National guidelines for diagnosis and treatment of prostate cancer 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Etiology

2.1 A ge and genetic factors

2.2 Exogenous factors

3.Pathological classification and grading system

3.1 Pathological grading and grouping of prostate cancer

3.2 Staging of prostate cancer

3.3 Risk grouping for patients with local or locally advanced prostate cancer

4.Diagnostic evaluation

4.1 Monitoring,screening and early diagnosis

4.2 Genetic testing

4.2.1 Providing genetic counseling and evaluating whether genetic testing is necessary

4.2.2 Treatment decision

4.3 Clinical diagnostic methods

4.3.1 DRE

4.3.2 MRI

4.3.3 Positron emission tomography-CT (PET-CT)

4.3.4 Prostate biopsy

5.Treatment of prostate cancer

5.1 Watchful waiting and active surveillance

5.2 Radical prostatectomy

5.2.1 Low-risk prostate cancer

5.2.2 Intermediate-risk prostate cancer

5.2.3 High-risk prostate cancer

5.2.4 Indications for nerve sparing surgery

5.2.5 PLND

5.2.6 Adjuvant therapy after radical prostatectomy

5.3 External radiotherapy

5.3.1 Indications for radical EBRT

5.3.2 Complications of EBRT for prostate cancer

5.3.3 Surgical treatment of biochemical recurrence after radiotherapy

5.3.4 Current situation and development of radiotherapy technology

5.4 Brachytherapy for prostate cancer

5.5 Proton therapy

5.6 Other treatments for localized prostate cancer

6.Treatment of metastatic prostate cancer

6.1 ADT

6.2 Combination therapy of ADT and other drugs

6.2.1 ADT with chemotherapy

6.2.2 ADT with abiraterone plus prednisone

6.2.3 ADT with enzalutamide

6.2.4 ADT with apalutamide

6.2.5 ADT with bicalutamide or flutamide

6.3 Local treatment of metastatic prostate cancer for primary and metastatic lesions

7.Treatment of CRPC

7.1 Definition of CRPC

7.2 Treatment of asymptomatic non-mCRPC (nmCRPC)

7.3 Treatment of mCRPC

7.3.1 Castration maintained treatment

7.3.2 New hormonal therapy in mCRPC

7.3.3 Chemotherapy

7.3.4 Tumor vaccine

7.3.5 PI3k/Akt pathway inhibitor ipatasertib

7.3.6 Second-line treatment of mCRPC

7.3.7 Skeleton health-related drugs for mCRPC patients

1.Overview

Prostate cancer is one of the most common malignancies in male genitourinary system.The 2020 edition of the Global Cancer Statistical Report published by the World Health Organization (WHO) International Agency for Research on Cancer in February 2021 shows that there were 1,414,259 new cases of prostate cancer worldwide in 2020,accounting for 7.3% of malignancies.The incidence rate is ranking third only after breast cancer and lung cancer;There were 375,304 deaths in 2020,accounting for 3.8% of malignant tumors,and ranks 8th in the mortality rate.In January 2019,the National Cancer Center announced the latest morbidity and mortality of malignant tumors in China in 2015.There were 72,000 new cases of prostate cancer,and the incidence rate was 10.23/100,000,ranking sixth among male malignant tumors.There were 31,000 deaths with the mortality rate of 4.36/100,000,and ranks 10th in male malignant tumors.The incidence of prostate cancer has obvious geographical and racial differences globally.Australia/New Zealand,North America and Europe have the highest incidence rate of more than 85/100,000;whereas Asia the lowest of 4.5/100,000?10.5/100,000.Although the incidence of prostate cancer is much lower in China than in Europe and America,however it has been increased in recent years.The reasons could be:aging population,change of lifestyles,and popularization and application of prostate cancer screening methods such as prostate-specific antigen (PSA).Another feature of prostate cancer in China is that the incidence is significantly higher in urban areas than in rural areas.In 2015,the incidence was 13.44/100,000 in urban areas and 6.17/100,000 in rural areas.

2.Etiology

The etiology and pathogenesis of prostate cancer are very complicated,and the exact cause is still unclear.Etiology studies show that prostate cancer is closely related to heredity,age and exogenous factors including environmental factors and diet habits.

2.1 A ge and genetic factors

The incidence of prostate cancer varies greatly among different races with the highest in African-American,secondly in whites,and the lowest in Asians,which suggests that genetic factors are one of the most important factors in the pathogenesis.Epidemiological studies have shown that if an immediate family member (brother or father)developed prostate cancer,the risk of prostate cancer would be more than double.If two or more close family members were affected,the risk could increase by 5?11 times.It is also associated with disease onset 6?7 years earlier than average.A US study showed that 15.6% of prostate cancer patients were found to have germline pathogenic variants(BRCA1,BRCA2,HOXB13,MLH1,MSH2,PMS2,MSH6,

EPCAM,ATM,CHEK2,NBNandTP53),while 10.9% of whom had germline pathogenic mutation in DNA repair genes such asBRCA2(4.5%),CHEK2(2.2%),ATM(1.8%)andBRCA1(1.1%).Prostate cancers with Gleason grade rated 8 or higher are strongly associated with mutation in DNA repair gene.

The incidence rate increases with aging,and the highest incidence is at the age of 65?80 years old.

2.2 Exogenous factors

Epidemiological data show that the incidence of prostate cancer in Asian-American populations will increase significantly after moving to the United States,implying an exogenous factors associated with geographical environment and dietary habits.Currently,exogenous risk factors for prostate cancer are still under study,and some are subject to debate.High alcohol intake has been associated with higher risk of prostate cancer and also associated with prostate-specific mortality.Both over-lowand over-high vitamin-D levels are associated with pathogenesis of prostate cancer,especially for high-grade disease.UV exposure may reduce the incidence of prostate cancer.Study found that vitamin E and selenium did not affect the incidence of prostate cancer.In hypogonadism patients,androgen supplementation did not increase the risk of prostate cancer.To date,there is no clear drug intervention or dietary approach to prevent prostate cancer.

3.Pathological classification and grading system

Seventy percent of prostate cancer occurs in the peripheral zone of the prostate and 15%?25% originates in the transition zone,the remaining 5%?10% in the central zone;85% of prostate cancer are characterized by multifocal growth.In the Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs published by WHO in 2016 characterize prostate cancer by pathological types.They include:adenocarcinoma (alveolar adenocarcinoma),intraductal carcinoma,ductal adenocarcinoma,urothelial carcinoma,squamous cell carcinoma,basal cell carcinoma,neuroendocrine tumors,etc.Among them,prostate adenocarcinoma accounts for the main part,so we usually refer to prostate cancer as prostate adenocarcinoma.

3.1 Pathological grading and grouping of prostate cancer

Gleason score is recommended for pathological grading of prostate adenocarcinoma.The score system divides the tissue into primary and secondary grading level,each of which consists of 5 levels.The degree of differentiation is measured by total score which is the sum of two scores.The Gleason score is currently the most widely used method for grading prostate adenocarcinoma.After several revisions since it released in 2004,new WHO classification described in detail as follows:1) Gleason score 2?5 is not suitable for evaluation of trucut biopsy,and should be used in caution when evaluating other samples from other source;2) sieve glands are classified as Gleason 4;3) if gland is glomerular structure,then the grading should be 4;4) the grading of mucinous adenocarcinoma should be judged according to its growth pattern,it should not simply graded as Gleason 4;5) beside sieve glands and glomerular structure,some poorly differentiated and fused glands should be graded as Gleason 4;6) comedo necrosis is graded as Gleason 5;7) ductal adenocarcinoma in the form of sieve and papillary should be Gleason 4,prostate intraepithelial neoplasia (PIN)-like ductal adenocarcinoma is graded as Gleason grade 3,and graded as Gleason 5 if there is necrosis;8) in high-grade adenocarcinoma,the low-grade component can be ignored if it is ＜5%.In contrast,if high-level component exists in biopsy specimen,then it should be included in the score regardless of its proportion;In the radical specimen,if more than 5% of Gleason grading 5 components were found in tissues with the Gleason score of 7 (4+3) according to the previous standard,the final score should be Gleason 9 (4+5);and 9)listing the proportion of Gleason grade 4 components are recommended for a diagnosis of a Gleason score of 7 in both needle biopsy and radical specimens because it is related to the patient’s treatment strategy.

The new published WHO grade group system for prostate cancer is based on the new grading system proposed at the 2014 International Society of Urological Pathology (ISUP) Consensus Conference,named the Prostate Cancer Grade Group system (also called ISUP grade).The ISUP system divides prostate cancer into five different groups according to combination of Gleason score since these five different combinations indicate different aggressiveness of the disease:

1) ISUP grade 1:Gleason score ≤6,consisting of only the single isolated,well-formed gland;

2) ISUP grade 2:Gleason score 3+4=7,consists of morphologically intact glands with lesser dysmorphic/fused/cribriform glands;

3) ISUP grade 3:Gleason score 4+3=7,consists of dysplastic glands/fused/cribriform glands with few wellformed glands;

4) ISUP grade 4:Gleason score 4+4=8,3+5=8 and 5+3=8,consists of poor developed glandular/fused glands/cribriform gland;or predominantly well-formed glands with a small amount of poorly differentiated glands;or predominantly poorly differentiated glands with few wellformed glands;

5) ISUP grade 5:Gleason score 9?10,absence of gland structures (or with necrosis),with or without dysplasia gland morphology/fused glands/cribriform glands.

3.2 Staging of prostate cancer

The most common staging system for prostate cancer is TNM stage system developed by the American Joint Committee on Cancer (AJCC),and the 8th edition was adopted in 2018.The purpose of staging is to guide the treatment and to evaluate prognosis.Clinical and pathological staging is mainly determined by digital rectal examination (DRE),PSA,the number and positive location and needles in needle biopsy,radionuclide whole-body bone imaging,prostate magnetic resonance examination(MRI) or computed tomography (CT),and lymph node dissection.

T staging:Indicating the local condition of the primary tumor through DRE,prostate MRI,the number and location of positive prostate biopsy.

N staging:Indicating the situation of regional lymph nodes through CT,MRI and ultrasonography.The probability of lymph node metastasis in patients with clinical stage lower than T2,PSA＜20 ng/mL and Gleason score ＜6 is less than 10%.Pelvic lymph node dissection(PLND) by open surgery or laparoscopy can accurately understand lymph node metastasis from pathology.

M staging:Indicating whether there is distant metastasis including metastases to lymph nodes outside the pelvis,bone metastases or metastases to other organs.Radionuclide whole-body bone scan is the main method for the diagnosis of bone metastases.Bone scan should be performed on prostate cancer patients with Gleason score＞7 or PSA＞20 ng/mL.X-ray examination,MRI or/and CT can be chosen to confirm the diagnosis when bone scan finds suspicious bone lesions.

Table 1shows the TNM staging system for prostate cancer.

Table 1 TNM staging system for prostate cancer

3.3 Risk grouping for patients with local or locally advanced prostate cancer

Currently,risk classification system from European Society of Urology for local or locally advanced prostate cancer is widely used in the world.The system is based on theD’Amico classification system,which based on the risk of biochemical recurrence in patients who have received radical prostatectomy or external radiotherapy.

(1) Low-risk group:PSA＜10 ng/mL,Gleason score ＜7(ISUP grade 1),clinical stage cT1?T2a.

(2) Medium-risk group:PSA 10?20 ng/mL,Gleason score 7 (ISUP grade 2/3),or clinical stage cT2b.

(3) High-risk group:PSA＞20 ng/mL,Gleason score ＞7(ISUP grade 4/5),clinical stage cT2c.

(4) High-risk group with local late stage:any PSA,any Gleason score,CT3?T4,or lymph node metastasis.

In addition,the prostate cancer guidelines of the national comprehensive cancer network of the United States also have similar risk classification standards,which are more detailed and graded.The purpose is to select different treatment protocols through more detailed patient stratification.

(1) Extremely low risk:T1c,Gleason score ≤ 6/ISUP 1,PSA＜10 ng/mL,the number of positive prostate needles biopsy is ＜3,cancer focus on each needle ≤50%,PSA density ＜0.15 ng/(mL·g).

(2) Low risk:T1?T2a,Gleason score ≤ 6/ISUP 1,PSA＜10 ng/mL.

(3) Moderate preference:T2b?T2C,or Gleason score 3+4=7/ISUP 2,or PSA 10?20 ng/mL,but the number of positive prostate needles biopsy is less than 50%.

(4) Moderate deviation:T2b?T2C,or Gleason score 3+4=7/ISUP 2,or Gleason score 4+3=7/ISUP 3,or PSA 10?20 ng/mL.

(5) High risk:T3a,or Gleason score 8/ISUP 4,or Gleason score 9?10/ISUP 5,or PSA＞20 ng/mL.

(6) Extremely high risk:T3b?T4,Gleason score 5 in main grading area.Or there are 4 or more needle biopsies with Gleason score of 8?10/ISUP 4 or 5.

4.Diagnostic evaluation

4.1 Monitoring,screening and early diagnosis

Screening for prostate cancer has been widely carried out in Western countries.The reduced mortality rate recently in the USA is considered as partly due to a widely adopted aggressive prostate cancer screening policy.As more prostate cancers are discovered and treated,the proportion of early prostate cancer is increasing;it might be associated with minor over-diagnosis and over-treatment.Therefore,screening based on the entire population remains a controversy in Western nations.Some policy guidelines may be diametrically opposed.However,since there has been no large-scale screening in China,a considerable number of highly invasive or advanced prostate cancers may exist in the population.Therefore,prostate cancer screening is necessary currently in China.

PSA-based prostate cancer screening is recommended for well-informed males over 50 years old,or older than 45 years of age with a family history of prostate cancer.

PSA is a single-chain glycoprotein with serine protease activity secreted by prostate acinar and ductal epithelial cells.It is mostly found in semen and participates in the liquefaction process of semen.PSA is mainly confined to prostate tissues and maintains a low serum level under normal condition.Two forms of PSA exist in serum,10%?40% are free PSA (f-PSA);60%?90% of them combine with α1-anti chymotrypsin,a small amount with α-2-macroglobulin,both form complex PSA.The sum of f-PSA and complexed PSA refers to as total serum PSA(t-PSA).Serum PSA will increase when cancerous cells destroy normal tissues,causing large amount of PSA enters the blood.The half-life of PSA is 2?3 d.

PSA result assessment:t-PSA＞4 ng/mL is considered abnormal.Patients with abnormal PSA at first time need follow up.The level of serum PSA was affected by age and prostate size.

The f-PSA had certain auxiliary diagnostic value when the t-PSA was 4?10 ng/mL.Free serum PSA level is negatively correlated with the occurrence of prostate cancer,when total f-PSA/t-PSA＜0.1,the probability of prostate cancer is 56%.When f-PSA/t-PSA＞0.25,the probability is only 8%.In China,f-PSA/t-PSA＞0.16 is recommended as the normal reference value.If the total PSA level is 4?10 ng/mL,and f-PSA/t-PSA＜0.16,prostate biopsy should be recommended.

In addition,the PSA density was calculated when prostate volume was measured by ultrasound or other methods.The greater the PSA density,the greater the possibility of clinically significant prostate cancer.PSA velocity and PSA doubling time can also be calculated from PSA values at different times.These two indicators have a certain role in judging the prognosis.However,due to interfering factors,the significance is relatively small at initial stage of diagnosis.

Since PSA shows a poor specificity,researchers have long been searching for new prostate cancer-specific markers.In recent years,PSA isomer 2 (p2PSA) and its derivatives,as well as prostate health index (PHI) and other evaluation indicators have gradually attracted attention.The results suggest that p2PSA is associated with prostate cancer and high-grade disease.PHI has outperformed t-PSA in the diagnosis of prostate cancer,especially with t-PSA between 4?10 ng/mL,which can reduce the number of unnecessary prostate biopsy.PHI is calculated by t-PSA,f-PSA and p2PSA in the following formula:PHI=p2PSA/f-PSA×

In addition,four kallikrein fractions were determined by jointly measuring total PSA,f-PSA/t-PSA,intact PSA and kallikrein like peptidase,and with taking the patient’s age,DRE and previous puncture results into account.The purpose was to reduce unnecessary prostate puncture biopsy.

4.2 Genetic testing

More evidences support that gene detection plays a very important role in the early diagnosis and comprehensive treatment of advanced prostate cancer.Based on the consensus of the latest guidelines at home and abroad,domestic experts have reached a certain consensus to further standardize and guide the object,content,technology,data processing and interpretation of prostate cancer gene testing.It is recommended that willing subjects undergo genetic testing to guide treatment decisions or genetic counseling.The characteristics of gene mutation in different conditions and treatment stages are different.Based on the clinical practice and current situation on drug research and development,it is recommended that the second generation sequencing technology be used for gene mutation detection.

4.2.1 Providing genetic counseling and evaluating whether genetic testing is necessary

Evaluating the need for genetic testing should be in conjunction with family history,clinical and pathological features.Following family history should be considered:1)whether there are any immediate relatives such as brothers,fathers or other family members diagnosed with prostate cancer or died of prostate cancer before the age of 60 years old;2) whether there are 3 or more patients in the same family members diagnosed with cancers including cholangiocarcinoma,breast cancer,pancreatic cancer,prostate cancer,ovarian cancer,colorectal cancer,endometrial cancer,gastric cancer,renal cancer,melanoma,small bowel cancer and urothelial cancer,especially the age of diagnosis ≤50 years old;3) whether the patient has a history of male breast cancer or pancreatic cancer;and 4)whether family member carry related germline pathogenic gene mutations.Carriers ofBRCA1/2mutations have an increased risk of prostate cancer before the age of 65 years,especially those withBRCA2germline mutations have a higher risk of early prostate cancer onset and death.For prostate cancer patients with very low to intermediate risk without risk assessment at the initial diagnosis,family history and genetic counseling are necessary before nextgeneration sequencing (NGS) testing:for those patients with clear related family history,or carrying germline pathogenic gene mutations in family member,detection of germline mutations on DNA-repair genes (especiallyBRCA2,BRCA1,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6,PMS2) is recommended.For patients with unknown family history,genetic counseling in combination with clinical characteristics are necessary to determine whether relevant tests are necessary.For patients with high risk,extremely high risk,local progression and with metastatic prostate cancer,detection of germline mutations of DNA repair genes (especiallyBRCA2,BRCA1,ATM,PALB2,CHEK2,MLH1,MSH2,MSH6andPMS2) is recommended.

4.2.2 Treatment decision

For all patients with metastatic castration resistant prostate cancer (mCRPC),detection of germline and somatic mutations containing at leastHRRgene is recommended,and instability of microsatellite and defect of DNA mismatch repair gene may also be considered.For patients who have found mutations in genes through tumor tissue testing which is related to the risk of cancer and lack verification of germline mutations,genetic counseling is recommended to decide further testing.

According to the detection purpose,it is necessary to distinguish mutations detection on germline (germline,mutations from parents’ germ cells,which can be inherited to offspring) or somatic (somatic,acquired gene mutations of body cells).The germline mutations can be detected by using the blood (priority),saliva,oral swab,etc.;On the other hand,germline+somatic mutations can be detected in the tumor tissues (fresh tumor tissues,paraffin embedded tissue section,etc.) or circulating tumor DNA(ctDNA).On the basis of tumor tissues or ctDNA detection,verification of germline gene mutations (or germline gene mutation detection) is necessary if required.Due to the existence of somatic mutations (especiallyHRRgene) in prostate cancer patients,germline mutation detection alone is not enough to reflect the actual gene mutation status in the tumor.

4.3 Clinical diagnostic methods

4.3.1 DRE

Prostate cancer much more often occurs in the peripheral zone of prostate.DRE plays an important role on early diagnosis and staging of prostate cancer.The typical manifestation of prostate cancer is palpable hard nodule with unclear boundary and no tenderness.However,no palpable nodules will not exclude the disease.Combined PSA and imaging examination are necessary for comprehensive diagnosis.DRE should be performed after the PSA test since it may squeeze PSA into the blood and affect the accuracy of serum PSA values.

4.3.2 MRI

MRI is one of the most important methods for diagnosing and staging of prostate cancer.Relying on T2-weighted imaging and with contrast-enhanced image,the characteristic manifestations of lesion is weak signal in T2-weighted imaging at peripheral zone of prostate,which are significant different from the normal high signal in the same zone;In addition,tumor areas often show the characteristics of early enhancement.MRI of prostate can show the integrity of the peripheral capsule of prostate cancer,whether it invades the adipose tissue around the prostate,bladder,seminal vesicle and other organs;The accuracy of predicting capsular invasion is 70%?90%,and the accuracy on whether seminal vesicle is invaded is 90%.It can also accurately detect pelvic lymph node and bone metastasis which is important on staging the prostate cancer.Multi-parameter megnetic resonance imaging(mpMRI) is more used in the diagnosis and staging of prostate cancer.mpMRI includes T2-weighted images,diffusion weighted images and dynamic contrast enhancement images.In addition,high-quality mpMRI requires 3.0T field strength.The need for an intrarectal coil is still controversial.mpMRI is used at different stages in the diagnosis and treatment of prostate cancer.mpMRI is useful for detecting large,poorly differentiated cancers(ie,Gleason score ≥7/ISUP＞2).It has been incorporated into the MRI/ultrasound fusion targeted biopsy protocol,which could diagnose high-grade cancers with fewer needle biopsy and reduce the detection of lower-grade and clinically non-significant cancers.mpMRI is also helpful in detecting whether or not the extra-capsular is invaded(stage T),and has high negative predictive value for lowrisk patients.The result may provide information on decision-making on nerve-sparing radical prostatectomy.mpMRI is equivalent to CT on pelvic lymph node evaluation.And,mpMRI is superior to bone scan with 98%?100% of sensitivity and 98%?100% of specificity when detecting bone metastasis.

Magnetic resonance spectroscopy (MRS) detects different spectral lines in prostate cancer tissues caused by metabolism of citrate,choline and creatinine with normal and proliferative prostate tissues.It reflects changes in cell metabolism with added value to conventional MRI,thus serving as reference for early diagnosis of prostate cancer.

4.3.3 Positron emission tomography-CT (PET-CT)

PET-CT uses11C-Choline to detect and distinguish prostate cancer from benign diseases in recent years.The sensitivity and specificity of this technique were 85% and 88%,respectively in biochemical reoccurrence and restaged evaluation.11C-Choline PET-CT may be helpful in detecting distant metastases of prostate cancer.Prostate specific membrane antigen (PSMA) is highly expressed on the surface of prostate cancer cells,which makes it of great research value in the field of molecular imaging and targeted therapy.In particular,the nuclide labeled PSMA molecule inhibitor revealed a promising future in the clinical application on molecular imaging diagnosis.The sensitivity and specificity of68Ga-PSMA PET-CT are 86%and 86%,80% and 97% on cancer lesions.The diagnostic accuracy of68Ga-PSMA PET-CT for prostate cancer is much higher than that of conventional imaging examinations,such as MRI,CT and prostate ultrasound.

4.3.4 Prostate biopsy

(1) Indications for systemic prostate trucut biopsy include:1) suspicious nodules found with DRE at any serum PSA value;2) suspicious lesions found in transrectal ultrasound or MRI at any serum PSA value;3) PSA＞10 ng/mL;and 4)PSA 4?10 ng/mL,with abnormal ratio of f-PSA/t-PSA or PSAD value.And contraindications for prostate trucut biopsy include:1) acute infection of prostate or fever;2)hypertensive crisis;3) decompensated cardiac failure;4)diseases with severe bleeding tendency;5) diabetes mellitus with unstable blood glucose;or 6) serious internal and external hemorrhoids,and perianal rectum or rectal lesions.(2) Routine examination before prostate biopsy:MRI should be performed before prostate biopsy in order to assess the stage of prostate cancer since prostate biopsy could interfere the imaging of MRI.Antibiotic prophylaxis is necessary before transrectal prostate biopsy,and oral or intravenous antibiotics are recommended.Quinolone is the drug of choice,and ciprofloxacin is usually superior to ofloxacin.Increased quinolone resistance is associated with severe post-biopsy infection.However prophylactic antibiotics is not necessary for transperineal biopsy of prostate.

Intestinal preparation:Intestinal enema is routine procedure before transrectal prostate biopsy.Suppositories glycerol instead of enema is recommended before procedure.

Anticoagulation and antiplatelet drugs in perioperative period:for patients with risk of cardiovascular,cerebrovascular diseases and history of stenting with longterm oral anticoagulation or antiplatelet drugs,the risk of bleeding and cardiovascular and cerebrovascular disease should be assessed during the perioperative period.Related drugs should be used with caution.

Number and location of prostate biopsies:eight or more cores are necessary for patients when the volume of prostate is 30?40 mL.The initial baseline cores of 10?12 is recommended.The incidence of complications do not correlate significantly with the number of cores,thus saturated biopsy could be an option.

(3) Repeated systemic prostate biopsy:Repeat prostate biopsy should be considered if first prostate biopsy is negative,while DRE,follow-up PSA or other levels of bioderivatives suggest suspicious prostate cancer.Repeat prostate biopsy should be considered under the following conditions:1) atypical hyperplasia or high-grade PIN is found in the initial pathological biopsy,especially in multicores results;2) repeated serum PSA is still above 10 ng/mL;3) repeated serum PSA 4?10 ng/mL,with abnormal f-PSA,PSAD,DRE or image results.If tranrectal ultrasound (TRUS) or MRI indicates suspicious cancer focus,imaging targeted biopsies of suspicious lesions can be obtained through image fusion technology;and 4) PSA should be examined every 3 months if PSA is 4?10 ng/mL,and f-PSA,PSAD value,DRE and imaging findings are normal,when if PSA＞10 ng/mL for two consecutive times,or PSA velocity is more than 0.75 ng/mL,repeated prostate biopsy is required.

In addition to routine examination,multi-parameter MRI is recommended before repeated prostate biopsy.Targeted biopsy based on multi-parameter MRI can significantly improve the positive rate of repeated prostate biopsy and avoid missing the diagnosis of high-risk prostate cancer.However,the schedule and interval between prostate biopsies are still controversial.The interval of three month or longer is recommended till the tissue structure is fully recovered from previous biopsy.If suspicious lesion is found by MRI before repeated puncture,targeted biopsy based on imaging should be performed.

(4) Limitations and new strategies for systemic prostate biopsies:the major limitations of transrectal or perineal systemic biopsy are false negatives,miss diagnosis of highrisk prostate cancer,or over-diagnosis.Improving the positive rate while avoiding over-diagnosis is a huge challenge in the early diagnosis of prostate cancer.In recent years,prostate biopsy with contrast-enhanced ultrasound,sonoelastography,and mpMRI has shown significant advantages in finding clinically significant prostate cancer and avoiding over-diagnosis.

MRI-guided targeted biopsy can directly extract samples from suspicious lesions and has the highest accuracy.A number of studies have shown that MRI-guided targeted biopsy can improve the detection rate of high-grade prostate cancer during repeated biopsy.However,the procedure is relatively complicated and more expensive to promote.

MRI/TRUS fusion technique combines the position accuracy of MRI with the convenience of TRUS-guided biopsy.It significantly increases the positive rate of prostate biopsy and the chance of discovering clinically significant prostate cancer while avoiding misdiagnosis on none clinical significant lesions.Comparing with MRI,the fusion technique is more convenience.

5.Treatment of prostate cancer

5.1 Watchful waiting and active surveillance

Watchful waiting refers to monitoring the course of prostate cancer in order to provide palliative treatment when symptoms appear,examination results change or PSA indicates that symptoms are about to appear.Therefore,it is different from active surveillance.The purpose of watchful waiting is to maintain life quality for patients by avoiding non-curative treatment when prostate cancer is unlikely to cause death or significant morbidity.The main advantage of watchful waiting is to avoid the possible side effects caused by unnecessary treatment such as androgen deprivation therapy (ADT).It is generally applicable to patients with life expectancy less than 10 years.

Active surveillance includes active and dynamic monitoring the disease process.Hoping that intervention aimed at curative purpose can be taken once tumor progression is found.It is more applicable to low-risk prostate cancer patients with a life expectancy of more than 10 years.The purpose is to delay possible curative treatment without affecting the overall survival (OS) time,so as to reduce possible side-effects caused by these curative treatments.Since these patients have a longer life expectancy,they should be followed closely,including DRE,PSA,mpMRI and repeated prostate biopsy.Once tumor progression is found,curative treatments should be started immediately to avoid missing the chance of cure.

The inclusion criteria of active surveillance include life expectancy of more than 10 years,tumor stage cT1 or cT2,PSA≤10 ng/mL,biopsy Gleason score ≤6,positive biopsy cores ≤2 and proportion of tumor in each core specimen ≤50%.Before conducting active surveillance,patients should be informed about the possibilities that they may undergo radical surgery and radiotherapy at some stages in the future.During the follow-up in active surveillance,DRE(at least once a year),PSA (at least once every six months),mpMRI and repeated prostate biopsy (at least once every 3?5 years) should be performed.Active surveillance should be adjusted to active treatment if the pathology has changed after repeated biopsy,such as value of Gleason score,the number of positive cores or the volume of cancer in each core,and/or the progression of the T stage.When choosing watchful waiting and active surveillance,patients and their family members should be fully informed about the possible benefits and risks for their understanding and cooperation.

5.2 Radical prostatectomy

Radical prostatectomy aims to completely remove the tumor while retaining the urinary continence and erectile function as much as possible.Radical prostatectomy can be performed with open,lapraroscopic or robot-assisted radical prostatectomy (RARP) approaches.RARP may shorten the operation time and reduce intraoperative blood loss.Regardless of the surgical method,for hospitals with a large number of cases per year and experienced surgeons,tumor is better controlled with low risk of positive pathological margin after operation.Pelvic floor muscle exercise before surgery is helpful for the recovery of urinary continence three months after operation.Therapeutic decisions should be made after all treatments have been discussed between multidisciplinary teams(including urologists,radiation oncologists,medical oncologists and radiologists) about the benefits of various treatment methods and possible complications.The effect of endocrine neoadjuvant therapy before radical operation is generally applied for 3 months before operation.There are some randomized controlled studies to explore its effectiveness.Preoperative endocrine neoadjuvant therapy can reduce the incidence of pT3,the incidence of positive margin,and the incidence of positive lymph nodes.The longer the treatment (up to 8 months),the more significant the above benefits.However,since there was no improvement in PSA-free recurrence and tumor-specific survival,the therapy is not a standard clinical practice and can only be carried out in some special populations.

5.2.1 Low-risk prostate cancer

Due to possibility of perioperative complications of radical prostatectomy for low-risk prostate cancer,radical prostatectomy is only applied to patients whose life expectancy is more than 10 years.Some studies have shown that the prostate cancer specific-mortality rate undergoing radical prostatectomy for 15 years is as low as 12%,while 5% for patients with low-risk prostate cancer.

A randomized clinical trial has conducted to compare the effects of radical prostatectomy and watchful waiting on 695 early prostate cancer patients (mostly stage T2).After a median 12.8 years of follow-up,there was a significant improvement in tumor-specific survival,OS,risk of metastasis and local progression in the radical prostatectomy group.Mortality was significantly reduced during the 23-year follow-up,with an absolute difference of 11%.In general,the number needed to treat (NNT) to prevent one death was eight.For patients under 65 years old,the NNT is 4,this finding supports the treatment option of radical prostatectomy for clinically localized prostate cancer,even in patient with low-risk prostate cancer.For low-risk prostate cancer,routine pelvic lymph node dissection is not recommended since the positive rate of pathological pelvic lymph nodes is less than 5%.

5.2.2 Intermediate-risk prostate cancer

A SPCG-4 study showed that for intermediate-risk localized prostate cancer,radical prostatectomy can reduce the total mortality,tumor-specific mortality and distant metastasis rate 18 years after operation.Another PIVOT study showed that radical prostatectomy could reduce the total mortality on 10 years after operation,but did not reduce the tumor-specific mortality.The positive rate of lymph nodes in intermediate-risk prostate cancer ranges from 3.7% to 20.1%.If positive lymph node exceeds 5%,extended lymph node dissection and radical prostatectomy should be performed simultaneously.

5.2.3 High-risk prostate cancer

Although not all high-risk prostate cancer patients have a poor prognosis after radical prostatectomy.These patients usually have a higher risk of PSA recurrence after radical prostatectomy and might need secondary treatment.They also have higher risk of disease metastasis and death.Nevertheless,there is no consensus treatment for those patients.Radical prostatectomy is still a reasonable option.Because the probability of positive pelvic lymph node is 15%?40% in high-risk prostate cancer,radical prostatectomy with extended lymph node dissection should be performed at the same time.

5.2.4 Indications for nerve sparing surgery

Most localized prostate cancer can be treated with nerve sparing radical prostatectomy.There is a clear contraindication for surgery if patients have high risk of extracapsular invasion,such as cT2c or cT3 prostate cancer,or patient with biopsy Gleason score ＞7.Preoperative mpMRI may be helpful in selecting patients.Surgeon should remove the vascular and nerve bundles if residual tumors are found during operation.Intraoperative freezing may be helpful to these decisions.

5.2.5 PLND

Although there is not enough evidence to prove that radical prostatectomy combined with pelvic lymph node dissection can benefit from tumor treatment,it is generally believed that pelvic lymph node dissection can provide important information for staging and prognosis,which nothing else could be matched by any other currently available procedures.The panel recommended the use of a nomogram developed at the Memorial Sloan-Kettering Cancer Center to predict the risk of lymph node metastasis,including pre-treatment PSA,clinical stage and Gleason score.PLND is performed according to the probability of its metastasis.A risk of 2% or 5% is a critical indication to perform extended pelvic lymph node dissection (ePLND).PLND should be performed with ePLND.The scope of the dissection includes:the upper boundary is external iliac vessel,the lateral is pelvic wall,the medial is bladder wall,the lower is the bottom of pelvic,the distal end is the Cooper’s ligament,and the proximal end is the internal iliac artery.Several studies have supported the survival advantage of extended pelvic lymph node dissection,which may be due to the removal of micro-metastases lesion.PLND can be performed by laparoscopy,robot-assisted laparoscopic or open surgery.The rate of complication for these surgical procedures is similar.Studies have shown that for cN0 patient,if PLND in radical prostatectomy confirmed that the N stage is pN1,then 15-year tumorspecific survival and OS rate would be 45% and 42%,respectively.The number of removed pelvic lymph node and positive lymph nodes,tumor volume within the lymph nodes,and capsular perforation of the nodal metastases are predictors of early recurrence after radical prostatectomy for pN1 patients.A lymph node density greater than 20%is associated with poor prognosis.Some studies showed that more positive lymph nodes could be removed by intraoperative injection of indocyanine green.However,there was no difference in biochemical recurrence after 22 months of follow-up.At present,there is no sufficient evidence to support the association between sentinel lymph nodes and tumor control,and sentinel lymph node biopsy is still in the experimental stage.

5.2.6 Adjuvant therapy after radical prostatectomy

The probability of local recurrence after 5 years is as high as 50% after radical prostatectomy for patients with extracapsular invasion of pT3,Gleason score ＞7,and positive incision margin (R1).There are three major RCT studies in the world related to postoperative adjuvant radiotherapy for such patients.The current conclusion is that for pT3 pN0 patients,although the postoperative PSA level is less than 0.1 ng/mL,the risk of local recurrence is higher due to positive margin (the most important factor),perforation of prostate capsule,or invasion of seminal vesicles.There are two options to communicate with patients:1) adjuvant radiotherapy in the surgical area immediately after the recovery of micturition function and 2) close follow-up and salvage radiotherapy when PSA exceeds 0.1 ng/mL.For patients with pN1,the tumorspecific survival rate may reach 80% after radical prostatectomy when combined endocrine therapy is at early stage.This improvement in tumor specific survival and OS has been demonstrated in prospective randomized controlled studies.Postoperative adjuvant radiotherapy may benefit for N1 patients.However,the degree of benefit depends mainly on the characteristics of the tumor,such as positive lymph nodes less than 3?4,Gleason score of 7?10,pT3?4 and positive margin.In a SEER retrospective study,no significant improvement on OS was observed when adjuvant radiotherapy was performed after radical surgery,and tumor-specific survival was not significantly prolonged either.There is no consensus on the extent of adjuvant radiotherapy although whole pelvic radiotherapy is given to most patients.After extended lymph node dissection,temporary observation can be performed for patients with 1?2 microscopic lymph node metastasis,PSA＜0.1 ng/mL and no extranodal invasion.No conclusion is available on adjuvant chemotherapy after radical surgery since it is still on clinical trials.

5.3 External radiotherapy

Similar to radical prostatectomy,external beam radiotherapy (EBRT) is one of the most important radical treatments for prostate cancer.The technique includes three-dimensional conformal radiotherapy (3D-CRT),intensity modulated radiotherapy (IMRT),image guided radiation therapy (IGRT),etc.,and these are the main technologies for radiation therapy on prostate cancer.The advantage of EBRT is effective,wide range of indication and few complications.It may achieve the similar result as radical prostatectomy in low-risk patients.EBRT is divided into three categories according to the purpose of radiotherapy on prostate cancer:radical radiotherapy as one of the radical treatments for patients with localized and locally advanced prostate cancer;postoperative adjuvant and salvage radiotherapy;palliative radiotherapy for metastatic cancer,which mainly reduces symptoms and improves quality of life.

5.3.1 Indications for radical EBRT

Localized prostate cancer:low-risk patients (T1?2a,Gleason 2?6,PSA＜10 ng/mL),EBRT and radical prostatectomy are first-line treatment,however EBRT is preferred for elderly patients.Intermediate-risk patients(T2b or Gleason 7 or PSA 10?20 ng/mL):radiotherapy and surgery are first-line treatment and elderly patients may choose radical external radiotherapy,or combined with neoadjuvant/synchronous/co-endocrine therapy for 4?6 months.High-risk patients (≥T2c or Gleason≥8 or PSA＞20 ng/mL):radical EBRT combines with long-term neoadjuvant/concurrent/2?3 years adjuvant endocrine therapy,some patients can still choose surgery.

Locally advanced prostate cancer (T3?4N0M0):radical EBRT combines with long-term (2?3 years) neoadjuvant/concurrent/adjuvant endocrine therapy.Surgery,radiotherapy and endocrine-therapy are different comprehensive treatment for locally advanced prostate cancer,which should be chosen according to patient’s condition.

5.3.2 Complications of EBRT for prostate cancer

Side effects caused by radiotherapy are associated with single and total dose,radiotherapy protocol and irradiated volume.Common acute side effects including frequent urination,hematuria,diarrhea,hemafecia,etc.would disappear several weeks after radiotherapy.The side effects in late stage include rectal bleeding,radiation cystitis,and so on.The incidence of these complications is significantly reduced after conformal and intensity modulated radiotherapy,but pelvic radiotherapy may increase the risk of a second primary tumor such as rectal or bladder cancer.

5.3.3 Surgical treatment of biochemical recurrence after radiotherapy

Radical prostatectomy after radiotherapy is a salvage treatment for patients with biochemical recurrence after external radiotherapy of prostate cancer.Compared with radical prostatectomy as the initial treatment,the incidence of complications (including urinary incontinence,erectile dysfunction and bladder neck contracture) is higher.The 10-year OS rate and tumor-specific survival rate were 54%?89% and 70%?83%,respectively.Patient selection is very important.Salvage prostatectomy should be performed by an experienced surgeon.

5.3.4 Current situation and development of radiotherapy technology

With the development of radiotherapy technology in the past decades,higher than conventional radiation doses has been possible for treatment.3D-CRT,using computer software in combine with anatomical CT images,may apply a higher cumulative dose with a lower risk of delayed side effect.Currently,IMRT,a 3D second-generation technology,has been used in clinical practice.The advantage of IMRT over 3D-CRT is that it reduces the risk of gastrointestinal toxicity.Daily IGRT must be used to localize prostate in order to achieve the goal of reduction of target boundary and accuracy for either 3D-CRT or IMRT.The conventional dose of 70 Gy is considered insufficient.A total of 75.6?79.2 Gy is appropriate for conventional prostate irradiation (with or without seminal vesicles) in low-risk patients.Intermediate-and high-risk patients can receive up to 81.0 Gy of radiotherapy.The hyperfractionation with IMRT protocol (2.4?4.0 Gy each,4?6 weeks) has similar efficacy and toxicity compared with conventional fractionated IMRT.The results of clinical randomized trials have shown that there is a correlation between the dose increase and the improvement of biochemical results.

Stereotactic body radiotherapy (SBRT) is an emerging therapeutic technology that provides high-dose conformal radiation therapy in equal or less than 5 fractions of treatment.The procedure is only safe under the precise image guidance.SBRT has better biochemical-free progression survival and similar early toxicity (bladder,rectum and quality of life) when compared with standard radiotherapy techniques.However,SBRT may have more serious adverse events compared with IMRT.

5.4 Brachytherapy for prostate cancer

Brachytherapy is a technique used for treating localized prostate cancer.By accurately positioning through threedimensional treatment planning system,radioactive seeds are implanted into the prostate.It allows the dose to be delivered in the treatment area while sparing the rectum and bladder with increasing the local dose and reducing the radiation impact on rectum and bladder.It has positive effect and small trauma,and is especially suitable for elderly patients who can not tolerate radical prostatectomy.Traditionally,brachytherapy has been used in low-risk patients.Early studies have shown that brachytherapy is less effective than EBRT in high-risk patients.With the advance in technology,more evidences suggest that brachytherapy can also play a role in high-risk localized and locally advanced prostate cancer.Two methods of brachytherapy are currently available:low-dose (LDR) and high-dose (HDR) brachytherapy.LDR brachytherapy uses radioactive seeds permanently implanted into the prostate.It allows sufficient radiation dose to prostate lesions while avoiding excessive irradiation to bladder and rectum.As a monotherapy,permanent brachytherapy is suitable for the treatment of low-risk patients (cT1c?T2a,Gleason score＜6,PSA＜10 ng/mL).For moderate-risk prostate cancer,brachytherapy may combine with EBRT (45 Gy) with or without neoadjuvant ADT.High-risk patients are generally considered unsuitable for permanent brachytherapy alone.Brachytherapy is not ideal for patients with large or small prostate,bladder outlet obstruction (high international prostate symptom score) and previous transurethral prostate surgery.Implantation of radioactive particle is more difficult and the risk of side effects increases.Highdose brachytherapy refers to the temporary insertion of radiation source.It is a new method to enhance the dose of EBRT in patients with high-risk prostate cancer.HDR brachytherapy inserts a radioactive source temporarily into the prostate to deliver radiation.It is often combined with EBRT at 40?50 Gy and is a new method to enhance radioactivity in treating high-risk local or locally advanced prostate cancer patient,while minimizing acute or late toxicity.Brachytherapy combined with EBRT and ADT (2 or 3 years) is a common protocol for high-risk patients.The combination is effective,and studies have shown that the 9-year disease-free survival and disease-specific survival are 87% and 91%,respectively.

5.5 Proton therapy

Proton beam radiotherapy has been used for cancer therapy since 1950s.Supporters believe that this form of radiotherapy is superior to X-ray (photon)-based radiation in some clinical situations.Proton therapy can deliver a highly conformal dose of radiation to the prostate.The normal tissues around prostate could be effectively spared.However,side effects caused by these tissues are not common in prostate radiotherapy,thus the benefits of reducing the dose to these non-critical tissues are not clinically significant.The American Society of Radiation Oncology (ASTRO) believes that there is no clear conclusion on the efficacy of proton beam radiotherapy versus other prostate cancer treatments.Therefore,the role of proton beam radiotherapy in the treatment of localized prostate cancer is still unclear.Although proton beam radiotherapy is not a new technology,its use in the treatment of prostate cancer continues to evolve (still promising,but experimental).ASTRO supports the development of patient data from clinical trials to achieve a consensus on proton beam radiotherapy for prostate cancer,especially comparing proton beam radiotherapy with other radiotherapy methods such as IMRT and brachytherapy.

5.6 Other treatments for localized prostate cancer

In addition to above therapeutic methods,a variety of other methods have emerged for localized prostate cancer.Focal cryosurgical ablation of the prostate (CSAP) and highintensity focused ultrasound (HIFU) are relatively mature and are supported by some data.

CSAP destroys tumor tissues through localized freezing technique.Studies have shown that five years biochemical recurrence-free rate was between 65% and 92% in low-risk patients.Cryotherapy has similar outcomes with radical prostatectomy for unilateral prostate cancer.In a study comparing the effects of cryotherapy and EBRT with T2 or T3 prostate cancer,all patients received neoadjuvant ADT treatment,and results showed no significant difference in 3-year OS and disease-free survival,whereas patients receiving cryotherapy had poor sexual function.However,some studies have suggested that cryoablation has a lower biochemical progression-free survival than EBRT,although tumor-specific survival and OS are similar.

Potentially indication for CSAP therapy is localized prostate cancer,PSA＜20 ng/mL,Gleason score ＜7,lowrisk or intermediate-risk prostate cancer but physical status not suitable for radiotherapy or surgery,and prostate volume ＜40 mL.There is still lack of long-term data on the therapeutic effect for patients over 10 years.Therefore,patients with a life expectancy for more than 10 years should be well-informed.

HIFU achieves therapeutic effect via ultrasonic wave,causing tumor tissue damage through mechanical and thermal effects.HIFU has been used for initial treatment and recurrence after radiotherapy.In a prospective study on 111 patients with localized prostate cancer,the result showed two-year survival rate without other radical treatment was 89%,and the percentage of patients who retained urinary and erectile function at 12 months was 97% and 78%,respectively.After a median follow-up of 64 months,48% of patients may avoid the use of ADT.

HIFU is also used in patients with relapse after radiotherapy.The study indicated that after HIFU treatment,the median biochemical recurrence-free survival was 63 months,the 5-year OS was 88%,and the tumorspecific survival was 94%.After a median follow-up of 64 months,48% of patients avoided the use of ADT.Other emerging therapies,such as vascular-targeted photodynamic (VTP) therapy,worth further investigation.In a multicenter,open,phase III randomized controlled trial,413 low-risk patients receive randomized VTP(intravenous paliporfin,inserting optical fiber into the prostate,followed by laser activation) or dynamic monitoring.After a median 24 months follow-up,28% of patients had disease progression in VTP group,compared with 58% in the active monitoring group.In VTP group,negative prostate biopsy results were more common,and the most common serious adverse event was urinary retention,which was alleviated within 2 months.Irreversible electroporation of prostate can kill cells by generating short and strong electric field pulses in tissues.The change of electric field causes the formation of nanopores on cell membrane,leads to instability of cell and death through apoptosis.The study showed that tumor detection rate in fusion region was 16%?25% six months after this technique.However,since such technique lack long-term follow-up and control study,the clinical trial should be carried out after strict medical ethics review and patients and their families be fully informed.

6.Treatment of metastatic prostate cancer

Metastatic prostate cancer is an important disease stage that seriously affects the prognosis of patients.Metastatic prostate cancer accounts for only 5%?6% of new prostate cancer in Europe and the United States,while in China,the proportion is as high as 54%.

ADT is the primary systemic treatment for patients with advanced metastatic prostate cancer.it is also the basis of various new combined treatment protocol.ADT includes a variety of implementation protocol,among which simple castration (surgical or drug castration) is the most widely accepted core treatment.In recent years,there have been a series of breakthroughs,mainly the combination of ADT and new endocrine therapy drugs or chemotherapy drugs,which has improved the overall treatment effect on metastatic prostate cancer.Nevertheless,we should pay attention to the drug toxicity and economic burden brought by various new combination and use as an important reference for clinical selection.The number of metastatic lesions and tumor burden are related to the prognosis.Publication of several large-scale clinical studies in recent years have gradually applied hierarchical evaluation method on clinical practice.High-and lowmetastatic tumor burden:CHAARTED study defined high metastatic burden as visceral metastasis,or bone metastasis≥4,of which at least 1 was outside the spine or pelvis.Lowmetastatic burden was defined as no visceral metastasis and with less than 3 bone metastases.The definition of highrisk and low-risk diseases also comes from large-scale clinical research.For high-risk disease,two of the three risk factors should be met by LATITUDE definition:Gleason score ≥8,bone metastasis ≥3,and visceral metastasis.Lowrisk diseases are those with no more than one of the above risk factors.

6.1 ADT

ADT can be achieved with surgical (bilateral orchiectomy)or drug castration.Surgical castration is achieved by bilateral orchiectomy to block testicular androgen secretion.The operation is relatively simple,the cost is low,and the adverse events are not serious.Serum testosterone level drops rapidly after the operation.Patient’s testosterone may usually reach the castration level within 12 h.When patients need to reduce testosterone immediately,such as bone metastasis to the spinal cord,bilateral orchiectomy is a reasonable choice.However,comparing with drug castration,surgical castration may bring negative psychological effects to patients.The principle of drug castration is to affect the hypothalamus pituitary gonadal axis,thus reducing androgens production by testis.Luteinizing hormone releasing hormone (LHRH)agonist or antagonist is commonly used.On initial LHRH agonist treatment,the combination of LHRH agonist and receptor results in the release of luteinizing hormone and follicle stimulating hormone,causing the sudden rise of testosterone level,which lead to“flare response”.This phenomenon may stimulate the growth of prostate cancer and aggravates symptoms such as bone pain,bladder outlet obstruction or spinal cord nerve compression.For patients with obvious metastasis,who may have sharp testosterone increase caused by use of LHRH agonists at the initial stage,classical non-steroidal antiandrogens can be used one week before ADT application,followed by 4 weeks combination therapy.LHRH antagonists can rapidly combine with LHRH receptors,reduce the release of luteinizing hormone and follicle stimulating hormone,inhibit the level of testosterone,avoid the aggravation of diseases caused by the increase of testosterone.It is not necessary to take drugs together with antiandrogens.

Currently,internationally recognized definition of castration level is testosterone ＜50 ng/dL (1.735 nmol/L).However,this standard was formulated many years ago and was limited by the detection technology that time.The existing methods confirm that the average level of testosterone after surgical castration is 15 ng/dL,thus testosterone ＜20 ng/dL (0.694 nmol/L) should be a reasonable castration level.A lower level of testosterone during ADT (deep reduction of testosterone) is associated with better disease prognosis and outcome.The management of testosterone runs through diagnosis,evaluation,treatment and prognosis evaluation.It has important clinical significance for patients at different stages.The transient or persistent failure of testosterone to reach the castration level during treatment is called testosterone escape,which can be caused by a variety of factors,such as diet structure,metabolic status,poor treatment compliance or injection operation errors.Testosterone should be detected on important disease stage such as initial stages (diagnosis,recurrence,new onset,metastasis,etc.) and treatment switching point (curative treatment,ADT method change,chemotherapy,etc.).Baseline value should be tested to provide reference for subsequent diagnosis and treatment.Currently,testosterone level ＜50 ng/dL (1.735 nmol/L) was still the castration standard internationally.Prostate cancer during ADT and castration-resistant prostate cancer (CRPC),castration level of testosterone level ＜50 ng/dL (1.735 nmol/L) should be maintained;However,the deep reduction of testosterone [testosterone level of ＜20 ng/dL(0.694 nmol/L)] during ADT,should be served as a reference for clinical prognosis and treatment adjustment.

6.2 Combination therapy of ADT and other drugs

6.2.1 ADT with chemotherapy

Randomized controlled studies to evaluate clinical efficacy of castration alone and combined chemotherapy docetaxel in the treatment of metastatic prostate cancer have been carried out.CHAARTED and STAMPEDE trials have shown that compared with castration alone,combined chemotherapy can significantly improve the overall prognosis of patients with high tumor burden.Therefore,castration combined with docetaxel chemotherapy is one of the standard treatment options for patients with high tumor burden.

6.2.2 ADT with abiraterone plus prednisone

Abiraterone is a CYP17 inhibitor.Its mechanism of action is to inhibit the production of androgens by testicular,adrenal and prostate cancer cells.The results of LATITUDE and STAMPEDE trials showed that compared with castration alone,the combination of abiraterone plus prednisone could significantly improve the prognosis of high-risk patients.The results of STAMPEDE trials showed that ADT combined with abiraterone could also prolong the OS time of low-risk metastatic patients.Therefore,ADT combined with abiraterone plus prednisone should be one of the standard treatment options for patients with metastatic prostate cancer.

6.2.3 ADT with enzalutamide

Enzalutamide is a new non-steroidal antiandrogen.It blocks the binding between androgen and its receptor,inhibiting the nuclear translocation of androgen receptor,affecting the binding between androgen receptor and DNA,and thus inhibiting the whole androgen receptor signal transduction,so as to inhibit the growth of prostate cancer cells.Two large randomized controlled studies of ENZAMET and ARCHES on enzalutamide have shown that ADT combined with enzalutamide could significantly improve the radiographic disease-free survival and prolong OS time of patients.

6.2.4 ADT with apalutamide

Apalutamide is a new androgen antagonist which is very similar to enzalutamide in structure and pharmacokinetics.It has higher affinity to androgen receptor and is not easy to penetrate the blood-brain barrier.Theoretically,the adverse events are mild.The large randomized controlled study of TITAN on apalutamide showed that compared with the placebo group,the OS time was significantly longer,and the radiographic progression-free survival significantly improved.From the current research results,ADT combined with new hormonal therapy (NHT) can significantly improve the prognosis of metastatic hormone sensitive prostate cancer.These drugs have been approved by Food and Drug Administration (FDA) and become one of the standard protocols for the treatment of metastatic prostate cancer.Currently,there is no significant difference between the therapeutic effects of these new medicines.In addition,in the case of combined therapy,there is no evidence to show whether addition with chemotherapy will further prolong the survival time,but it is certain that the adverse events are increased.Therefore,new antiandrogenic drugs combined with chemotherapy can only be used in clinical trials.As for ADT combined chemotherapy,there is no head-to-head comparison between ADT combined with NHT and ADT combined chemotherapy.According to their respective clinical research data,the survival time benefits are similar.Therefore,we should take into account the patient’s willingness,special adverse events,tolerance to chemotherapy,as well as the availability and cost of drugs when selecting the treatment plan.

6.2.5 ADT with bicalutamide or flutamide

ADT or surgical castration combined with a traditional anti-androgen agent is called combined androgen blockade.This combined treatment regimen is still used in China.The meta-analysis results from European and American populations showed that the combination of androgen blockade with ADT could increase the absolute value of 5-year survival rate by 2.9% (from 24.7% to 27.6%)compared with ADT alone.Therefore,it is still one of the options in China.

6.3 Local treatment of metastatic prostate cancer for primary and metastatic lesions

Over the past 10 years,a number of retrospective studies have reported that patients with metastatic hormone sensitive prostate cancer have benefited from primary surgery or radiotherapy.However,not all treatments for the primary lesion can help the prognosis.Some studies have shown that young patients with low metastatic tumor burden,low Gleason score,in general good condition,are relatively likely to benefit from local radiotherapy on primary lesion.Therefore,clinical research should be carried out carefully for tumor cytoreductive prostatectomy.For metastatic patients with spinal cord compression,pathological fracture and other emergency complications,surgery or radiotherapy at the site of metastasis may be considered after evaluation and under the full consent with patients and their families.

7.Treatment of CRPC

7.1 Definition of CRPC

CRPC refers to one of the following conditions after testosterone reaches the castration level (＜50 ng/dL or 1.7 nmol/L):1) PSA rises for three consecutive times at an interval of more than one week.The two rises are above 50% of PSA’s low point,and PSA＞2 ng/mL or 2) imaging progression:2 or more new bone metastases revealed by bone scan,or new soft tissue lesions evaluated by Response Evaluation Criteria In Solid Tumor (RECIST).Symptomatic progression alone could not be diagnosed as CRPC and further evaluation is needed.There are two key points for diagnosis of CRPC:1) whether testosterone reaches castration level and 2) whether the disease continues to progress after the castration condition is reached.

7.2 Treatment of asymptomatic non-mCRPC (nmCRPC)

nmCRPC can be diagnosed if the following conditions are met:1) serum testosterone is maintained below the castration level,which means serum testosterone ＜50 ng/dL or 1.7 nmol/L;2) PSA progression:PSA＞2 ng/mL,with an interval of 1 week,and increased by more than 50% compared with the baseline for 3 consecutive times;and 3) conventional imaging examination including CT,MRI and bone scan did not find distant metastasis.nmCRPC patients,especially those PSA doubling time is within 10 months,are prone to metastasis and lead to death in the process of disease development.Therefore,on nmCRPC stage,if time to enter mCRPC can be delayed,the OS time will be prolonged.The latest three clinical studies on nmCRPC have changed the current standard on treatment for nmCRPC patients.Three study,SPARTAN,PROSPER and ARAMIS,use metastasis-free survival time as the main end point.The included patients with PSA doubling time were within 10 months,and 2/3 of them had a doubling time less than 6 months.All three studies showed significant benefit in metastasis-free survival time.The median survival time of the treatment and the placebo group were 40.5 and 16.2 months in the SPARTAN group;36.6 and 14.7 months in PROSPER (enzalutamide) group;and 40.4 and 18.4 months in ARAMIS group.Based on the above study results,combination of apalutamide,enzalutamide,or darolutamide with ADT is recommended for nmCRPC patients with high-risk metastasis (PSA doubling time within 10 months).

Apalutamide and enzalutamide have been launched in market earlier.Darolutamide is a new non-steroidal androgen receptor inhibitor,which has unique molecular structure and pharmacokinetics compared with the other two inhibitors.Darolutamide has high affinity with androgen receptor,and low affinity with γ-aminobutyric acid receptor,a neurotransmitters.Its permeability of blood-brain barrier is low,the effect on metabolic enzymesin vivois weak,and the possibility of drug-drug interaction is weak as well.

7.3 Treatment of mCRPC

7.3.1 Castration maintained treatment

Only two studies confirmed the weak survival advantage of maintained castration treatment in the second-and thirdline treatment.However,in the absence of prospective research,the possible benefits of maintained castration treatment exceed the possible risks of treatment.Currently,all clinical studies are based on maintaining castration level.Therefore,castration treatment should be maintained in this group.

7.3.2 New hormonal therapy in mCRPC

(1) Abiraterone:Study COU-AA-302 included mCRPC patients who had not received chemotherapy before.The results showed that abiraterone significantly prolonged the median time without imaging progression (16.5vs.8.2 months) and the median survival time (34.7vs.30.3 months) as compared with patients in placebo.In addition,abiraterone can slow the progress of pain and delay the use of chemotherapy and opioids.

(2) Enzalutamide:The PREVAIL study also included mCRPC patients who had not received chemotherapy before.Patients in the placebo group were cross over after data unblinding.The 5-year long-term follow-up results showed that enzalutamide could significantly prolong the survival time (36vs.31 months),reduce the risk of death by 17%,and is well tolerated in people over 75 years old.

7.3.3 Chemotherapy

Chemotherapy is also one of the standard treatments for mCRPC.The protocol is based on the research results of TAX327.TAX327 study compared the therapeutic effect of docetaxel (weekly or every 3 weeks)+prednisone and mitoxantrone+prednisone.mCRPC patients treated with docetaxel achieved a higher median OS than mitoxantrone(18.9vs.16.5 months).The survival benefit was maintained during the extended follow-up period.Mitoxantrone +prednisone is also an effective treatment option,which can control disease progression to a certain extent,improve quality of life,especially reduce pain.Therefore,it can be used in patients with docetaxel intolerance or treatment failure.

Cabazitaxel is a semi-synthetic derivative of the taxane.The latest results of phase III FIRSTANA trial indicated that cabazitaxel has clinical significance for mCRPC patients who have not received chemotherapy.The median survival time of cabazitaxel and docetaxel regimens was similar,which were 24.5 and 24.3 months,respectively.Compared with docetaxel,cabazitaxel has a lower rate of peripheral neuropathy.Therefore,patients who are not suitable for docetaxel chemotherapy or who have mild peripheral neuropathy may consider cabazitaxel.

7.3.4 Tumor vaccine

On April 2010,Sipuleucel-T was approved by the FDA as the first immunotherapy drug for prostate cancer.The autologous tumor“vaccine”includes collecting antigen presenting leukocytes from the patient,exposing these cells to prostatic acid phosphatase granulocyte macrophage colony stimulating factor,and then reinfusing back to the body.The result of a phase III multicenter randomized double-blind clinical trial (D9902B) indicated that the median survivals were 25.8 months in vaccine groupvs.21.7 months in control group,respectively.Sipuleucel-T treatment reduced the risk of death by 22%.

7.3.5 PI3k/Akt pathway inhibitor ipatasertib

Ipatasertib is a PI3k/Akt pathway inhibitor.The proportion of PTEN deletion in patients with mCRPC is about 40%?50% and PTEN deletion will lead to the activation of Akt pathway and patient has poor prognosis.IPATential150 is a phase III randomized,double-blind study to evaluate the efficacy and safety of ipatasertib combined with abiraterone in the treatment of asymptomatic or mild symptomatic mCRPC patients.The median imaging progression-free survival time of patients with PTEN deficiency was 18.5 months in the ipatasertib+abiraterone group and 16.5 months in the abiraterone alone.The incidence of adverse events was 40% and 23%,respectively,and the drug withdrawal rate caused by adverse events was 21% and 5%,respectively in the two groups.The long-term data on survival time need to be further verified.

7.3.6 Second-line treatment of mCRPC

(1) Cabazitaxel:On June 2010,the FDA approved cabazitaxel for patients with mCRPC who failed docetaxel chemotherapy.In an international phase III trial(TROPIC),the OS for cabazitaxel was extended by 2.4 months as compared with mitoxantrone group.For patients who failed in docetaxel,and/or a new endocrine therapy drug (abiraterone or nzalutamide),cabazitaxel has certain therapeutic effect.CARD study,a phase III randomized placebo-controlled trial,evaluated the therapeutic effect of cabazitaxel after failure of docetaxel,abiraterone or enzalutamide.The results showed that imaging disease-free progression time was nearly doubled and the risk of death was reduced by 36% in the treatment group.

(2) Abiraterone:On April 2011,FDA approved abiraterone combined with low-dose prednisone for the treatment of mCRPC patients who failed docetaxel treatment.The treatment is based on the result of COU-AA-301,a phase III randomized placebo-controlled clinical trial.The median survival time in the abiraterone and placebo groups was 15.8 and 11.2 months,respectively.Abiraterone group also had improvement in imaging progression time,PSA decline and pain relief.

(3) Enzalutamide:On August,2012,FDA approved enzalutamide for the treatment of mCRPC patients who failed in docetaxel treatment,based on results of a phase III randomized placebo-controlled trial (AFFIRM).The median survival time of enzalutamide and placebo group were 18.4 and 13.6 months,respectively.In different subgroups,patients with visceral metastases also benefit in survival time.

(4) Radium-223:Radium-223 belongs to α particle targeted therapy and it is the only radionuclide therapy that can improve the survival of CRPC patients with bone metastasis.The results of phase III trial (ALSYMPCA)suggest that patients who failed or could not tolerate chemotherapy were significantly improved in treatment groupvs.placebo.The OS time of mCRPC patients with bone metastases was 14.9vs.11.3 months,and the occurrence time of symptomatic skeletal events was significantly delayed (15.6vs.9.8 months) as compared with in placebo.Radium-223 was well tolerated,and the proportion of patients with all levels of treatment-related adverse events in radium-223 group was lower than that of placebo group.A safety study with a follow-up period of up to 3 years confirmed that the long-term safety of radium-223 was good,and the incidence of myelosuppression in follow-up patients (all levels) was ≤3%.And radium-223 can improve patients’ quality of life compared with placebo,and the percentage of improvement in EQ-5D utility score and total FACT-P score are higher in radium-223 group.A large number of real-world data (PARABO,ROTOR,iEAP,FLATIRON,REASSURE etc.) have verified the OS benefit of CRPC patients with bone metastases and the improvement of their quality of life when treated with radium-223.

(5) β radioactive particles:for patients with extensive metastasis,β radioactive drug is also a treatment option,especially when such patients are not suitable for effective chemotherapy.Strontium-89 and samarium-153 are the most commonly used radiotherapy for patients with bone metastases.Since these patients often complained multifocal bone pain,these radiation therapies can alleviate the pain.However,compared with radium-223 therapy,β particle therapy has no survival advantage and can only be used as palliative therapy.Moreover,the incidence of myelosuppression is high,which may affect the follow-up systemic therapy.

(6) Poly adenosine diphosphate ribose polymerase (PARP)inhibitor:PARP is a multifunctional protein posttranslational modification enzyme that exists in most eukaryotic cells.It is activated by recognizing DNA fragments that are structurally damaged and is considered a sensor of DNA damage.It can also ribosylate many nuclear proteins.It modified histone,RNA polymerase,DNA polymerase,DNA ligase,etc.,and the histone can be separated by adenosine diphosphate ribosylation of histone,which is helpful to repair the binding of protein and repair the damage of DNA.Meanwhile,PARP is the cleavage substrate of caspase,the core member of apoptosis.Therefore,it plays an important role in DNA damage repair and apoptosis.PARP inhibitors can inhibit repairment of DNA damage,promote the apoptosis of tumor cells,and therefore achieve the purpose of treatment.PROfound is a prospective,multicenter,randomized,phase III clinical trial designed to evaluate the efficacy of PARP inhibitor olaparib in the treatment of mCRPC patients who have disease progression after treated with enzalutamide or abiraterone,and who carry BRCA1/2 mutations,ATM mutations (subset ofHRRgene mutation),or mutations in any of the 12 genes in the HRR signal pathway.The results showed that olaparib reduced the risk of disease progression or death by 66%,and the median time of radiographic progression-free survival was 7.4 months,compared with 3.6 months for enzalumide or abiraterone.The OS time has extended to 19.0 months,compared with 14.6 months for enzalutamide or abiraterone.The PROPEL phase III clinical trial(NCT01972217) to compare the efficacy of abiraterone alone and olaparib plus abiraterone in mCRPC patients has been launched.The trial to evaluate the safety of pabolizumab combined with olaparib in mCRPC patients who did not receive docetaxel is still in progress(NCT02861573).In addition,the safety and efficacy of several other PARP inhibitors,such as rucaparib,niraparib and talazoparib,in the treatment of mCRPC patients are also being studied.

(7) Therapeutic radiopharmaceuticals related to PSMA:177Lu-PSMA-617 is the main therapeutic radiopharmaceutical related to PSMA.The first patient was treated internationally in 2014.However,the main data source was from the same medical center.A recent phase II study compared mCRPC patients treated with 177Lu-PSMA,cabazitaxel and docetaxel.177Lu-PSMA group has obvious advantages in patient whose PSA decreased by more than 50% at end point.The long-term follow-up data need to be further studied.

(8) Immunotherapy:FDA approved PD-1 inhibitor pembrolizumab for treatment of mCRPC patient with mismatch repair defect and highly unstable microsatellite.In 2020,American Society of Clinical Oncology (ASCO)published the results of KEYNOTE-199 phase II clinical trial.The study included 258 mCRPC patients with measurable positive PD-L1 lesions,negative PD-L1 lesions and bone metastasis taken no account of PD-L1 status.The three groups included 133,66 and 59 patients,respectively.The disease control rate was 10% in group 1,9% in group 2,and 22% in group 3.Median OS was 9.5 months for group 1,7.9 months for group 2,and 14.1 months for group 3.In addition,pembrolizumab combined with enzalutamide showed good tolerance and tumor response rate after the failure of abiraterone treatment in the keynote-365 phase Ib/II clinical trial on mCRPC patients.

In 2020,a phase II clinical trial (checkmate650)published the result on the treatment of nivolumab combined with ipilimumab on mCRPC patients before/after docetaxel chemotherapy.Patients who directly used the combination without chemotherapy and patients who used the combination after chemotherapy were followed up for 11.9 and 13.5 months,respectively.The objective response rates were 25% and 10% and the OS time was 19.0 and 15.2 months,respectively.Patients with PD-L1≥1%,mutation of DNA damage repair,homologous recombination defects or high tumor mutation load had higher objective response rates.

7.3.7 Skeleton health-related drugs for mCRPC patients

In a multicenter study of bone health-related drugs for mCRPC patients,643 mCRPC patients with asymptomatic or mild bone metastases were randomly assigned to receive intravenous zoledronic acid or placebo once every 3 weeks.At 15 months,the number of patients with skeleton related events in the zoledronic acid (4 mg) group was significantly lower than that in the placebo group (33%vs.44%).The updated report on 24 months showed a significant increase in the median time on the first skeleton-related event (488 and 321 d).There was no significant difference in OS time.Other bisphosphonates have not been shown to be effective in preventing disease-related skeleton complications.

Receptor activators of nuclear factor κ Bligand (RANKL)is a RANK binding cytokine expressed by osteoclasts.It is a key signal molecule for maintaining bone integrity.Denosumab is a monoclonal antibody against RANKL,which has been proved to be superior to zoledronic acid in preventing skeleton-related events and delaying the time of the first skeleton-related event.A randomized,doubleblind,placebo-controlled study compared the efficacy of denosumab and zoledronic acid in patients with mCRPC.The absolute incidence of skeleton-related events was similar in both groups;however,compared with the zoledronic acid group,the median time of the first skeleton-related event in the denosumab group was delayed by 3.6 months (20.7 and 17.1 months).Similar treatmentrelated toxicities were reported for zoledronic acid and denosumab,including hypocalcemia (more commonly denosumab,13%vs.6%),arthralgia,and jaw necrosis(incidence rate was 1%?2%).

Working group members

Group leader:Jianye Wang

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

Translation group member

Yong YangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute