Prostate Cancer Treatment Protocols

Treatment protocols for prostate cancer are provided below, including general treatment recommendations and those for the following:

• Localized prostate cancer
• Recurrent disease
• Advanced or metastatic disease

General treatment recommendations for prostate cancer

Selecting initial treatment requires assessing the risk of the disease spreading or progressing, which is based on evaluation of the following patient factors:

• Life expectancy
• Comorbidities
• Biopsy grade (Gleason score)
• Clinical stage
• Prostate-specific antigen (PSA) level

Treatment recommendations for clinically localized prostate cancer

Very low risk of recurrence:

• Patients with clinical stage T1c, Gleason score ≤6, PSA < 10 ng/mL, fewer than three positive prostate cores, ≤50% cancer in each core, and PSA density < 0.15 ng/mL, with a life expectancy ≤20 y, should be treated with active surveillance.

• Active surveillance includes periodic PSA testing, digital rectal examination (DRE), and prostate biopsy. The optimal protocol for surveillance is still unknown, ^{[1, 2]} but may include PSA as often as every 3 mo or at least every 6 mo, DRE as often as every 6 mo but at least every 12 mo, and repeat biopsy within 18 mo but as often as every 12 mo or if PSA and DRE change. ^{[3, 4, 5]}

• For treatment recommendations for patients with a life expectancy ≥20 y, see initial therapy for Low Risk of Recurrence, below.

Low risk of recurrence:

• Treatment for patients with clinical stage T1-T2a, Gleason score 2-6, PSA < 10 ng/mL, who have a life expectancy < 10 y includes observation, with continued monitoring until symptoms develop or appear imminent based on changes in exam or PSA, then initiation of palliative androgen deprivation therapy (ADT) ^[6]

• Treatment for patients with a life expectancy ≥10 y includes active surveillance or

• Radical prostatectomy (RP) with or without pelvic lymph node dissection (PLND); RP is the standard therapy for localized prostate cancer, involving the removal of the prostate and seminal vesicles with or without pelvic lymph nodes; this may be done using either open or laparoscopic (robotic-assisted) technique ^{[7, 8, 9]} or

• External beam radiation therapy (EBRT) is a standard therapy for patients with localized disease; 3-dimensional (3D) techniques such as 3D conformal radiation treatment (3D-CRT) offer reduced toxicity and the use of higher doses; second-generation techniques, including intensity-modulated radiation therapy (IMRT), are also required, especially if doses ≥78 Gy are administered ^[10]

• Radiation therapy doses of 75.6-79 Gy in conventional 36-41 Gy fractions to the prostate ^[10] with 3D-CRT/IMRT with daily image-guided radiotherapy (IGRT) or brachytherapy (recommended dose rate: 145 Gy for iodine-125 and 125 Gy for palladium-103): A study by Haverkort et al found that position verification using gold markers and reduced planning target volume margins yielded adequate treatment of the prostate and a lower rectal wall dose in patients treated with curative EBRT ^[11]

• Patients with low-risk cancer are not candidates for pelvic lymph node irradiation or androgen deprivation therapy (ADT) ^[12]

Intermediate risk of recurrence:

• Treatment options for patients with clinical stage T2b-T2c, Gleason score 7 or PSA 10-20 ng/mL, who have a life expectancy <  10 y, include active surveillance or

• Radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with daily IGRT with or without short-term neoadjuvant/concomitant/adjuvant ADT for 4-6 mo with or without brachytherapy (recommended dose rate: 145 Gy for iodine-125 and 125 Gy for palladium-103) ^{[13, 14]}

• Treatment recommendations for patients with a life expectancy ≥10 y include RP with PLND or

• Radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with daily IGRT with or without short-term neoadjuvant/concomitant/adjuvant ADT for 4-6 mo with or without brachytherapy (recommended dose rate: 145 Gy for iodine-125 and 125 Gy for palladium-103)

• For intermediate-risk cancers, consider combining brachytherapy (recommended dose rate: 145 Gy for iodine-125 and 125 Gy for palladium-103) with EBRT (40-50 Gy) with or without 4-6 mo neoadjuvant/concomitant/adjuvant ADT

• Administering ADT before, during, and after radiation prolongs survival ^[15]

High risk of recurrence:

• Clinical stage T3a, Gleason score 8-10, PSA > 20 ng/mL

• Treatment options include RP plus PLND for selected patients or

• Radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT plus long-term neoadjuvant/concomitant/adjuvant ADT for 2-3 y or

• Radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with daily IGRT plus brachytherapy (recommended dose rate: 145 Gy for iodine-125 and 125 Gy for palladium-103) with or without short-term neoadjuvant/concomitant/adjuvant ADT for 4-6 mo or

• High-risk cancers may be treated with combination EBRT (40-50 Gy) and brachytherapy with or without 4-6 mo neoadjuvant/concomitant/adjuvant ADT

Alternative treatment recommendations for localized prostate cancer

Other treatments that have been used in the initial management of localized prostate cancer include the following:

• Cryotherapy
• High-intensity focused ultrasound
• Particle beam therapy

Cryotherapy:

• Cryotherapy (also known as cryosurgery or cryoablation) involves using transrectal ultrasonographic guidance; percutaneous cryoprobes are placed and used to freeze prostate tissue

• This treatment is not preferred as a standard curative treatment option but may be used in select patients with localized prostate cancer or as focal therapy in low-risk patients (experimental) ^[16]

• Can also be considered as salvage therapy after failed radiation therapy ^[17]

• Complications include tissue sloughing, perineal ecchymosis, stricture or contracture, incontinence, impotence, and fistula formation between the urinary and gastrointestinal tracts

High-intensity focused ultrasound:

• Acoustic ablative technique that uses ultrasound to induces immediate and irreversible coagulative necrosis with sharply delineated boundaries; performed under spinal anesthesia on an outpatient basis ^[18]
• Widely used outside the United States; approved for ablation of prostate tissue by the US Food and Drug Administration in 2015 ^[19]
• Used for both whole-gland treatment and focal therapy (“male lumpectomy”) ^[20]

Particle beam therapy ^[21] :

• Radiation therapy that uses protons for energy; outside the United States, carbon ions are also used
• Performed at specialized facilities
• Combined use of proton beam therapy with standard radiotherapy resulted in a relatively higher occurrence of severe gastrointestinal and genitourinary toxicities
• Proton beam therapy alone has produced favorable outcomes with respect to disease control and toxicity

Biochemical recurrence

See the list below:

• Approximately 20-30% of patients treated with intent for cure will have biochemical recurrence, defined as a detectable PSA that increases on two subsequent measurements or a PSA that fails to fall to undetectable levels, without clinical or radiologic evidence of disease. ^{[22, 23, 24]}
• PSA that fails to fall to undetectable levels after RP may indicate residual prostate cancer
• PSA cut points for defining recurrence have typically ranged from 0.2-0.4 ng/mL, but 0.4 ng/mL correlates most strongly with systemic progression. ^{[25, 26]}
• Biopsy of the prostatic bed is usually not recommended unless the patient is a candidate for salvage therapy
• Monitor PSA, alkaline phosphatase, and calcium every 6 months to determine whether the doubling time is less than 1 year
• Treatment options for post-RP recurrence include salvage radiation therapy, androgen deprivation, and surveillance
• Adjuvant radiation therapy may be more beneficial than salvage radiation therapy in men with poor pathologic features ^{[27, 28]}
• Treatment options for post–radiation therapy recurrence include salvage prostatectomy, ADT, surveillance, high-intensity focused ultrasound (clinical trials), cryotherapy, repeat irradiation

Treatment recommendations for locally advanced prostate cancer

Molecular testing of either tissue or liquid biopsy should be done to check for germline mutations. Somatic testing should be done to check for possible targetable mutations, including homologous repair mutations. ^[29]

Very high risk:

• Clinical stage T3b-T4 treatment options include radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT plus  long-term neoadjuvant/concomitant/adjuvant ADT for 2-3 y or

• Radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with daily IGRT plus brachytherapy with or without short-term neoadjuvant/concomitant/ADT for 4-6 mo or

• RP plus PLND for selected patients (those with clinically localized prostate cancer that can be completely excised surgically, life expectancy of at least 10 years, and no serious comorbid conditions that would contraindicate elective surgery) ^[6] or

• ADT alone, in patients with T3 disease and/or node-positive disease and PSA doubling time less than 10 months

For biochemical recurrence of nonmetastatic castration-resistant prostate cancer with doubling time of less than 10 months, improvement in metastasis-free survival has been reported with use of the following androgen receptor inhibitors:

• Apalutamide 240 mg (ie, four 60-mg tablets) PO daily ^{[30, 31]} or
• Enzalutamide 160 mg PO once daily ^[32]   or 
• Darolutamide 600 mg PO BID ^[33] plus
• A gonadotropin-releasing hormone analog, unless the patient has had bilateral orchiectomy

Metastatic disease:

• Any T, N1: Treatment includes ADT or radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with IGRT plus long-term neoadjuvant/concomitant/adjuvant ADT for 2-3y

• Any T, any N, M1: Treatment includes only ADT for patients with M1

Androgen deprivation therapy recommendations for advanced or metastatic disease

See the list below:

• ADT is a preferred initial treatment for symptomatic metastatic prostate cancer because androgenic effects promote the growth and malignant transformation of prostatic tissue ^[34]

• ADTs include luteinizing hormone (LH) receptor agonists (eg, histrelin, leuprolide), gonadotropin-releasing hormone (GnRH) receptor agonists (eg, goserelin, histrelin, leuprolide, triptorelin) and antagonists (eg, degarelix, relugolix), and complete androgen blockade (CAB)

• CAB includes medical castration with an oral antiandrogen (eg, bicalutamide, flutamide, nilutamide) or surgical castration ^[35]

• Patients who do not show an adequate suppression of serum testosterone (< 50 ng/dL) may be considered for CAB

• Monotherapy with nonsteroidal antiandrogens is less effective but these agents are associated with fewer hot flashes and fatigue and do not impair libido

• If hormone therapy fails, that therapy should be continued into and through the next hormone manipulation

• Patients with hormone-sensitive metastatic prostate cancer with synchronous disease should be offered triple therapy with leuprolide, darolutamide, and docetaxel (see below) ^[36]

• Based on the clinical situation a doublet should at least be offered in the form of leuprolide plus enzalutamide or apalutamide or abiraterone acetate

Gonadotropin-releasing hormone agonists:

• Therapy with GnRH analogs may induce medical castration by suppressing luteinizing hormone (LH) production

• These agonists can potentially cause a transient surge of LH when therapy is initiated before the LH levels fall (flare phenomenon)

• GnRH agonists are offered in 1 mo, 3 mo, and once-yearly depots; premedication with antiandrogen is necessary to prevent flare phenomenon

• Leuprolide: 7.5 mg intramuscularly (IM) monthly or  22.5 mg IM every 3 mo or  30 mg IM every 4 mo or  45 mg intravenously (IV) every 6 mo or

• Histrelin: one 50-mg subcutaneous (SC) implant every 12 mo ^[37] ; continue therapy until disease progression or

• Goserelin: 3.6-mg implant SC monthly or  a 10.8-mg implant ^[37] SC every 3 mo or

• Triptorelin: 3.75 mg IM monthly or  11.25 mg IM every 3 mo or 22.5 mg IM every 6 mo

Gonadotropin-releasing hormone antagonists:

• Pure GnRH antagonists suppress testosterone and avoid the flare phenomenon associated with GnRH agonists
• Important for patients with no prior hormone treatment who are diagnosed with significant metastasis.
• Degarelix: 120 mg SC × two doses (ie, two separate injections totaling 240 mg), then, after 28 days, monthly maintenance doses of 80 mg SC
• Relugolix: Loading dose of 360 mg PO × 1, then 120 mg PO once daily ^[38]

Nonsteroidal antiandrogens for non–castrate-resistant disease:

• Antiandrogens bind to androgen receptors and competitively inhibit their interaction with testosterone and dihydrotestosterone

• These agents do not decrease LH levels and androgen production

• Antiandrogens are usually used in combination with a GnRH agonist, to prevent a disease flare caused by the transient increase in testosterone levels

• Bicalutamide 50 mg PO daily; often given prior to treatment with leuprolide, to prevent tumor flare

• Enzalutamide (160 mg PO daily), which was previously indicated only for metastatic castration-resistant prostate cancer in patients who had received docetaxel, is now approved also for patients who have not received chemotherapy ^[39]

Chemohormonal therapy for hormone-sensitive metastatic disease

• Docetaxel 75 mg/m ² IV with dexamethasone premedication 8 mg PO at 12 hours, 3 hours, and 1 hour before docetaxel infusion; repeat cycle every 21 days for up to a total of 6 cycles ^[40]
• Abiraterone (Zytiga) 1000 PO once daily plus  prednisone 5 mg PO BID or  abiraterone (Yonsa) 500 mg PO once daily plus methylprednisolone 4 mg BID ^[41]
• Enzalutamide 160 mg PO once daily; administer with GnRH analog concurrently, unless the patient has had bilateral orchiectomy ^[42]
• Darolutamide 600 mg PO BID plus  docetaxel 75 mg/m ² IV  plus  ADT q3Weeks for 6 cycles ^{[43, 36]}

Treatment recommendations for castration-resistant prostate cancer

See the list below:

• All cases of metastatic disease become resistant to ADT
• Radiation may be used for palliation in patients with painful bone metastases or impending spinal cord compression
• Surgical intervention may be necessary for weight-bearing bones involved in pathologic fracture
• Therapeutic options are limited, and the focus is on improving quality of life using single or multimodal therapies
• Docetaxel every 3 wk plus prednisone is the treatment of choice for men with symptomatic castration-resistant advanced prostate cancer; ^{[44, 45]} recommended dose is docetaxel 75 mg/m ² IV on day 1 plus  prednisone 5 mg PO BID; repeat cycle every 21 days for up to 10 cycles (premedicate with oral corticosteroids starting 1 day before docetaxel administration to reduce incidence of hypersensitivity reactions and fluid retention)
• Abiraterone (Zytiga) is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who are either chemotherapy-naïve or who have had prior docetaxel therapy; recommended dose is 1,000 mg PO once daily plus  prednisone 5 mg PO BID ^{[46, 47, 48, 49]} ; in addition, de Bono et al reported that abiraterone prolonged overall survival in patients with mCRPC who had received prior chemotherapy. ^[50]
• Abiraterone is available as an ultramicronized tablet (Yonsa) that may be administered with or without food; the original tablet formulation (Zytiga) must be administered 1 hour before or 2 hours after meals. Abiraterone (Yonsa): 500 mg (four 125-mg ultramicronized tablets) PO daily plus methylprednisolone 4 mg PO BID 
• Niraparib/abiraterone (200 mg/1,000 mg) fixed dose combination (Akeega) PO once daily plus prednisone 10 mg PO once daily for deleterious or suspected deleterious BRCA-mutated mCRPC ^[51]  
• Cabazitaxel with prednisone can be used for patients who have mCRPC that was previously treated with a docetaxel-containing treatment regimen; cabazitaxel 25 mg/m ² IV every 3 wk; infuse IV over 1 h; use inline filter (0.22 µm) during administration plus  prednisone 10 mg PO daily; reduce cabazitaxel dose to 20 mg/m ² with prolonged or febrile neutropenia or with persistent or severe diarrhea
• Enzalutamide (Xtandi): 160 mg PO once daily
• Darolutamide 600 mg PO BID is indicated for nonmetastatic CRPC ^[33]
• Symptomatic men who are not candidates for docetaxel-based regimens may be candidates for mitoxantrone 12 mg/m ² IV on day 1 plus  prednisone 5 mg PO BID daily; repeat cycle every 21 days ^{[52, 44, 45]}
• Rucaparib 600 mg PO BID until disease progression or unacceptable toxicity for deleterious BRCA mutation (germline and/or somatic)–associated mCRPC in patients previously treated with androgen receptor–directed therapy and taxane-based chemotherapy ^[53]
• Olaparib 300 mg PO BID until disease progression or unacceptable toxicity for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC that has progressed after treatment with enzalutamide or abiraterone ^[54]
• Lutetium Lu 177 vipivotide tetraxetan 7.4 GBq (200 mCi) IV q6Weeks for up to 6 doses, or until disease progression or unacceptable toxicity, ^[55] for patients with progression after treatment with docetaxel and oral ADT

Treatment recommendations for castrate-resistant metastatic disease:

• Docetaxel 75 mg/m ² IV, with dexamethasone premedication 8 mg PO at 12 hours, 3 hours, and 1 hour before docetaxel infusion; repeat cycle every 21 days for up to a total of 10 cycles
• Abiraterone 1000 mg (Zytiga; two 500-mg tablets or four 250-mg tablets) PO daily plus  prednisone 5 mg PO BID or  abiraterone 500 mg (Yonsa; four 125-mg ultramicronized tablets) PO daily plus methylprednisolone 4 mg PO BID 
• Enzalutamide 160 mg (four 40-mg tablets) PO daily
• Radium-223 50 kBq (1.36 microcurie) per kg IV infused over 1 minute; repeat q 4 wk for six cycles total; dosage calculation must be based on decay correction factor of radium-223
• Sipuleucel-T therapy comprises three complete doses IV given at approximately 2-wk intervals (median dosing interval, 2 wk; range, 1-15 wk); infuse IV over 60 min; premedicate with oral acetaminophen and an antihistamine approximately 30 min before administration. ^{[56, 57, 46, 47]}  Men with less advanced disease, good performance status, life expectancy > 6 mo, no visceral disease, and no or minimal symptoms and whose disease is resistant to standard hormone treatment may be candidates for autologous immunotherapy with sipuleucel-T ^[56]

Treatment recommendations for patients with castration-recurrent prostate cancer and bone metastases

Treatment with one of the following agents is recommended for all men with hormone-refractory prostate cancer and bone metastases, to reduce skeleton-related events such as pathologic fracture ^[6] :

• Zoledronic acid 4 mg IV annually over no less than 15 min ^{[58, 59]} or
• Denosumab 120 mg SC every 4 wk ^[60]

The radiopharmaceutical radium-223 dichloride (Xofigo) is approved for men with mCRPC with symptomatic bone metastases and no known visceral metastatic disease:

• 50 kBq (1.36 microcurie) per kg IV infused over 1 minute; repeat q 4 wk for six cycles total; dosage calculation must be based on decay correction factor of radium-223 (listed in prescribing information) ^{[61, 62]}