Prostate Cancer Guidelines

Prostate Cancer Facts

• Almost all prostate cancers are adenocarcinomas¹
• It is the second most common type of cancer, and cancer death, in men in the United States with an estimated annual incidence of 268,490 cases and an estimated 34,500 deaths annually²
• 1 in 8 men will be diagnosed with prostate cancer in their lifetime²
• It is the second most common cause of cancer death in men in the US with an estimated 34,500 deaths annually²
• The age at which screening is recommended for prostate cancer varies depending on the individual patient’s risk. When appropriate, most commonly used measures are:
  • Prostate-Specific Antigen (PSA) blood test
  • Digital Rectal Exam (DRE)³

Prostate Cancer Risk Factors

• Age: average age is 66 yo, 6 out of 10 cases are in men over 65⁴
• Race/Ethnicity: more common in African American men ⁵
• Geography: most common in North America, northwestern Europe, Australia, and on Caribbean islands ⁵
• Family History: having father or brother with the disease more than doubles risk⁵
• Genetic mutations: BRCA1/BRCA2, Lynch Syndrome⁵

Prostate Cancer Testing

PSA

• No set “cutoff” point to determine if men have prostate cancer
• Most men with PSA < 4 ng/mL do not have prostate cancer
• PSA value between 4-10 ng/mL have about 25% risk of having prostate cancer
• PSA > 10 ng/mL have >50% risk of prostate cancer
• Many factors other than cancer can raise and/or lower PSA levels
  • Raise = enlarged prostate (benign prostatic hyperplasia (BPH)), older age, prostatitis, ejaculation, urologic procedures, elevated testosterone
  • Lower = 5-alpha reductase inhibitors, herbal mixtures
• Repeating the PSA blood test after about 4 weeks is reasonable if the initial PSA value is in the borderline range (4-7 ng/mL).⁶

DRE

• Abnormal texture (bumps or hard areas) can be an indication of prostate cancer⁶
  • A systematic review found the pooled sensitivity of DRE performed by primary care physicians is 0.51 (95% CI, 0.36-0.67; I² = 98.4%), leading to doubt that DRE is a reliable tool for prostate cancer screening⁷

Transrectal Ultrasound (TRUS)

• Can be used to look for suspicious areas in prostate, to guide the prostate biopsy needle, to measure the size of the prostate gland, and as a treatment guide⁸

Magnetic Resonance Imaging (MRI)

• Can be used to determine if the patient needs a prostate biopsy, to help locate and target areas of cancer, to guide the prostate biopsy needle, and to determine stage of the cancer
• Multiparametric MRI (mpMRI) is usually used to define areas of cancer in the prostate⁸
  • Reported using the Prostate Imaging Reporting and Data System (PIRADS)
  • Classified from PIRADS 1-5 (1 being very unlikely to 5 being very likely to have clinically significant prostate cancer)

Bone Scan

• Can show if the cancer has spread to bone⁸

Positron Emission Tomography (PET) Scan

• Uses radioactive tracers that collect in cancer cells to detect prostate cancer⁸

CT Scan

• Can show if the cancer has spread to nearby lymph nodes⁸

Prostate Biopsy

• Results positive for cancer will be assigned a Gleason Score (GS) and Grade Group (GG)
• Results can also show potentially pre-cancerous lesions, including:
  • High Grade Prostatic Intraepithelial Neoplasia (HGPIN)
  • Atypical Small Acinar Proliferation (ASAP)
  • Proliferative Inflammatory Atrophy (PIA)
• Results can be negative for cancer ⁸

Genetic Testing

• Should be performed when the patient has prostate cancer AND:
  • Positive family history of cancer
  • High risk, very high risk, regional or metastatic prostate cancer
  • Ashkenazi Jewish ancestry
  • Intraductal histology
• Germline testing should include:
  • MLH1, MSH2, MSH6, and PMS2 (for Lynch Syndrome)
  • BRCA2, BRCA1, ATM, PALB2, and CHEK2 ⁹

Prostate Cancer Prognosis

The overall 5-year survival rate is 98%, however, this number varies depending on tumor histology, stage, and grade.¹⁰

Tumor Histology

• Prostate cancer histology is most commonly acinar adenocarcinoma (90-95%), but can also be ductal adenocarcinoma (0.4-0.8%)
• There are other rare types including: ¹¹
  • Transitional Cell Carcinoma (2-4%)
  • Small Cell Carcinoma (<2%)
  • Squamous Cell Carcinoma (0.5-1%)
  • Sarcoma (0.7%)
  • Lymphoma (0.09%)

Staging

The 3 aspects used in determining stage are:¹²

1. Tumor size (T)
   • Clinical T stage (cT) = based on physical exam, prostate biopsy, and/or imaging tests
   • Pathologic T stage (pT) = stage determine by the pathology of the cancer
2. Spread to lymph nodes (N)
3. Spread to distant organs/lymph nodes (M)

Table 1. Stages of Prostate Cancer¹²

AJCC Stage	Stage grouping	Stage description
I	cT1, N0, M0 GG 1 (GS 6 or less) PSA less than 10	The tumor is not felt or seen with an imaging test such as TRUS. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and PSA level is less than 10.
	OR
	cT2a, N0, M0 GG 1 (GS 6 or less)   PSA less than 10	The tumor can be felt by DRE or seen with imaging such as TRUS. The cancer is in one half or less of only one side (left or right) of the prostate. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and the PSA level is less than 10.
	OR
	pT2, N0, M0 GG 1 (GS 6 or less) PSA less than 10	The prostate has been excised and the tumor was only in the prostate. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and the PSA level is less than 10.
IIA	cT1, N0, M0 GG 1 (GS 6 or less) PSA at least 10 but less than 20	The tumor is not felt or seen with imaging such as TRUS. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and the PSA level is at least 10 but less than 20.
	OR
	cT2a or pT2, N0, M0 GG 1 (GS 6 or less) PSA at least 10 but less than 20	The tumor can be felt by DRE or seen with imaging such as TRUS and is in one half or less of only one side (left or right) of the prostate.   OR   The prostate has been excised and the tumor was only in the prostate. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and the PSA level is at least 10 but less than 20.
	OR
	cT2b or cT2c, N0, M0 GG 1 (GS 6 or less) PSA less than 20	The tumor can be felt by DRE or seen with imaging such as TRUS. It is in more than half of one side of the prostate, or it is in both sides of the prostate. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 and the PSA level is less than 20.
IIB	T1 or T2, N0, M0 GG 2 (GS 3+4=7) PSA less than 20	The cancer has not spread outside the prostate. It might be felt by DRE or seen with imaging such as TRUS. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 2 and the PSA level is less than 20.
IIC	T1 or T2, N0, M0 GG 3 or 4 (GS 4+3=7 or 8) PSA less than 20	The cancer has not spread outside the prostate. It might be felt by DRE or seen with imaging such as TRUS. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 3 or 4 and the PSA level is less than 20.
IIIA	T1 or T2, N0, M0 GG 1 to 4 (GS 8 or less) PSA at least 20	The cancer has not spread outside the prostate. It might be felt by DRE or seen with imaging such as TRUS. The cancer has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 to 4 and the PSA level is at least 20.
IIIB	T3 or T4, N0, M0 GG 1 to 4 (GS 8 or less) Any PSA	The cancer has grown outside the prostate and might have spread to the seminal vesicles. It may have spread into other tissues next to the prostate, such as the urethral sphincter, rectum, bladder, and/or the wall of the pelvis. It has not spread to nearby lymph nodes or elsewhere in the body. The GG is 1 to 4 and the PSA can be any value.
IIIC	Any T, N0, M0 GG 5 (GS 9 or 10) Any PSA	The cancer might be growing outside the prostate and into nearby tissues. It has not spread to nearby lymph nodes or elsewhere in the body. The GG is 5 and the PSA can be any value.
IVA	Any T, N1, M0 Any GG Any PSA	The tumor might be growing into tissues near the prostate. The cancer has spread to nearby lymph nodes but has not spread elsewhere in the body. The GG can be any value and the PSA can be any value.
IVB	Any T, any N, M1 Any GG Any PSA	The cancer might be growing into tissues near the prostate and might have spread to nearby lymph nodes. It has spread to other parts of the body (distant lymph nodes, bones, or other organs). The GG can be any value and the PSA can be any value.

Grade

• The Gleason Grading System (GS) is the traditional system used to grade prostate cancer. ⁸
  • The grades range from 1-5, with 1 being assigned if the tissue looks more like normal prostate tissue and 5 for tissue that looks extremely abnormal.
  • The grades of 2-4 have tissue features between the two extremes (1 and 5).
• Prostate cancers often have areas with different grades. The first grade assigned is the grade most common in the tumor. For example, if most of the tumor tissue is grade 3 and the second most common grade is 4, the GS would be written as 3+4=7.
• Recently, Grade Groups (GG) have developed as a system to better grade prostate cancer. The GG and GS grading systems correlate as follows:

Table 2. Tests for prostate cancer: Prostate cancer diagnosis. ⁸

GG1 = GS 6 or less = well differentiated	Low grade cancer
GG2 = GS 7 (3+4) = moderately differentiated	Intermediate grade cancer
GG3 = GS 7 (4+3) = moderately differentiated	Intermediate grade cancer
GG4 = GS 8 = poorly differentiated	High grade cancer
GG5 = GS 9 and 10 = poorly differentiated	High grade cancer

Prostate Cancer Survival Rates

5-year survival rates can be categorized based on SEER Stage of cancer.¹⁰

Table 3. Prostate Cancer 5-year relative survival rates¹⁰

SEER Stage	5-year Relative Survival Rate
Localized*	>99%
Regional**	>99%
Distant***	31%
All SEER stages combined	98%

*Localized: No sign the cancer has spread outside the prostate.
**Regional: The cancer has spread outside the prostate to nearby structures or lymph nodes.
***Distant: The cancer has spread to more distant parts of the body, such as the lungs, liver, or bones.

Management of Prostate Cancer

Management of Prostate cancer depends on numerous factors including stage and grade of the prostate cancer, patient age, life expectancy, patient/provider experience, likelihood that treatment will cure the cancer, and side effects of treatment.

Treatment of Localized Prostate Cancer

The recommended treatment for localized prostate cancer depends largely on risk stratification: ¹³

Table 4. Risk Stratification for Localized Prostate Cancer¹

Very Low Risk/Low Risk:

• Active surveillance (AS) is the best available treatment option for very low-risk and low risk localized prostate cancer patients.
• Definitive treatment (i.e., radical prostatectomy or radiotherapy) is an option for select low risk localized prostate cancer patients who may have a high probability of progression on AS.
• Observation or watchful waiting are options for men with a life expectancy ≤5 years with low risk localized prostate cancer.

Intermediate Risk:

• Radical prostatectomy or radiotherapy plus androgen deprivation therapy (ADT) are standard treatment options for patients with intermediate risk localized prostate cancer.
• Observation or watchful waiting are options for men with a life expectancy ≤5 years with intermediate risk localized prostate cancer.

High Risk:

• Radical prostatectomy or radiotherapy plus ADT are standard treatment options for patients with high-risk localized prostate cancer.

Treatment of Locally Advanced/Metastatic Prostate Cancer

The recommended treatment for locally advanced/metastatic prostate cancer is variable depending on the disease stage, which ranges from PSA recurrence after exhaustion of local treatment options to widespread metastatic disease. ¹⁴

Table 5. Advanced Prostate Cancer: AUA/Astro/SUO Guildeline¹⁴

Stage	Definition	Treatment Options
Biochemical Recurrence without Metastatic Disease after Exhaustion of Local Treatment Options	Patients with rising PSA after failure of local therapy and no metastatic disease by conventional imaging	Optimal management of these patients is largely unestablishedSalvage radiation is the standard approachConcurrent use of antiandrogen therapy with radiationIntermittent Androgen Deprivation Therapy (ADT) is preferable to continuous therapyObservation or clinical trial enrollment15
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)	Prostate cancer that has spread past the prostate and into the rest of the body, but can be treated with hormone therapy	Androgen Deprivation Therapy (ADT) with Luteinizing hormone-releasing hormone (LHRH) agonists or antagonists or surgical castrationContinued ADT in combination with either androgen pathway directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel)In select mHSPC patients with low-volume metastatic disease, primary radiotherapy to the prostate in combination with ADT is an option
Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)	Prostate cancer progression (e.g., rising PSA) despite castrate levels of testosterone and no detectable metastases on imaging	Apalutamide, darolutamide, or enzalutamide with continued ADT for patients with nmCRPC at high risk for developing metastatic diseaseObservation with continued ADT for nmCRPC patients at lower risk to develop metastatic disease
Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Prostate cancer progression with metastases despite castrate levels of testosterone	In newly diagnosed mCRPC patients, continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamideIn mCRPC patients who are asymptomatic or minimally symptomatic, sipuleucel-T can be offeredRadium-223 for patients with symptoms from bony metastases and without known visceral disease or lymphadenopathy >3cmCabazitaxel should be offered in patients who received prior docetaxel chemotherapy with or without prior abiraterone acetate plus prednisone or enzalutamideCabazitaxel should be offered to patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamideA PARP inhibitor should be offered to patients with deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy

Surveillance Following Therapy

Following treatment for prostate cancer, it is recommended to have PSA blood tests every 6 months for the first 5 years to monitor for recurrence and/or potential metastases. Most patients will continue PSA blood tests at least yearly after this to continue monitoring. Bone scans or other imaging tests may be done as well. A patient who underwent treatment at a higher stage of cancer may require more frequent follow up. ¹⁶

References

1. What is prostate cancer? American Cancer Society. Updated August 1, 2019. Accessed September 19, 2022.
2. Key statistics for prostate cancer: Prostate cancer facts. American Cancer Society. Updated January 12, 2022. Accessed September 19, 2022.
3. American Cancer Society recommendations for Prostate Cancer Early Detection. American Cancer Society. Updated April 23, 2021. Accessed September 19, 2022.
4. Schatten H, Schatten H. Brief Overview of Prostate Cancer Statistics, Grading, Diagnosis and Treatment Strategies. In: Cell & Molecular Biology of Prostate Cancer Updates, Insights and New Frontiers. Vol 1095. Switzerland: Springer International Publishing; 2018:2-2. doi: 10.1007/978-3-319-95693-0_1.
5. Prostate cancer causes, risk factors, and prevention. American Cancer Society. Updated June 9, 2020. Accessed September 20, 2022.
6. Prostate cancer early detection, diagnosis, and staging. American Cancer Society. Updated January 4, 2021 Accessed September 21, 2022.
7. Naji L, Randhawa H, Sohani Z, Dennis B, Lautenbach D, Kavanagh O, Bawor M, Banfield L, Profetto J. Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis. Ann Fam Med. 2018 Mar;16(2):149-154. doi: 10.1370/afm.2205.
8. Tests for prostate cancer: Prostate cancer diagnosis. American Cancer Society. Updated March 24, 2022. Accessed September 21, 2022.
9. Schaeffer E. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate Cancer. Published September 16, 2022. Accessed September 23, 2022.
10. Survival rates for prostate cancer. American Cancer Society. Updated March 1, 2022. Accessed September 22, 2022.
11. Types of prostate cancer. Cancer Research UK. Updated April 27, 2022. Accessed September 23, 2022.  
12. Prostate cancer stages. American Cancer Society. Updated October 8, 2021. Accessed September 22, 2022.
13. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. American Urological Association (AUA) / American Society for Radiation Oncology (ASTRO) / Society of Urologic Oncology (SUO). April 2017:3-4. doi: 10.1016/j.juro.2017.11.095.
14. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline. AUA/ASTRO/SUO Guideline. June 2020:2-4.  doi: 10.1097/JU.0000000000001375.
15. Simon NI, Parker C, Hope TA, Paller CJ. Best approaches and updates for prostate cancer biochemical recurrence. American Society of Clinical Oncology Educational Book. 2022;(42):352-359. doi:10.1200/edbk_351033
16. Living as a prostate cancer survivor: After prostate cancer treatment. American Cancer Society. Updated March 16, 2022. Accessed September 22, 2022.

Author Bio

Dr. Laura Bukavina is a urologic oncology fellow at Fox Chase Cancer Center, with focus in bladder and kidney cancer. She is an incoming urologic oncology faculty at University Hospitals Cleveland Medical Center/Case Western Reserve University. Dr. Bukavina’s career commitment is to advance the understanding and treatment of bladder cancer through integration of science and surgery. She continues her work with support from American Urologic Association and Bladder Cancer Advocacy Network grants focusing on microbiome modulation, tumor microenvironment and treatment response. The goal of her research is to understand responses to therapy based on unique patient immune environment and interaction with host bacteria. More information about her research can be seen here:

Twitter:        @LauraBukavinaMD

Dr. Spencer Bell is a urology research fellow at Fox Chase Cancer Center, with experience in clinical trials patient recruitment. He graduated from Brody School of medicine at East Carolina University. His research interest has focused on assessment of financial toxicity of urologic cancer treatment and surveillance.

Twitter:        @spencer_bell416