”margin-left: 61pt”>
• Combination with abiraterone
  

Abiraterone is a CYP17 inhibitor whose mechanism of action is to inhibit testicular, adrenal, and prostate cancer tumor cell production of androgens. The results of the LATITUDE trial and the STAMPEDE trial showed that compared to depot treatment alone, the combination of The results of the STAMPEDE trial showed that the combination of abiraterone and prednisone significantly improved the prognosis of high-risk patients compared with depot treatment alone, and the results of the STAMPEDE trial showed that depot combined with abiraterone also prolonged the overall survival of patients with low-risk metastatic prostate cancer. Therefore, depot combined with abiraterone plus prednisone should be a standard treatment option for patients with metastatic prostate cancer.

style=”margin-left: 61pt”>
• Combined with enzalutamide
  

Enzalutamide is a new non-steroidal anti-androgen drug that blocks the binding of androgens to receptors, inhibits nuclear translocation of androgen receptors, and affects the interaction between androgen receptors and DNA. Roman”>DNA binding thereby blocking androgen-mediated transcription and inhibiting overall androgen receptor signaling, thereby inhibiting prostate cancer cell growth. Two studies on en

Large randomized controlled studies of enzalutamide ENZAMET and ARCHES showed that depot treatment combined with enzalutamide significantly improved imaging disease-free survival and prolonged overall patient survival.

style=”margin-left: 61pt”>
• Combined with apatamide
  

Apatamide is a new androgen antagonist that is structurally and pharmacokinetically very similar to enzalutamide, with a higher affinity for the androgen receptor, and does not readily cross the blood-brain barrier, with theoretically slightly less adverse effects. A large randomized controlled study of apatamide, TITAN showed significantly longer overall survival and significantly better imaging disease-free survival compared to the placebo group.

From the available findings, it is clear that depot combination with novel endocrine agents can significantly improve the prognosis of metastatic hormone-sensitive prostate cancer, and these agents have received FDA approval as a standard of care for patients with metastatic prostate cancer. There is no significant difference in the efficacy of these new endocrine agents. In addition, there is no evidence whether the addition of chemotherapy in combination therapy prolongs survival, but it is certain that there is an increase in adverse effects, and therefore the newer antiandrogenic drugs in combination with chemotherapy are currently only used in clinical trials. There is no head-to-head comparison between ADT combined with chemotherapy or ADT combined with novel endocrine therapy. The clinical selection of treatment options should take into account patient preference, specific adverse effects, tolerance to chemotherapy, as well as drug accessibility and cost.

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• Combination with bicalutamide or flutamide
  

Drug or surgical debridement combined with a traditional anti-androgen agent is known as combined androgen blockade. This combination regimen is still being used in China. A meta-analysis of European and American populations showed that this combination androgen blockade regimen increased the absolute 5-year survival rate by 2.9% compared to depot treatment alone. Roman”>2.9%

(from 24.7% up to 27.6%). Therefore, this combination therapy is still used as one of the available options in China.

(iii) Local treatment of metastatic prostate cancer for both primary and metastatic foci.

In recent 10 years, several retrospective studies have reported that metastatic hormone-sensitive prostate cancer treated with primary site The benefits of surgery or radiation therapy for patients with metastatic hormone-sensitive prostate cancer have been reported in several retrospective studies over the years. However, not all treatments for the primary site are prognostic. Some studies have shown that patients with metastatic prostate cancer who are young and in good general condition, have a low metastatic tumor load and a low Gleason score are relatively likely to benefit from local radiation therapy to the primary site. Therefore, a cautious clinical study approach is recommended for subtractive prostatectomy.

For patients with metastases that will lead to urgent complications such as spinal cord compression and pathologic fractures, surgery or radiation therapy to the metastatic site may be considered with adequate communication with the patient and family, based on a full assessment of the benefits and harms of treatment.

Sixth: Treatment of CRPC

(a) Definition of CRPC.

CRPC is a condition in which testosterone reaches a depressed level (＜ 50 ng/dl or 1.7 nmol/L), the presence of 1.7 nmol/L for the following conditions New Roman”>1 species.

style=”margin-left: 57pt”>
• interval 1 week or more consecutively 3 3 several PSA increases, with 2 increases in PSA
  

low point 50% or more, and PSA> 2 ng/ml.

• imaging progression: the presence of new lesions, including bone scans suggestive of 2 or more new bone metastases, or A new soft tissue lesion evaluated using clinical outcome evaluation criteria for solid tumors. Symptomatic progression alone is not diagnostic of CRPC and further evaluation is required.
  

  Key to diagnosing CRPC 2 points: (1) whether testosterone is at depleted levels.

  (2) Whether the disease continues to progress after the depot condition is reached.

  (2) Asymptomatic nonmetastatic desmoplastic-resistant prostate cancer.

  A diagnosis of non-metastatic castration-resistant prostate cancer (non-metastatic castration-resistant prostate cancer, is made when the following conditions are met span style=”font-family:Times New Roman”>nmCRPC): 1) serum testosterone maintained below the depressed level: i.e. serum testosterone level <50ng/dl or 1.7 nmol/L; (ii) PSA progression: PSA value > 2ng/ml at intervals of 1 < /span>weeks, with >3 consecutive elevations >50% from basal; (iii) conventional imaging including CT, MRI and bone scan did not reveal distant metastases. Patients with nmCRPC , especially PSA multiplication times in within 10 months, are prone to metastasis and eventual patient death during disease progression. Therefore, in the nmCRPC phase, if the time to mCRPC can be delayed, it will ultimately prolong the patient s overall survival time.

  The latest 3 clinical studies on nmCRPC changes the current mCRPC study. style=”font-family:Times New Roman”>nmCRPC patients from the current standard treatment regimen. The SPARTAN (apatamide) study, the PROSPER (enzalutamide) study, and the ARAMIS (dalostamide) study, all of which had metastasis-free survival time as the primary study endpoint and studied patient populations with PSA The study population was patients with a doubling time of 10 months, of which 2/3 patients had a doubling time of less than 6 months. All 3 studies showed a significant benefit in metastasis-free survival time, with median survival times in the treatment versus placebo groups of SPARTAN (abata

AMINE) study 40.5 months versus 16.2 months; PROSPER (enzalutamide) study

• months versus 14.7 months;ARAMIS< span style="font-family:Arial">(Darotrimide) study 40.4 months and < /span>18.4 months. Based on the results of the above study, for patients with nmCRPC at higher risk of metastasis (PSA doubling time 10 < span style="font-family:Arial">within 10 months), it is recommended that on top of ADT Apatamide and enzalutamide have been described earlier and will not be repeated here. Darotamide is a novel nonsteroidal androgen receptor inhibitor with a unique molecular structure and pharmacokinetic properties compared to the other two novel androgen receptor inhibitors. It has a high affinity for androgen receptors, a low affinity for the neurotransmitter γ-aminobutyric acid, a low blood-brain barrier permeability, a low impact on metabolic enzymes in vivo, and a low potential for drug interactions.

  (ii) Treatment of mCRPC.

  style=”margin-left: 46pt”>
  • Maintenance depot therapy
    

  Prostate cancer eventually enters the CRPC stage with only 2 studies have demonstrated a relatively modest survival benefit of maintaining denervation in second- and third-line therapy. However, in the absence of prospective studies, the potential benefits of maintenance denervation outweigh the potential risks of treatment, and all current clinical studies are based on the level of maintenance denervation, so it should be maintained in this patient population.

  style=”margin-left: 46pt”>
  • New Endocrine Drug Therapy
    

  Abiraterone: COU-AA-302 The study enrolled previously chemotherapy-naïve mCRPC patients who had not received prior chemotherapy. The results showed that abiraterone significantly prolonged median image-free progression time (16.5 versus 8.2 months) and median survival time (34.7 versus 30.3
  

months). In addition, abiraterone can slow pain progression and delay chemotherapy and opioid use.

Enzalutamide: PREVAIL The study also included patients who had not received prior chemotherapy and who had not received prior chemotherapy. style=”font-family:Times New Roman”>mCRPC patients who had not received prior chemotherapy. The study crossed over patients in the placebo group after data unblinding, and 5 year long-term follow-up showed that enzalutamide significantly prolonged patient survival (36 versus 31 months), with a reduced risk of death of 17%, in < span style="font-family:Times New Roman">well-tolerated in people over 75 years of age.

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• Chemotherapy
  

Docetaxel-based chemotherapy is also one of the standard treatment regimens for mCRPC. This regimen is based on the results of the TAX327 study. The TAX327 study compared docetaxel (dosing every 3 weeks or weekly 1 times) + prednisone versus mitoxantrone + prednisone with different therapeutic effects. Docetaxel achieved a higher median overall survival time compared with mitoxantrone (18.9 versus 16.5 months). This survival benefit was maintained during the extended follow-up period. Of course the mitoxantrone + prednisone regimen is also an effective treatment option to control disease progression to some extent and improve quality of life, especially in terms of pain relief. It can therefore be used in patients who are intolerant to docetaxel or who have failed treatment.

Cabazitaxel is a semi-combined purpurenine derivative. III phase

The results of the FIRSTANA study showed that cabazitaxel was effective in chemotherapy-naïve mCRPC patients with clinical relevance. The median survival times for the cabazitaxel and docetaxel regimens were similar, at 24.5 months and 24.3 months, respectively. months. Cabazitaxel has a lower rate of peripheral neuropathy compared with docetaxel. Therefore, it is not suitable for docetaxel

Patients treated with docetaxel regimens or who already have mild peripheral neuropathy may be considered for cabazitaxel regimens.

style=”margin-left: 57pt”>
• Tumor vaccines
  

2010 April , Sipuleucel-T was the first novel tumor immunotherapy drug to receive FDA approval. This autologous tumor “vaccine, “, involves collecting white blood cells containing antigen-presenting cells from each patient and exposing these These cells were exposed to proliferative acid phosphatase granulocyte macrophage colony-stimulating factor and then re-infused. The Phase III multicenter randomized double-blind clinical trial of Sipuleucel-T (D9902B) showed that the median survival time in the Sipuleucel-T treatment group was 25.8 months and 21.7 months in the control group. Sipuleucel-T treatment reduced the risk of death by 22%.

style=”margin-left: 57pt”>
• PI3K/Akt Access Inhibitors Ipatasertib
  

Ipatasertib is a pathway inhibitor

Ipatasertib is a PI3K/Akt pathway inhibitor. PTEN deficiency occurs in mCRPC patients at a rate of approximately 40% to 50%, and PTEN deficiency leads to Akt pathway activation and poor prognosis for patients. IPATential150 is a test to evaluate Ipatasertib in combination with abiraterone for efficacy and safety of mCRPC in asymptomatic or mildly symptomatic Phase III randomized double-blind study. Median imaging disease-free survival time in PTEN deficient patients with Ipatasertib+ A BitTorrent group was

18.5 months in the abiraterone alone group and 16.5 months. The incidence of adverse reactions was 40% and 23%, respectively, and the discontinuation rate due to adverse reactions in the two groups was < span style="font-family:Times New Roman">21% and 5%. Long-term survival time data need to be further validated.

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• mCRPC of second-line treatment
  

• Cabazitaxel:2010 YearJune ,FDA approved cabazitaxel for mCRPC patients who have failed docetaxel chemotherapy. In an internationalphase III randomized clinical trial (TROPIC), compared with the mitoxantrone group, the median in the cabazitaxel group
  

  Total survival was prolonged by 2.4 months.

  For patients who failed docetaxel and failed one of the new endocrine therapies (abiraterone or enzalutamide), cabazitaxel also had a therapeutic effect. The Phase III randomized placebo-controlled trial, the CARD study, evaluated cabazitaxel after failure of docetaxel and abiraterone or enzalutamide. The results showed that the cabazitaxel-treated group had a nearly 1-fold longer time to disease progression-free imaging and a 36% lower risk of death.

• Abiraterone:2011 Year4 in Aprilthe FDAapproved abiraterone in combination with low-dose prednisone for the treatment of patients with mCRPC who have failed docetaxel treatment, based on a =”font-family:Yu Gothic UI”>IIIphase randomized placebo-controlled clinical trial
  

  (COU-AA-301) results. The median survival time was 15.8 months versus 11.2 months in the abiraterone and placebo groups, respectively. The abiraterone group also showed improvements in time to imaging progression, degree of PSA decline, and pain relief.

• Enzalutamide:2012 2012 8 in August the FDAapproved enzalutamide for the treatment of docetaxel treatment-naïve mCRPC patients, based on a Phase IIIrandomized placebo-controlled trial (AFFIRM< span style="font-family:Arial">) results. In the enzalutamide and placebo groups
  

  The median survival time was 18.4 months and 13.6 months, respectively. In different subgroups, including patients with visceral metastases, there was a benefit in survival time.

• Radium-223:Radium-223 is among the alphaparticle-targeted therapeutics that are currently the only drugs that can CRPC with bone metastases is the only nuclear therapy drug that can improve survival in patients with CRPC .
  

Radium -The results of the 223Phase III clinical study (ALSYMPCA) suggest that the treatment group is more effective than the

significantly improved the overall survival time of patients with mCRPC bone metastases who failed chemotherapy or were intolerant to chemotherapy in the placebo group (14.9 months) than 11.3 months) and significantly delayed symptomatic skeletal events (SSE) (15.6 compared with 9.8 months). Radium -223 was well tolerated, with a lower proportion of patients in the radium -223 group compared with the placebo group experiencing all grades of treatment-related The proportion of patients with treatment-related adverse events was lower. The results of a safety study with follow-up of up to 3 years confirmed the favorable long-term safety profile of radium -223 , with follow-up patients having The incidence of bone marrow suppression (all grades) was ≤3%. Compared with placebo radium -223 improved patients’ quality of life (QoL), and patients receiving radium -223-treated patients with EQ-5D utility score improvement and FACT-P significantly higher percentages of total score improvement. A large amount of real-world data (PARABO, ROTOR, iEAP, FLATIRON, REASSURE and other studies) have validated the overall survival benefit of radium -223 treatment of mCRPC bone metastases in patients with mCRPC bone metastases and the impact on patient survival. Patients’ overall survival benefit and improvement in patients’ quality of life.

• radiopharmaceuticals with beta particles: for patients with extensive metastases, the use of emissionbetaparticle radiopharmaceuticals are also a treatment option for patients with extensive metastases, especially when such patients are not candidates for effective chemotherapy. The most commonly used radiopharmaceuticals for the treatment of painful bone metastases from prostate cancer include strontium-89 and samarium. “font-family:Times New Roman”>-153. Since such patients often have multifocal bone pain, this radioactive systemic targeted therapy can provide pain relief. However, with radiumαparticles that emit -223 differs from the current radioactiveβparticle therapy has no survival benefit and can only be used as palliative treatment with a high incidence of myelosuppression, which may interfere with subsequent systemic therapy.
  

  (6 )Poly(adenosine diphosphate) ribonuclease [poly( adenosine diphosphate ribose) polymerase, PARP] inhibitor: PARP is the inhibitor of survival

A multifunctional protein post-translational modifying enzyme in most eukaryotic cells. It is activated by recognition of structurally damaged DNA fragments and is considered a receptor for DNA damage. It also performs polyadenosine diphosphate ribosylation of many nuclear proteins. Proteins modified by it are histones, RNA polymerase, DNA polymerase, DNA ligase, etc., and detachment of histones by adenosine diphosphate ribosylation of histones, which contributes to the binding of repair proteins for DNA damage repair. At the same time, PARP is a cleavage substrate for cystatin protease, a core member of apoptosis. Therefore, it plays an important role in DNA damage repair and apoptosis. PARP inhibitors are used to treat tumor cells by inhibiting DNA damage repair and promoting apoptosis in tumor cells. tumors. PROfound is a prospective and

multicenter, randomized, Phase III clinical trial to evaluate PARP inhibitor ola

PARPARP treatment in mCRPC patients who were previously treated with enzalutamide or abiraterone who had disease progression and who carried BRCA1/2 mutations, ATM mutations (< span style="font-family:Times New Roman">HRR mutation subgroup), or HRR signaling pathway in the mutations in any of the 12 genes. The results of the study showed that olaparib reduced the risk of disease progression or death by 66%, with a median progression-free survival time of 7.4 months compared with 3.6 months for enzalutamide or abiraterone.

Overall survival was extended to 19.0 months compared with 19.0 months for enzalutamide or abiraterone.

14.6 months.

Efficacy of olaparib in combination with abiraterone versus abiraterone alone in patients with mCRPC < span style="font-family:Times New Roman">PROPEL Phase III clinical trial (NCT01972217) is now initiated. Trials to assess the safety of pablizumab in combination with olaparib in patients with mCRPC not treated with docetaxel are still ongoing

( NCT02861573). In addition, several other PARP inhibitors, such as lucaparib, niraparib, and Talazoparib are The safety and efficacy in treating patients with mCRPC is also being studied.

• PSMARelated Therapeutic Radiopharmaceuticals:PSMA Related Therapeutic Radiopharmaceuticals The main therapeutic radiopharmaceutical is 177Lu-PSMA-617, which has been used internationally since “font-family:Times New Roman”>treated its first patient in 2014 , but the primary source of data was only from the same medical center.
  

  A recent Phase II study compared 177Lu-PSMA with cabazitaxel for the treatment of novel

  endocrine drugs and docetaxel in mCRPC patients after treatment. The primary study endpoint proportion of PSA decreased by 50% or more in patients with Lu-PSMA group has a significant advantage, and long-term follow-up data remain to be further investigated.

• Immunotherapy:FDA approves PD-1< span style="font-family:Arial">inhibitor pablizumab for the treatment of mismatch repair defects detected and highly unstable microsatellitesmCRPC =”font-family:Arial”>patients. 2020 Year ASCO announced KEYNOTE-199 results from a Phase II clinical trial that included patients with measurable lesions that were PD-L1 positive,PD-L1 negative and not considered PD-L1 status for bone metastases only 258 patients with mCRPC , three cohorts were enrolled separately . span>133 cases,66 66 cases and 59 cases of patients. The disease control rate for cohort 1 was 10% and cohort 2 is 9%, the queue is 3 is 22%. The median overall survival time for cohort 1 was 9.5 months, cohort 2 for 7.9 months, cohort “font-family:Times New Roman”>3 for 14.1 months. In addition, pablizumab in combination with enzalutamide for abiraterone treatment
  

  after failure of mCRPC of KEYNOTE-365 Ⅰb/Phase II clinical trials have also shown

  Better tolerability and tumor response rates.

  Published in 2020 Navulizumab in combination with Ipilimumab for docetaxel before /chemotherapy Phase II clinical trial of mCRPC progressing after chemotherapy

(CheckMate650) results suggest that patients treated with the combination directly without chemotherapy are more likely to be treated with the combination than those treated with chemotherapy followed by the combination. Patients treated with chemotherapy followed by the combination were followed up for 11.9 months and

13.5 months, respectively, with objective response rates of 25% and 10%, respectively, with overall survival times of 19.0 months and 15.2 months. PD-L1≥1%, presence of DNA damage repair, the presence of homologous recombination defects, or high tumor mutational load had higher objective response rates.

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• mCRPCPatients’ Bone Health-Related Medications
  

In a multicenter study, 643 cases of asymptomatic or mild risk symptoms of bone metastases mCRPC patients were randomized to receive intravenous zoledronic acid or placebo once every 3 weeks. At month 15 , significantly fewer patients in the zoledronic acid 4 mg group had bone-related events than in the placebo group (4 mg). span style=”font-family:Times New Roman”>33% versus 44%). The updated report at 24 months showed a significant increase in median time to first bone-related event (488 days versus < span style="font-family:Times New Roman">321 days). No significant differences were found in overall survival time. Other bisphosphonates have not been shown to be effective in preventing disease-related bone complications.

Nuclear factor κB ligand () receptor activator of nuclear factor κB ligand, RANKL, RANKL) receptor activator is an osteoclast-expressed RANK binding cytokine that is a key signaling molecule for maintaining skeletal integrity. Denosumab, a monoclonal antibody against RANKL, has been shown to be superior to zoledronic acid in preventing bone-related events and delaying the time to first bone-related event. A randomized, double-blind, placebo-controlled study compared the efficacy of denosumab with zoledronic acid in patients with mCRPC. The absolute incidence of bone-related events was similar in both groups; however, the median time to first bone-related event was delayed by 3.6 months in the denosumab group compared with the zoledronic acid group (20.7 months vs. 17.1 months).

Treatment-related toxicities reported for zoledronic acid and denosumab were similar, including hypocalcemia (more common with denosumab, 13%) and hypocalcemia (more common with denosumab, 13%). vs 6%), arthralgia, and osteonecrosis of the jaw (incidence 1% to 2%).

Attachments

Prostate Cancer Treatment Guidelines (2022 Edition) Validation Panel

(in surname stroke order)

Team leader.

Members: Wang Linhui, Ye Dingwei, Xing Nianzeng, Liu Yueping, Guan Youyan, Li Changling, Li Hanzhong, Yang Lin, He Qun, Zhang Yi, Zhang Qian, Chen Min, Zhou Liqun, Zheng Rong, Gao Xin