Management of Localized Prostate Cancer

*****These notes provide an overview on the established treatments in localized prostate cancer. For notes on selecting treatment for localized prostate cancer, please see the 2017 AUA Guideline on Clinically Localized Prostate Cancer Notes*****

Established Treatment Options for Localized Prostate Cancer

• Conservative management
  • Watchful waiting
  • Active surveillance
• Radical prostatectomy
• Radiation

Pre-treatment Risk Evaluation

• Treatment recommendations in prostate cancer are based on:
  1. Disease characteristics
  2. Life expectancy
  • Disease characteristics
    • Based on clinical stage, serum PSA level, and biopsy characteristics (Gleason score, # cores positive, maximum % core involvement, etc.).
      • Each characteristic is individually prognostic, but their combination improves predictive performance.
    • AUA Risk Stratification
      • Very low risk
        1. PSA <10 ng/ml AND
        2. Grade Group 1 AND
        3. Clinical stage T1-T2a AND
        4. <34% (i.e. one-third or less) of biopsy cores positive AND
        5. No core with >50% involved AND
        6. PSA density <0.15 ng/ml/g
      • Low risk (i.e. first 3 criteria of very low-risk)
        1. PSA <10 ng/ml AND
        2. Grade Group 1 AND
        3. Clinical stage T1-T2a
      • Intermediate risk
        • PSA 10-<20 ng/ml OR
        • Grade Group 2-3 OR
        • Clinical stage T2b-c
          • Favorable: Grade Group 1 (with PSA 10-<20) OR Grade Group 2 (with PSA<10)
          • Unfavorable: Grade Group 2 (with either PSA 10-<20 OR clinical stage T2b-c) OR Grade Group 3
      • High risk
        • PSA >20 ng/ml OR
        • Grade Group 4-5 OR
        • Clinical stage ≥T3*
          • *Clinical stage T3 cancer is considered locally advanced and, therefore, outside the scope of this guideline.
      • For very-low risk, targeted biopsies should not be included in the total percent of cores positive.
        • if a 12-core systematic biopsy finds 4/12 cores positive (1/3 of cores), and a targeted biopsy with 3 cores all of which are positive, the patient should be considered very-low risk (4/12 cores positive, not 7/15 cores positive), assuming he meets all other low-risk criteria and assuming the targeted biopsy was in the same location as one of the systematic biopsies.
        • If the targeted biopsy was outside the location of a systematic biopsy, then it should count as one additional core. In this scenario, the patient would have 5/13 cores positive and be considered low-risk, but not very low-risk.
      • D'Amico risk stratification into low-, intermediate-, and high-risk groups is adopted by many guidelines, including AUA and NCCN. These risk strata are based on PSA, biopsy grade, and clinical T stage and were originally developed to predict biochemical recurrence after definitive treatment.
        • Design: retrospective cohort study
        • Population: 1872 men with clinically localized prostate cancer undergoing definitive local therapy (external beam radiotherapy (EBRT), brachytherapy, brachytherapy + ADT, or radical prostatectomy).
          • Patients risk-stratified into low-, intermediate-, and high-risk based on PSA, biopsy grade, and clinical T stage.
        • Results:
          • Patients with intermediate- or high-risk prostate cancer are more likely to have biochemical recurrence with brachytherapy, compared to radical prostatectomy. No difference in risk of biochemical recurrence with EBRT or brachytherapy + ADT, compared to radical prostatectomy.
        • D'Amico, Anthony V., et al. "Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer." JAMA 280.11 (1998): 969-974.
    • Other risk stratification models
      • Epstein criteria (developed in 1994):
        • Pre-operative clinical and pathological parameters are used to predict which tumors (clinically insignificant cancer) can be observed without aggressive treatment, some of which have been adopted to define very-low risk:
          • Model 1:
            • No Gleason pattern 4 or 5 in the biopsy specimen
            • PSA density ≤ 0.1 ng/mL/g
            • <3 biopsy cores involved (with a minimum of six total cores being obtained)
            • No core with >50% involvement
          • Model 2
            • PSA density of 0.1-0.15 ng/mL/g
            • Cancer smaller than 3 mm on only one prostate biopsy sample
          • Epstein, Jonathan I., et al."Pathologic and clinical findings to predict tumor extent of nonpalpable (stage t1 c) prostate cancer." JAMA 271.5 (1994): 368-374.
        • Subsequently in 1998, Epstein et al. updated the model to include a free/total PSA ratio (0.15) and favorable needle biopsy findings (<3 cores involved, no core with > 50% tumor, and Gleason score of ≤6)
          • Epstein, Jonathan I., et al. "Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings." The Journal of urology 160.6 Part 2 (1998): 2407-2411.
      • Cambridge prognostic groups
        • Developed to predict cancer-specific survival
        • Gnanapragasam, Vincent J., et al. "Improving clinical risk stratification at diagnosis in primary prostate cancer: a prognostic modelling study." PLoS medicine 13.8 (2016): e1002063.
    • Life expectancy
      • Most prostate cancers are indolent; the benefits of treatment need to be considered against the competing risk of death from other causes.
      • Life expectancy calculators
        • NHS Predict Prostate
        • Memorial Sloan Kettering Cancer Center Male Life Expectancy Survey
        • Cambridge Prognostic Groups (requires registration)
        • US Social Security Administration

Conservative management

Observation/watchful waiting

• Refers to monitoring the patient until he develops metastases that requires palliative treatment
• Indications
  1. Asymptomatic males with limited life expectancy
     • Threshold varies between guidelines
       • 2017 AUA: < 5-years life expectancy
       • 2021 NCCN:< 5-10 years life expectancy
       • Symptomatic men should be treated
• Life expectancy calculators (listed above) can help estimate the patient's risk of death from competing causes.
  • Clinician-based life expectancy estimates are not robust.[1][2][3][4]
• RCTs comparing treatment and observation (3): PIVOT, SPCG-5, PROTECT
  • PIVOT
    • Population: 731 US men from Department of Veterans Affairs and National Cancer Institute medical centers, with:
      • cT1-2NxM0 prostate cancer
      • Any grade
      • PSA < 50
      • Life expectancy ≥ 10 years
    • Randomized to observation vs. radical prostatectomy
    • Outcomes:
      • Primary: overall survival
      • Secondary: cancer-specific survival
    • Results:
      • Cohort characteristics:
        • Mean age ≈67
        • Mean PSA ≈10 (median ≈8)
        • ≈50% cT1c
        • ≈70% Gleason score ≤ 6
        • ≈40% low-risk
      • Median follow-up: 10 years (initial 2012 publication, updated in 2020 to 18.6 years)
      • Primary outcome: no significant difference in overall survival in initial publication
        • In 2020 publication with median follow-up in survivors 18.6 years, overall survival significantly improved in radical prostatectomy group
          • Emphasizes importance of long-term follow-up in studies evaluating survival in prostate cancer.
        • 2020 subgroup analyses:
          • Age: benefit less pronounced in age ≥ 65
          • Risk stratum: benefit less pronounced in low-risk
      • Secondary outcome: no significant difference cancer-specific survival in initial publication
    • Criticisms:
      • Underpowered to detect a difference in survival, enrollment could not be achieved
      • Conducted in Veterans Affairs hospitals where many men had relatively poor health; disease; other-cause mortality in this trial was higher than in other trials, suggesting that men enrolled had more comorbidities
      • Radical prostatectomies were performed with higher complication rates with worse cancer control outcomes compared with the series from the centers of excellence
      • Follow-up is insufficient to assess the mortality caused by prostate cancer
    • Wilt, Timothy J., et al. "Radical prostatectomy versus observation for localized prostate cancer." N Engl J Med 367 (2012): 203-213.
    • Wilt, Timothy J., et al. "Follow-up of prostatectomy versus observation for early prostate cancer." New England Journal of Medicine 377.2 (2017): 132-142.
    • Wilt, Timothy J., et al. "Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT)." European urology (2020).
  • SPCG-4 – NET BENEFIT
    • Population: 695 men from Sweden, Finland, and Iceland, with localized prostate cancer with
      • cT1-2NxM0 prostate cancer
      • Well differentiated to moderately well differentiated
      • PSA < 50
      • Life expectancy ≥ 10 years
    • Randomized to observation vs. radical prostatectomy
    • Outcomes: survival
    • Results
      • Cohort characteristics:
        • Mean age ≈65
        • Higher-risk population than PIVOT
          • cT2 75% vs. 45% PIVOT
          • Mean PSA 13 vs. 10 PIVOT
      • Median follow-up: 8.2 years (initial 2005 publication, updated in 2018 to 23.6 years)
      • Overall, cancer–specific, distant metastases-free survival were significantly worse in patients managed with watchful waiting (in initial and updated publication)
      • Men on watchful waiting experienced significantly more obstructive voiding complaints and bowel problems
    • Bill-Axelson, Anna, et al. "Radical prostatectomy versus watchful waiting in early prostate cancer." N Engl J Med 352 (2005): 1977-1984.
    • Bill-Axelson, Anna, et al. "Radical prostatectomy or watchful waiting in prostate cancer—29-year follow-up." New England Journal of Medicine 379.24 (2018): 2319-2329.
  • PROTECT – SOME BENEFIT
    • Population: 1643 men from UK with localized prostate cancer
    • Randomized to surgery, radiotherapy, vs. “active monitoring”
      • No rigorous AS follow-up protocol; patients followed with serial PSA, no mandated repeat biopsy
    • Outcomes:
      • Primary: cancer-specific survival
      • Secondary: overall survival, metastases, clinical progression, primary treatment failure, treatment complications.
    • Results
      • Cohort characteristics:
        • Mean age 62
        • Lowest risk, compared to PIVOT and SPCG-4
          • Median PSA 4.7-4.9
          • ≈75% Gleason score 6, ≈20% Gleason score 7
          • ≈75% cT1c, ≈25% cT2
      • Median follow-up: 10 years
      • Primary outcome: no significant difference in cancer-specific survival
      • Secondary outcomes:
        • No significant difference in overall survival
        • Metastasis significantly increased in observation group
    • Hamdy, Freddie C., et al. "10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer." New England Journal of Medicine 375.15 (2016): 1415-1424.
  • Trials in context: older men with low-risk disease, especially those with associated comorbidities are unlikely to benefit from curative intervention.
• At 10-years, the risk of metastasis is ≈20% in men on observation/watchful waiting
• Follow-up
  • History and physical examination (including DRE), PSA and creatinine measurement at 6-month intervals, and an annual bone scan has been suggested
    • Progression of disease among men on watchful waiting could occur as a result of local tumor growth and/or metastatic spread of disease to lymph nodes or bone.
      • Local extension of disease may result in lower urinary tract symptoms (irritative and obstructive) or upper tract obstruction from invasion into the trigone of the bladder
    • While disease progression would most often be accompanied by increases in PSA, poorly differentiated cancers producing little PSA can progress without a rising PSA, especially with neuroendocrine differentiation. Thus, follow-up should not rely on serial PSA measurements alone.
    • Campbells: "Because the goal of watchful waiting is to limit morbidity and not to administer potentially curative treatment, PSA testing, repeat biopsy, and imaging studies are unimportant."
  • Indications for intervention (androgen deprivation therapy as palliative care) on watchful waiting:
    1. Symptomatic progression
    2. Evidence of upper urinary tract obstruction
    3. Evidence of metastatic disease

Active surveillance (AS)

• Refers to delayed primary treatment (with curative intent) if there is biochemical or histologic evidence of cancer progression
• Disease-specific and all-cause survival have been high and compare favorably with longer-term outcomes after prostatectomy or various forms of radiotherapy in similar-risk men of low-risk tumors
• Advantage of surveillance:
  1. Reduce overdiagnosis/overtreatment of prostate cancer
     • Overdiagnosis refers to a cancer detected by screening that would not be detected during the patient’s lifetime without screening or would never cause disability or death.
       • There is substantial overdiagnosis of prostate cancer as a result of widespread PSA screening coupled with aggressive biopsy regimens.
       • Any screening program will involve detection of some cancers that would not have been otherwise detected.
     • Overtreatment refers to treatment of men who would otherwise not have known about their cancer in the absence of PSA testing.
       • The risk of overtreatment of prostate cancer is high when prostate cancer is discovered on prostate biopsies triggered by PSA testing—the most common scenario.
• Disadvantages of surveillance:
  1. Risk of multiple biopsy procedures
     • Risks of repeat biopsies include infections, erectile dysfunction, complicate subsequent attempts at nerve-sparing surgery
  2. Delaying treatment and possibly missing the window of opportunity for cure
• Disease Reclassification on AS
  • Reclassification vs. progression
    • The term progression while on AS should be replaced with disease reclassification, since most patients meeting surveillance criteria who are found to have high-grade or more extensive disease on surveillance biopsies are thought to have been misclassified initially, rather than experiencing true disease progression
      • One study found that 36% of men with Gleason score 5-6 on needle biopsy were found to have higher-grade disease at radical prostatectomy when tertiary grade was considered. Another study found that the 10-year actuarial rate of upgrading on annual surveillance biopsies in a large active surveillance experience was ≈30%. The similarity in the rate of upgrading at radical prostatectomy, and reclassification to high-grade disease on annual biopsies for men with low-grade cancer, strongly suggest that initial misclassification is the more common reason for re-classification on surveillance, and not “true” disease progression from low to high grade.
  • ≈25-50% of patients on AS develop evidence of disease reclassification within 5 years, depending on their individual risk factors:
    • Patient factors
      • Race
        • African-American males are at increased risk of progression on AS
      • Germline mutations
        • BRCA
          • BRCA 2 associated with higher risk than BRCA 1
            • BRCA 1 associated with 4x higher risk of prostate cancer
            • BRCA 2 associated with 9x higher risk of prostate cancer, higher Gleason scores, more advanced tumor stage, and shorter median survival
      • Age, comorbid illness, and willingness to adhere to surveillance strategies must also be considered during patient selection
    • Disease factors
      • The Epstein criteria were selected to identify potentially low-risk tumors and are among the most popular used for patient selection for active surveillance. By these criteria, “insignificant” tumors are predicted by:
        • Grade group 1 disease on biopsy and
        • Clinical stage T1c and either
          • PSA density ≤ 0.1 ng/mL per gram, ≤ 2 positive biopsy cores, and no cores with > 50% involvement or
          • PSA density of ≤ 0.15 ng/mL per gram or less and cancer smaller than 3 mm on only one biopsy core.
      • More extensive biopsies during the standard 12-core biopsy have not been shown to be helpful in selecting patients for AS
• Indications (2017 AUA Guideline on Localized Prostate Cancer Notes)
  • Best option for very low-risk patients
  • Preferred option for most low-risk patients
  • May be offered to select patients with favorable intermediate-risk disease; however, patients should be informed that this comes with a higher risk of developing metastases compared to definitive treatment.
    • Patients with small volume cancer on biopsy who have < 10% Gleason pattern 4 may be favorable candidates
• Surveillance protocol
  • Tumour grade is the best predictor of cancer biology and is is the strongest predictor of long-term freedom from disease in untreated men. As such, there has been an effort to predict grade reclassification among men considered for surveillance or being monitored, through the use of:
    • Prostate biopsy features
    • Imaging
    • Biomarkers.
  • Reclassification Biopsy
    • Repeat prostate biopsies over time are the cornerstone of active surveillance.
      • The critical role of repeat prostate biopsy for successful identification of higher-risk disease during surveillance cannot be overemphasized.
    • Biopsy re-classification on surveillance can be defined in terms of a greater extent of disease at biopsy and/or higher grade of disease at biopsy, both predictive of adverse features at radical prostatectomy
    • Early “confirmatory” biopsy serves to limit the risk of clinical undergrading resulting from sampling
      • Many advocate for this repeat biopsy within 3-6 months of diagnosis
        • Gleason grade changes and thus risk reclassification occur in 2.5-28% after the first repeat biopsy. These numbers are sensitive to selection criteria and biopsy technique.
    • Serial prostate biopsies are variably performed from an annual basis to once every 3 to 4 years.
      • The risk of disease reclassification continues over time while on surveillance, likely a result of both undersampling and true histologic disease progression in either tumor grade or volume.
  • Imaging
    • mpMRI has been reported to have high sensitivity and specificity for high-grade prostate cancers and thus could be of value in reducing disease misclassification and selecting and monitoring individuals interested in active surveillance
      • ASIST
        • Objective: determine if the addition of MRI with targeted biopsies could identify progression on active surveillance better than systematic biopsy alone
        • Population: 273 men diagnosed with Grade Group 1 cancer within 1 yr prior to study entry in whom a confirmatory biopsy was indicated
        • Randomized to systematic biopsy +/- MRI with targeted biopsy
        • Primary end point was the proportion upgraded to Grade Group ≥2
        • Results: no significant difference in rate of upgrading
        • Klotz, Laurence, et al. "Active Surveillance Magnetic Resonance Imaging Study (ASIST): results of a randomized multicenter prospective trial." European urology 75.2 (2019): 300-309.
  • Biomarkers
    • Volume-adjusted PSA (PSA density) has been a consistent independent predictor of disease reclassification (both cancer volume on biopsy and grade) during surveillance.
    • PSA kinetics (velocity or doubling time) has been associated with adverse pathology in men on surveillance, but not consistently associated with disease reclassification
    • 2 gene expression (Oncotype DX and Polaris, see PSA and Other Markers Chapter Notes) assays are now commercially available for prostate cancer and are integrated with baseline clinical variables to provide more precise risk assessment for patients; however, to date it is unknown what role these tests will have in AS
  • Guideline recommendations
    • AUA (2017 AUA Guideline on Localized Prostate Cancer Notes)
      • Routine surveillance PSA testing and DRE, frequency not specified
      • Confirmatory biopsy within the initial 2 years and surveillance biopsies thereafter
    • CUA (2015 CUA Guideline on Prostate Cancer Active Surveillance Notes)
      1. PSA every 3-6 months
      2. DRE every year
      3. Confirmatory biopsy within the initial 6-12 months, then serial biopsy a minimum of 3-5 years thereafter
    • None of the current active surveillance studies have found DRE to be an independent predictor of cancer progression, although it can be useful in determining that a repeat biopsy should be taken.
• Indications for intervention on AS (4):
  1. Progression in cancer grade on repeat biopsy
     • High-grade disease (Gleason score ≥7) on surveillance biopsies has been considered a trigger for intervention in most active surveillance programs.
  2. Progression in cancer volume on repeat biopsy
  3. Rapidly rising PSA
  4. Patient anxiety

Radical prostatectomy (RP)

• The first treatment used for prostate cancer and has been performed for almost 150 years
• Recent innovations that have led to wider use include (3):
  1. Development of the anatomic radical retropubic prostatectomy, which allows the dissection to be performed with good visualization and preservation of the cavernosal nerves responsible for erectile function and preservation of the external sphincter muscle that yields urinary continence rates in excess of 90%.
  2. Development of extended ultrasound-guided biopsy regimens, performed under local anesthesia as an office procedure
  3. Widespread use of PSA testing, which has led to the great majority of patients being diagnosed with clinically localized disease.
• Advantages of RP (3):
  1. Possibility of cure with minimal collateral damage to surrounding tissues
  2. Accurate tumor staging by pathologic examination of the surgical specimen
  3. Treatment failure more readily identified, allowing for potentially curative salvage radiotherapy to be undertaken
• Disadvantages of RP (3):
  1. Necessary hospitalization and recovery period
  2. Possibility of incomplete tumor resection, if the operation is not performed properly or if the tumor is not contained within the prostate gland
  3. Treatment-related morbidity (risk of erectile dysfunction and urinary incontinence)
• Surgical approaches
  • Open
    • See Open Radical Prostatectomy Chapter Notes
    • Approaches: perineal vs. retropubic
      • Perineal
        • Advantages (2):
          1. Reduced blood loss than the retropubic approach
          2. Shorter operative time than the retropubic approach
        • Disadvantages (3):
          1. No access for a pelvic lymph node dissection
          2. Higher rate of rectal injury
          3. Occasional post-operative fecal incontinence that does not occur commonly with other approaches
      • Retropubic
        • Advantages/disadvantages opposite of perineal and surgeons more familiar with surgical anatomy
  • Laparoscopic
    • Can be performed through a transperitoneal or extraperitoneal approach
      • Transperitoneal approach facilitates the lymphadenectomy but carries a higher risk of intestinal and vascular injury, urinary ascites, and post-operative ileus and intestinal obstruction.
      • Extraperitoneal approach poses logistical limitations, especially with the use of a robot.
    • Robot-assisted
      • See BJUI Surgical Atlas for details and figures
      • RCT comparing open to robotic RP (2018)
        • Population: 326 men with newly diagnosed clinically localised prostate cancer
        • Randomized to robot-assisted laparoscopic prostatectomy or open radical retropubic prostatectomy
        • Primary outcomes: urinary, sexual, and oncologic at 24 months
        • Results:
          • Urinary: no difference
          • Sexual: no difference
          • Oncologic: biochemical recurrence significantly worse in open RP (absolute risk difference 6%)
        • Author’s advise caution in interpreting the oncological outcomes of our study because of the absence of standardisation in postoperative management between the two trial groups and the use of additional cancer treatments. Clinicians and patients should view the benefits of a robotic approach as being largely related to its minimally invasive nature.
        • Coughlin, Geoffrey D., et al. "Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study." The Lancet Oncology 19.8 (2018): 1051-1060.
      • Health Quality Ontario
        • No high-quality evidence that robot-assisted RP improves functional and oncological outcomes compared with open and laparoscopic approaches. However, compared with open RP, the costs of using the robotic system are relatively large while the health benefits are relatively small.
        • Health Quality Ontario. "Robotic surgical system for radical prostatectomy: a health technology assessment." Ontario health technology assessment series 17.11 (2017): 1.
  • Antibiotic prophylaxis at the time of catheter removal after radical prostatectomy
    • Population: 167 patients undergoing radical prostatectomy
    • Randomized to antibiotic prophylaxis (2 doses of oral ciprofloxacin prior to urinary catheter removal) vs. control (no antibiotics given prior to urinary catheter removal).
    • Primary outcome: development of symptomatic UTI within 6 weeks after catheter removal
    • Results:
      • No significant difference between prophylaxis (4%) vs. control (6%)
    • Berrondo, Claudia, et al. "Antibiotic prophylaxis at the time of catheter removal after radical prostatectomy: A prospective randomized clinical trial." Urologic Oncology: Seminars and Original Investigations. Vol. 37. No. 3. Elsevier, 2019.
• Selection of patients
  • The generally accepted upper age limit for RP is ≈76 years
  • The role of nerve-sparing surgery is questionable when there is:
    1. Extensive cancer in the biopsy specimens
    2. Palpable extraprostatic tumor extension
    3. Serum PSA level > 10 ng/mL
    4. Biopsy Gleason score > 7
    5. Poor-quality erections preoperatively
    6. Current and future lack of a sexual relationship
    7. Other medical conditions that may adversely affect erections (e.g., diabetes mellitus, hypertension, psychiatric diseases, neurologic diseases, or medications that produce erectile dysfunction)
• Complications
  • Open
    • See Open Radical Prostatectomy Chapter Notes
  • Robotic
    • Incisional hernia
      • Transverse skin incision for camera port placement and transverse fascial incision for prostate specimen extraction has been associated with a decrease in the risk of incisional hernia from 5.4% to 0.4%.
      • Fascial closure is required for non-bladed trocar sizes of 10 mm or more.
      • No evidence that specimen extraction above versus below the umbilicus affects the likelihood of incisional hernia.
      • Squeezing around the specimen through a minimally-sized incision increases the risk of tearing the fascia and subsequent incisional hernia formation.
      • Some evidence that interrupted versus continuous closure may result in lower risk of incisional hernia, particularly for midline hand-assisted approaches.
• Cancer control
  • RP can provide long-term cancer control in ≈50% of highly selected men with high-risk or locally advanced disease
  • Biochemical recurrence is frequently used as an intermediate end point for treatment outcomes; however, not all patients with biochemical recurrence ultimately develop metastases or die of prostate cancer (See Pound et al.)
  • Independent clinical prognostic factors [for biochemical recurrence] are tumor pathology, Gleason score, pre-operative PSA level, and treatment.
    • Adverse prognostic features include:
      • Non–organ-confined disease
      • Lymphovascular space invasion
      • Extraprostatic extension
      • Positive surgical margins
      • Seminal vesicle invasion
      • Lymph node metastases
  • Nomograms
    • Partin tables
      • Preoperative clinical and pathologic parameters (PSA, clinical stage, Gleason score) are used to predict the pathologic stage in patients undergoing radical prostatectomy
    • Kattan nomogram
      • Preoperative clinical and pathologic parameters (PSA, clinical stage, Gleason score) are used to predict the risk of biochemical recurrence after prostatectomy
      • Kattan, Michael W., et al. "A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer." JNCI: Journal of the National Cancer Institute 90.10 (1998): 766-771.
    • CAPRA score
      • Developed to predict biochemical-recurrence after radical prostatectomy
      • Based on 5 criteria:
        • Age
        • PSA
        • Clinical stage
        • Gleason score
        • % of positive biopsy cores that were positive for cancer
      • Score ranges from 0-10
      • Cooperberg, Matthew R., et al. "The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy." The Journal of urology 173.6 (2005): 1938-1942.
  • In rare instances with high-grade or neuroendocrine tumors that do not produce much PSA, there can be palpable evidence of recurrence despite an undetectable PSA level, indicating a role for DRE in monitoring of patients.
• Neoadjuvant ADT
  • May be associated with clinical stage downstaging and lower rate of positive margins; however, not associated with pathological downstaging, lymph node metastases rates, cancer- specific or overall survival
    • Neoadjuvant hormone therapy does not enhance the resectability of prostate cancer and often increases the difficulty of performing nerve-sparing surgery (Soloway et al, 2002).
  • May have benefit in patients with high-risk disease
    • Klotz, L. H., et al. "Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy." The Journal of urology 170.3 (2003): 791-794.
    • Aus, G., et al. "Three‐month neoadjuvant hormonal therapy before radical prostatectomy: a 7‐year follow‐up of a randomized controlled trial." BJU international 90.6 (2002): 561-566.
• Neoadjuvant chemotherapy
  • Rarely produces pathologic complete responses

Radiation therapy

• See Radiation Therapy in Prostate Cancer Chapter Notes
• Pre-RT prognostic factors in localized disease:
  1. Pre-treatment PSA level and velocity
  2. Biopsy grade group
  3. Percentage of positive prostate biopsy scores
  4. Clinical T stage
  5. MRI findings
• Contraindications ST-LIAR (Size, TURP, LUTS, IBD, Ataxia telangiectaisia, Radiation)§
  • Absolute (2)
    1. Prior TURP for brachytherapy if the TUR defect precludes adequate placement of seeds (also associated with increased risk of stricture)
       • Note that Campbell's considers prior TURP a relative contraindication for both brachytherapy and EBRT but the 2017 AUA Localized Prostate Cancer Guidelines describe the above contraindication)
    2. Ataxia telangiectasia (severe response to ionizing radiation)
  • Relative (4)
    1. Significant baseline Lower urinary tract voiding symptoms (can cause acute urinary retention and worsen storage and voiding symptoms, risk increased with brachytherapy; on the other hand, radiotherapy can gradually relieve obstructive urinary symptoms in men with urinary outflow obstructive symptoms)
    2. Large prostate Size >60 cc for brachytherapy (increased risk of urinary side effects)
    3. Inflammatory bowel disease (increased risk for treatment-related morbidity)
    4. History of prior pelvic Radiotherapy (increased risk for treatment-related morbidity)

• End points for treatment success or failure
  • Cancer cells are not killed immediately after exposure to ionizing radiation. Rather, they sustain lethal DNA damage, but do not die until their next attempt to enter into cell division.
  • The PSA level gradually decreases for up to 2-3 years after the completion of radiotherapy; the PSA level is usually monitored at 6-month intervals until it reaches a nadir
  • Nadir PSA
    • Sources of PSA that potentially contribute to the nadir (3):
      1. Residual benign prostatic epithelium
         • Unlike the situation after radical prostatectomy, residual benign glands may be responsible for a low level of PSA production following RT; however, an “acceptable” PSA level after successful RT is markedly lower than the normal range for an age-matched population because of marked atrophy of non-malignant acini
      2. Residual local prostate cancer cells
      3. Subclinical micrometastases
    • Prognostic significance
      • The use of PSA nadir of 0.2 ng/mL for patients treated with combined external beam therapy (EBRT) and brachytherapy has been recommended. Failure to achieve this nadir by 60 months almost always is associated with persistent disease.
        • No absolute nadir threshold can or should be used to define cure
        • Post-treatment PSA levels are usually higher in patients treated with EBRT only, and thus these patients might not easily achieve a nadir of 0.2 ng/mL.
          • With EBRT, the prostate gland is not completely ablated (more organ sparing than brachytherapy) and the remaining prostate epithelium continues to produce PSA.
      • Nadir PSA is a significant predictor of distant metastases, cancer-specific survival, and reflects the pattern of failure
        • A nadir > 2 ng/mL is associated with distant failure
        • The time to PSA nadir is also associated with distant metastases and cancer-specific survival
        • The longer the time to nadir and the lower the absolute nadir, the more likely it is that only benign prostatic epithelium remains.
          • A higher radiation dose achieves a more complete ablation of normal epithelium and thus a lower nadir.
          • Residual local prostate cancer cells: for patients in whom radiotherapy fails to eradicate all the local tumor, the PSA declines progressively until the rate of growth of the surviving prostate cancer cells is greater than the death rate of those fatally damaged by the radiation, at which point the PSA begins to rise, generally relatively slowly.
          • Subclinical micrometastases continue to grow unchecked despite successful treatment of the primary tumor. This growth rate outstrips the rate of decline in the local tumor population relatively early after treatment, leading to a higher and earlier nadir and a more rapid doubling time.
      • The post-nadir PSA doubling time also reflects the pattern of failure
        • Distant failures: shorter PSA doubling times of 3-6 months
        • Local failures: PSA doubling time > 12 months
      • An interval to biochemical failure of < 2 years and a PSA doubling time of < 12 months are associated with worse cancer-specific survival
        • PSA doubling time is the most predictive factor of prostate cancer-specific mortality in patients who have a recurrence after definitive local treatment.
  • Definitions of treatment failure
    • 1996 American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure: 3 consecutive PSA increases measured 6 months apart and backdating the time of cancer progression to halfway between the PSA nadir and the first rising PSA level
    • 2005 Phoenix definition of biochemical failure: PSA nadir + 2 ng/mL; failure is not backdated. Thus the time to recurrence is further prolonged after the PSA level begins to rise, and often it takes a considerably longer time for the PSA level to increase by 2 ng/mL
    • The Phoenix definition of definition of failure is associated with fewer false positives for failure than the ASTRO definition
    • Given the differences in defining failure, it is not possible to make fair comparisons between radical prostatectomy and radiotherapy by use of these outcome measurements; other measurements such as metastasis-free survival or cancer-specific survival are more appropriate comparisons of treatment failure
  • Post-radiation PSA “bounce”§
    • Defined as a rise in PSA (variable threshold from 0.1-0.5 ng/mL§; Campbell's Chapter 116 says 0.2 ng/mL) over the pre-bounce PSA level, with a subsequent rapid decrease in the PSA level to the nadir
      • In the presence of residual benign epithelium or before the full effect of RT has been expressed, PSA may fluctuate or show several consecutive increases, possibily due to:
        1. Post-treatment prostatitis
        2. Delivery of a sublethal dosage of radiation with associated delayed cellular death
    • Occurs in ≈20% of patients, usually within the first 2 years after treatment (within 12 months of completing EBRT§); rarely, a PSA bounce can occur up to 3 years after therapy
      • More common with brachytherapy than EBRT
        • ≈35% of men will experience a PSA bounce of ≥0.2 ng/mL after LDR brachytherapy
    • Currently, there is no reliable way to discern whether a rising PSA in the first 3 years after radiation (brachytherapy or EBRT§) represents treatment failure; it is recommended that a rising PSA within 30 months of brachytherapy be monitored
      • In patients with a continuously rising PSA, especially those who are candidates for salvage therapy, evaluation for locally recurrent vs metastatic disease should be considered before attainment of the Phoenix BCR threshold.§
      • If the rise approaches 10 ng/mL, systemic staging is warranted
      • If the bounce persists > 30 months, a prostate biopsy is warranted
    • When neoadjuvant androgen deprivation is used before radiotherapy, patients often start radiotherapy with an already undetectable PSA. If the PSA remains undetectable, it is impossible to determine a true nadir or time to nadir. A substantial proportion of patients treated with EBRT and ADT experience a PSA increase when the testosterone recovers. Subsequently, as the effect of the radiotherapy is expressed, the PSA declines once again.
  • Evaluating treatment failure
    • Serum PSA is the most useful marker to assess relapse.
    • Although serum PSA nadir has been widely adopted as a surrogate end point to determine RT efficacy, it cannot distinguish between local and systemic failure
    • Post-RT biopsy
      • Can be used to assess the efficacy of local therapies to control cancer; however, major issues involve timing of the biopsies with respect to completion of RT, interpretation of indeterminate biopsies that show marked radiation effect, and the uncertainty imposed by sampling error.
        • The optimal time to biopsy is 30 to 36 months after radiotherapy
        • Gleason scoring of irradiated prostate cancer should be performed only if the histologic evidence of radiation effect is absent or minimal.
          • Inappropriate application of the Gleason scoring system to disintegrating malignant glands showing a marked RT effect results in a false-positive biopsy often misinterpreted as high grade and may lead to unnecessary salvage therapy
        • Scoring systems for the degree of radiation effect have been proposed based on cytoplasmic and nuclear changes and can be helpful in interpreting the biopsy. Their importance is to emphasize the need to differentiate between biopsies showing no or minimal radiation effect and those showing marked treatment effect
    • Imaging
      • MRI is preferred as it offers vastly improved soft tissue definition over either CT or US
      • TRUS alone is of limited diagnostic use after radiotherapy because the increase in fibrosis alters the echogenic characteristics of the irradiated prostate

• External beam radiotherapy (EBRT)
  • Most commonly involves the use of gamma radiation, usually photons, directed at the prostate and surrounding tissues.
  • Advances in Radiation Technology
    • In the era before CT [pre-1990s], RT technique was sometimes referred to as conventional radiation
    • 3D tumor visualization and treatment planning using CT scans began in the 1990s. The result is described as 3DCRT because the radiation beams conform to the shape of the treatment target
    • A major advance in the delivery of radiation came with the advent of intensity-modulated radiation therapy (IMRT). IMRT is a sophisticated way of treatment delivery in which the intensity of radiation can be varied from each beam angle.
      • IMRT requires the use of advanced software, specialized personnel, and hardware adaptations to linear accelerators
      • IMRT results in reduced radiation doses to the rectum, bladder, femoral heads, and small bowel compared to 3DCRT
    • Image-guided radiation therapy (IGRT) is a method in which imaging techniques are used to guide IMRT to the target area. Image guidance was development based on a realization that the
      1. Daily location of the prostate within the pelvis throughout the course of RT is not identical (interfraction motion)
      2. Prostate is mobile even during a single session of RT (intrafraction motion).
      • With image guidance, the location of the prostate can be verified daily before delivering radiation
    • Stereotactic body radiotherapy (SBRT, CyberKnife) defines an external-beam RT that delivers a high dose each treatment using precisely targeted and highly conformal radiation in a small number of fractions (hypofractionation).
      • Limited results have been published in a small number of patients with low-risk disease
  • Radiation dose and field of treatment
    • Currently, doses of 76-80 Gy or more have been shown to improve cancer control
      • Low-risk patients are now frequently treated with 70-72 Gy, intermediate-risk patients with 75-76 Gy, and high-risk patients with ≥80 Gy
      • Randomized trials consistently show that higher dose radiation improved disease control have led to the dose-escalated RT, the current standard of care
  • Combining EBRT and ADT for localized PCa
    • Intermediate-risk
      • 2017 AUA Guidelines: short-term (6-month) concurrent ADT with EBRT is recommended in patients with intermediate-risk, localized disease
        • 2 randomized trials (RTOG 94-08 and D’Amico JAMA 2015) support the addition of ADT to EBRT for intermediate-risk prostate cancer. 4-6 months of ADT were used in these trials. A caveat to these trials was the use of lower radiation doses no longer considered standard today. Therefore, the benefit of adding ADT to modern higher doses of radiation is the subject of continued investigation.
          • In a randomized trial, D’Amico and colleagues confirmed that 6 months of ADT improved outcomes, mostly in the intermediate-risk patients; However, all of the benefit was observed in patients with no or minimal comorbidities. Men with comorbidities did worse with ADT. ADT was associated with an earlier onset of fatal myocardial infarcts in this study.
    • High-risk
      • 2017 AUA Guidelines: long-term (24-36 months) concurrent ADT with EBRT alone or EBRT combined with brachytherapy is recommended
        • No randomized trial has exclusively studied the additional benefit of ADT in the high-risk patients receiving radiotherapy for localized prostate cancer. However, on the basis of the trials involving locally advanced disease, concurrent ADT is recommended
        • EORTC 22863 (Bolla et al. NEJM 1997)
          • Population: 415 men with (cT1-T2 and grade 3, cT3-T4 and any grade) disease
          • Randomized to EBRT +/- 3 years ADT (goserelin)
          • Primary outcome: disease-free survival (time to clinical progression or death)
          • Secondary outcomes: overall survival, distant metastasis
          • Results:
            • Median follow-up: 9.1 years in 2010 publication (5.5 in original)
            • Significantly improved DFS (absolute difference 25%, 10-year DFS 48% ADT group vs. 23% in the RT-alone) with concurrent ADT
            • Significantly improved OS (absolute difference 18.4%, OS 58% vs. 40%) with concurrent ADT
            • Distant mets, locoregional failure, biochem failure significantly favour ADT + rads
          • Bolla, Michel, et al."External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study." The lancet oncology 11.11 (2010): 1066-1073. (original publication 1997)
        • RTOG 86-10
          • Population: 471 men with bulky tumors (T2–T4) with or without pelvic lymph node involvement and without evidence of distant metastases
          • Randomized to EBRT +/- 4 months ADT
          • Results:
            • Significant improvement in local control, distant metastases, disease-free survival, and cancer-specific mortality with ADT, but no benefit in OS (but OS benefit in patients with Gleason score 2-6)(median follow-up 6.7 years)
          • Pilepich, Miljenko V., et al."Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate." International Journal of Radiation Oncology* Biology* Physics 50.5 (2001): 1243-1252.
        • Duration of ADT
          • RTOG 92-02
            • Population: patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level < 150 ng/mL
            • Randomized to radiation + 4 months of ADT before and during radiation therapy vs. radiation + 28 months of ADT before, during, and after radiation therapy
            • Results:
              • Significant improvement in all clinical end points except for overall survival with 28 months of ADT. However, an overall survival benefit of a longer course of hormone therapy was observed in patients with Gleason grade 8 to 10 disease.
          • EORTC 22961
            • Population: 970 men with histologically confirmed prostate adenocarcinoma T1c to T2a–b, pathological nodal stage N1 or N2, and no clinical evidence of metastatic spread (M0) OR with clinical tumor stages T2c to T4, clinical nodal stages N0 to N2, and no clinical evidence of metastatic spread
            • Randomized to radiation + 6 months ADT vs. radiation + 3 years ADT
            • Results:
              • Radiotherapy plus 6 months of ADT provided inferior survival compared with radiotherapy plus 3 years of ADT.
      • The trials above have evaluated the benefit of adding ADT to radiation. It has been questioned whether the benefits of radiation plus ADT are superior to ADT alone for locally advanced disease.
        • PR3/PR07 trial
          • Population: 1,2015 men with with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10
          • Randomized to lifelong ADT +/- radiation
            • Compared to the previous study, in this study, patients had more advanced disease, ADT was accomplished by either continuous LHRH agonist or orchiectomy, and pelvic nodes were treated with RT.
          • Results:
            • Improved OS and DFS with addition of RT to ADT (8 years follow-up in 2015 publication)
          • Mason, Malcolm D., et al."Final report of the intergroup randomized study of combined androgen-deprivation therapy plus radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate cancer." Journal of Clinical Oncology 33.19 (2015): 2143.(original publication 2011)
        • SPCG-7/SFUO-3
          • A Scandinavian trial comparing ADT alone with ADT plus radiation in patients with locally advanced prostate cancer revealed that ADT plus radiotherapy halved the 10-year prostate cancer–specific mortality and substantially decreased overall mortality with fully acceptable risk of side effects compared with ADT alone (Widmark et al, 2009)
    • Of note, radiation doses used in the modern era for prostate cancer are much higher than those used in these trials and should be even more effective.
• Brachytherapy
  • Brachytherapy (“short” therapy) is the placement of radioactive sources into or near tumors for therapeutic purposes
  • The goal of prostate brachytherapy is to deliver a homogeneous dose to the prostate while minimizing dose to nearby sensitive normal structures such as the rectum and urethra; seeds should be distributed evenly throughout the gland with periurethral sparing. Radioactive sources (seeds or needles) are implanted directly into the prostate gland, sometimes into the surrounding tissues
  • There is no preferred isotope for brachytherapy.
    • The most commonly used permanent implants are iodine-125 (125I), palladium-103 (103Pd), or cesium-131 (131Cs) seeds.
  • Assessment of permanent implant quality
    • Post-implant dosimetry in these dose-limiting regions is important to assess implant quality.
      • Post-implantation CT with or without MRI is performed to determine seed localization and reference the dose to the prostate and other structures of importance. A significant source of error in these calculations is prostatic edema, which is invariably observed after implantation
    • Dosimetry can be adversely affected by poor implantation or migration of the seeds after implantation
  • Brachytherapy radiation dose and fields
    • The doses delivered to the prostate substantially higher than those for EBRT: ≈145 Gy for iodine and 125 Gy for palladium
      • Although the prostate itself can tolerate high doses of radiation, the rectal toxicity limits the dose that can be given in brachytherapy
  • Brachytherapy Combined with ADT
    • ADT should not be added to brachytherapy except to reduce the size of the prostate to allow the dosimetry to be optimized
      • In patients who have an enlarged prostate gland, it can be technically challenging to implant the entire prostate volume, especially anteriorly. Accordingly, patients are often treated with ADT to shrink the prostate before brachytherapy is performed.
      • There are no randomized trials demonstrating a survival benefit from adding ADT to low-dose rate or high-dose rate brachytherapy monotherapy
  • Brachytherapy Combined with External Irradiation
    • Although outcomes in patients with low-risk prostate cancer using brachytherapy are excellent, biochemical control can be improved for intermediate-risk and the higher risk subset of intermediate-risk patients by combining brachytherapy with EBRT; the role of EBRT + brachytherapy versus brachytherapy alone for selected intermediate-risk men is being investigated in a randomized clinical trial by RTOG 0232
    • The brachytherapy is usually given first, so that the EBRT can be discontinued if the patient begins to experience toxicity
  • High-dose-rate (HDR) Brachytherapy
    • Permanent seed implantation delivers a dose over a number of weeks to months depending on the isotope chosen, hence the term low dose rate. An alternative method of brachytherapy, which delivers short but high doses of radiation using temporary catheters, is HDR brachytherapy.
    • HDR has been used primarily as a boost in combination with EBRT for patients with intermediate-risk or high-risk features, although it is becoming more common as monotherapy in patients with low-risk disease.
    • HDR brachytherapy as a monotherapy has been reported to achieve results similar to EBRT in intermediate-risk prostate cancer

• Complications of radiotherapy for prostate cancer
  • Adverse effects are primarily related to injury to the microvasculature of the bladder, rectum, striated sphincter muscle, cavernous nerves, corpora cavernosa, and urethra.
  • ≈1/3 of patients experience acute proctitis or cystitis during the course of radiotherapy.
    • Symptoms usually subside after the completion of therapy, however, ≈5-10% have permanent symptoms, such as irritable bowel syndrome, intermittent rectal bleeding, bladder irritability and intermittent gross hematuria§.
    • In some patients, chronic symptoms develop years after treatment.
    • Some patients require laser cauterization or argon plasma coagulation of radiation-induced telangiectasia for bleeding from the bladder or the rectum.
  • GU toxicity
    • Less common with EBRT than brachytherapy, especially in patients with prostatic hyperplasia.
    • To avoid these problems, α-adrenergic blockers and ADT are usually administered before treatment and may decrease the severity and duration of urinary symptoms
    • ERBT
      • Acute urinary symptoms recover over time
      • Urinary incontinence is uncommon after RT
    • Brachytherapy
      • The IPSS tends to increase significantly immediately after implantation and then decrease, at a rate depending on the half-life of the isotope used
      • Significant post-brachytherapy voiding symptoms refractory to medical management occur in ≈2-3% of patients
      • Brachytherapy after TURP is associated with increased risk for urinary incontinence
      • Acute urinary retention
        • Occurs between 12-35% of patients undergoing brachytherapy
        • Risk factors§
          • Prostate volume of > 35 grams
          • Post-treatment volume of > 55 grams
          • Number of needle punctures > 33
          • AUA Symptom Score of > 12.
        • Management
          • Usually initially treated with an indwelling urethral catheter and medical management with alpha-blocker and/or 5-alpha-reductase inhibitor.
          • After a 1-2 weeks with the catheter, a voiding trial is usually attempted, but patients often fail this and go on CIC
          • Patients with retention following seed implant may resolve retention following 6-12 months of CIC.
          • If patients remain in retention after an adequate trial of CIC, TURP may be required.
            • The timing of this second procedure should be delayed for as long as possible and should not be attempted until at least one year after seed implantation.
            • Iodine-125 (125I) has a half-life of 60 days and TURP has been suggested to be contraindicated in the first 9 months after treatment because of the risk of radioactive exposure to the surgeon, operating room personnel, and pathologists.
  • GI toxicity
    • 5-10% persistent irritable bowel symptoms and 10-15% intermittent rectal bleeding
    • More common with EBRT than brachytherapy
    • EBRT
      • Acute bowel symptoms including urgency and frequency, partially recover with time
      • Compared to 3DCRT, IMRT is associated with lower rates of acute and late GI toxicity, but not GU toxicity, despite being used to give higher doses to the prostate; advances in radiation technology have simultaneously allowed a higher radiation dose to be given while resulting in lower toxicity.
    • Brachytherapy
      • Acute minor rectal symptoms secondary to brachytherapy are usually self-limiting.
      • Late rectal toxicity—specifically, rectal bleeding secondary to radiation proctitis—can be a minor, self-limiting side effect of radiation or a major toxicity requiring surgical intervention such as argon plasma coagulation or, in the worst cases, diverting colostomy
      • Dose delivered to the rectum is directly related to the likelihood and degree of late morbidity from brachytherapy
  • Erectile dysfunction
    • Studies suggest that erectile dysfunction after radiation is caused predominantly by vascular damage
    • Prostate Cancer Outcome Study
      • Population: 1655 males who had undergone either surgery or radiotherapy for localized prostate cancer
      • Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis
      • Results
        • 78.8% of post-prostatectomy patients not having erections firm enough for intercourse two years after surgery compared to 60.8% of men having ED two years following prostate radiotherapy.
        • After 15 years from the time of treatment, the prevalence of ED increases further to 87% post-prostatectomy and 94% post-radiiotherapy
      • Resnick, Matthew J., et al. "Long-term functional outcomes after treatment for localized prostate cancer." N Engl J Med 368 (2013): 436-445.
    • ≈50% of patients develop erectile dysfunction after radiotherapy for prostate cancer
      • More common with EBRT than brachytherapy
        • In a prospective QoL study, poor erections at 60 months increased by 44% after radical prostatectomy, 23% after EBRT, and 21% after brachytherapy from baseline
        • Another study found that the predicted probability of maintaining erectile function after brachytherapy was 0.76, after brachytherapy plus EBRT 0.60, after EBRT 0.55, after nerve-sparing radical prostatectomy 0.34, after standard radical prostatectomy 0.25, and after cryotherapy 0.13.§
        • 2017 AUA Guidelines on Localized Prostate Cancer suggest similar ED rates
    • Usually begins about 1 year after the completion of treatment
      • Decline worse in patients receiving combination with ADT
    • Younger patients with good baseline erectile function are more likely to retain adequate erections
  • Secondary radiation-induced malignancies
    • Incidence of new primary prostate cancers and highly aggressive second malignancies ≈1/70 patients living > 10 years after treatment with radiotherapy for prostate cancer, especially radiation-induced cancers of the bladder and rectum; however, the true magnitude of risk is difficult to quantify
  • Other complications associated with brachytherapy include seed migration and rectourethral fistula

• Pre-operative radiotherapy for high-risk disease
  • Pre-operative radiotherapy may have advantages over post-operative treatment.
  • A phase I study for high-risk prostate cancer demonstrated no dose-limiting toxicity with 54 Gy given preoperatively

Comparing RP and radiotherapy

• No RCT comparing RP to radiotherapy
• No modality affords 100% local control.
  • Surgery is more likely to fail at the margins, and radiotherapy is more likely to fail in the center of the tumor.
  • An important limitation of radiotherapy is tumor heterogeneity with respect to radiation sensitivity. Tumor persistence within the fields of radiation may occur in up to 40% of patients with clinically localized prostate cancer treated with radiation therapy. The strategies of using ADT, dose escalation, and better dose placement are designed to improve the central local control.

Other treatments

Primary hormone therapy

• See Hormonal Therapy in Prostate Cancer Chapter Notes
• Definition of primary hormonal therapy: administration of ADT to men without metastases as sole therapy at the time of diagnosis
• Does not provide a survival benefit for most men with clinically localized prostate cancer
  • Bicalutamide Early Prostate Cancer Programme
    • Population: 3,292 men with T1b-4, N0-Nx (N+ not allowed) M0 prostate cancer who had undergone radical prostatectomy or radiotherapy
      • 657 men with locally advanced prostate cancer
    • Randomized to bicalutamide 150mg daily vs. placebo
    • Outcomes: progression-free and overall survival
    • Results:
      • Localized-disease subgroup:
        • No significant difference in progression-free survival (HR 0.93 (0.82–1.06))
        • Almost significantly reduced overall survival (HR 1.15 (1.00-1.32))
      • Locally-advanced subgroup:
        • Significantly improved progression-free survival (HR 0.67 (0.56–0.80))
        • No significant difference in overall survival(HR 0.89 (0.74–1.07))
    • Iversen, Peter, et al."Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow‐up of 9.7 years." BJU international 105.8 (2010): 1074-1081.
• May be acceptable for select older men with evidence of progressive disease who have significant medical comorbidities that preclude the use of curative therapy, or those who do not wish to undergo curative therapy
  • ADT therapy is never curative; nevertheless, many patients experience long-term remissions
• Cardiovascular evaluation is prudent before treatment of men at risk for cardiovascular complications

Focal therapy

• Proposed as an alternative to active surveillance or radical treatment for localized prostate cancer
• Goal is to treat only those foci of cancer that will affect the patient’s survival or quality of life while preserving surrounding tissue and structures and in turn, the patient’s sexual and urinary function.
• Biologic basis for prostate focal therapy
  • Cancer grade is an indication of cancer aggressiveness
    • Natural history studies suggest that tumor grade, serum PSA levels, and clinical stage are the best predictors of prostate cancer–related mortality. Among these phenotypic expressions of aggressivity, cancer grade remains the earliest indication of lethal potential in low-volume, localized prostate cancer.
  • Multifocality of prostate cancer vs. the index lesion hypothesis
    • The majority of prostate cancer (50-91%) is multifocal
    • It is thought that the index lesion, the largest tumor focus within the prostate, determines the subsequent course of the cancer. This hypothesis is supported by:
      1. Most of the time, the grade/stage is determined by the index lesion.
      2. Most of the tumor volume is contributed by the index lesion.
      3. The majority of satellite tumors are small and low grade.
      4. Genetic studies suggest a monoclonal origin of metastatic or lethal prostate cancer.
    • If the index lesion can be accurately identified and ablated, the majority of tumor within the prostate, and its most aggressive components, can be treated, metastasis and death could theoretically be prevented by removing the lethal component of the prostate cancer.
      • Pathologic features of aggression such as largest tumor size, highest Gleason score, or highest stage, do not always occur in the same nodules, and in fact, may occur in satellite rather than index lesions; these biologic variations will contribute to treatment failures in focal therapy applied to the index lesion
• Clinical applications of focal therapy
  • A successful focal strategy depends on:
    1. Accurately determining the disease extent/location through advanced imaging and biopsy
       • The aggressive lesion within the prostate must be identified and its extent carefully delineated to completely ablate it
       • Advanced radiologic techniques such as mpMRI allow the entire prostate gland to be visualized and, in some cases, predict a more aggressive histology.
       • However, because of the potential 10-15% false-negative rate with mpMRI, there remains consensus to histologically confirm the aggressiveness of the lesion through biopsy. Furthermore, current imaging studies remain imperfect in predicting the absence of aggressive cancer, and many experts would advocate a systematic biopsy to more comprehensively evaluate the gland.
    2. Ascertain that the patient will benefit from treatment and be compliant to follow-up
       • A 2016 consensus on patient selection for prostate focal therapy defined Gleason 3+4 lesions as the “sweet spot” for focal therapy.
       • With higher-grade lesions, there is a concern about increasingly aggressive cancer portending a higher likelihood of EPE outside the image-guided target zone that may need to be met with more radical types of treatment.
    3. Completely ablate the index lesion(s)
       • A complementary strategy of treating intermediate or high-grade cancer foci with focal therapy, while monitoring the remainder of the gland having low-grade cancer with active surveillance. During surveillance, if any higher-grade cancers are detected, they could potentially be treated focally again.
    4. Monitor the patient post-treatment utilizing advanced imaging and biopsy with a view to future targeted treatment of either persistent or de novo disease, or conversion to whole-gland treatment as necessary
  • Advanced imaging techniques in prostate cancer
    • Multiparametric MRI
      • Developments have positioned mpMRI as a key enabler for prostate focal therapy and have been responsible for renewed interest in this area because of its ability to do the following:
        1. Preferentially detect high-grade lesions.
        2. Improve the detection of anterior zone prostate cancers.
        3. Improve the detection of EPE.
        4. Accurately identify the index lesion.
      • Historadiologic correlation studies consistently show that mpMRI underestimates histologic tumor volume by 5-30%, after accounting for shrinkage and other artifacts; this poses significant challenges for lesion-based ablation, and complete ablation may ultimately require hemiablation or zonal ablation.
  • Ablation patterns and current technologies
    • Approaches
      • The prostate can be accessed for ablation via a transrectal, transperineal, or less commonly, a transurethral approach. The approach chosen will depend largely on the following:
        1. Location of the tumor
        2. Desired ablative technology that is available
        3. Any other anatomic consideration unique to the patient
      • Transrectal approaches allow for ease of access to the posterior zone, and transperineal approaches offer better access to the anterior zone of the prostate.
      • Treatment can be applied in various patterns (hemiablation, quadrant ablation, lesion ablation)
    • Modality
      • Several different forms of thermal energy have been used for focal treatment of prostate cancer, including cryoablation, HIFU, laser ablation therapy, radiofrequency ablation, and photodynamic therapy. Limited data on the long-term efficacy of these procedures.
      • Cryoablation
        • A thermal ablative modality achieving cell kill through extraction of heat producing lethal cold temperatures.
        • Can be used as primary whole-gland therapy, as a salvage treatment option after radical prostatectomy or radiotherapy
        • Has been advocated in elderly men who may have underlying comorbidity that precludes radical prostatectomy; there are no studies directly comparing focal cryotherapy to established treatments such as radical prostatectomy or radiation.
        • Better suited for less bulky prostate cancer; gross extracapsular tumor extension or seminal vesicle invasion are usually treated with neoadjuvant hormone therapy to reduce the tumor volume and allow for easier inclusion within the ice ball
        • No universally accepted definition for treatment failure after cryoablation
        • Complications of cryotherapy have include urinary incontinence, urethral sloughing, osteitis pubis, transient penile paresthesia, perineal and rectal pain, rectal fistula, need for a TURP for urinary obstruction, and erectile dysfunction
      • High-intensity Focused Ultrasound (HIFU)
        • A transducer focuses multiple ultrasound beams onto a preset point,generating a temperature of at least 55°C, thus ablating focal lesions or the entire gland
        • Transrectal HIFU is well suited for treatment of posterior-zone lesions. However, the anterior gland may be more difficult to treat because of energy dissipation over the intervening prostate tissue and displacement of anterior zone targets with gradual edema of the prostate tissue as treatment progresses
        • Treatment is performed with use of general or spinal anesthesia and takes 1-4 hours, depending on the prostate volume, which should not exceed 40 mL
        • In-bore MRI-guided focused ultrasonography (MRgFUS) allows for monitoring of treatment temperatures within the target area using MR thermometry, as well as ensuring safe temperatures in the urethra and sphincter
        • Usually well tolerated; the most common side effect is acute urinary retention, occurring in ≈20% of patients. Other potential complications are urinary fistula (2%), incontinence (up to 10%), erectile dysfunction (20-60%), dysuria, urethral stricture, and perineal pain
        • Should be reserved for men with a life expectancy < 10 years and for whom sexual function is not an important issue
        • Clinical studies have reported mixed results regarding the efficacy and safety of HIFU therapy
        • Focal HIFU: results are substantially worse than those of radical prostatectomy or radiotherapy
      • Laser
        • Focal laser ablation refers to the creation of coagulative necrosis using an interstitially placed laser fiber.
      • Irreversible Electroporation
        • A nonthermal ablative technique that uses short pulses of direct-current electricity to produce irreversible pores in the cell membrane, leading to cell death
      • Photodynamic therapy (PDT)
        • Based on tumor cell destruction by light emitted from a laser fiber interacting with a photosensitizing drug delivered to the tumor tissue..
        • Photosensitizing agents accumulate preferentially in cancer cells; 2 types of photosensitizing agents:
          • Tissue-activated photosensitizers
            • Require hours to days to achieve therapeutic concentrations within the tumor
            • Can accumulate in the skin and eyes, and be activated within those organs for some time after administration; therefore, protection of the skin and eyes against light is required.
          • Vascular-activated photosensitizers
            • Advantage of having a short drug-light interval because they achieve peak concentrations in the vasculature within minutes. Because the clearance is also rapid, patients can be discharged on the day of treatment without light protection.
        • The laser fiber is inserted transperineally using a brachytherapy template under ultrasound guidance. After fiber placement, interstitial illumination must be conducted in a darkened room to prevent cutaneous photosensitization.
        • Treatment of anteriorly situated lesions may be limited by pubic arch anatomy.
        • Oncologic treatment outcomes and side effects have not been well documented because of the limited studies
      • Focal brachytherapy
        • The benefit of brachytherapy is the sharp falloff in radiation dose within a few millimeters of the radiation source.
      • Stereotactic radiotherapy
        • Dosimetric feasibility has been demonstrated in the use of stereotactic body radiotherapy for focal therapy though there has not been any clinical trial
  • Post-focal therapy follow-up
    • With focal therapy, traditional markers of therapeutic success may be less relevant. After curative radical prostatectomy, PSA is expected to be undetectable, and after radiation therapy, a significant rise is needed to define biochemical recurrence. After focal therapy, however, the expected fall in PSA has been variable, with some studies reporting a 50-80% reduction. The PSA level would depend on the amount of residual prostate epithelium that may continue to grow and is thus less informative as an absolute marker.
    • Similarly, clinical examination of the prostate may be affected by post-treatment scarring and contraction of the original tumor site, making follow-up biopsy less reliable. These post-treatment findings are seen on mpMRI, TRUS, and contrast-enhanced ultrasonography (CEUS), with increasing ablation zone volume in the early post-treatment period followed by a gradual overall reduction in prostate volume caused by ablation zone fibrosis and deformation
    • In a 2015 Joint International Consultation on Urological Diseases (ICUD)/Society Internationale de Urologie (SIU) project on image-guided focal therapy, success was defined as the following
      1. Within the treated or infield area as the:
         1. Eradication of the tumor focus in the short term.
         2. Absence of clinically significant cancer in the intermediate to long-term.
         • Development of clinically significant cancer should be observed within the untreated or outfield area.
           • In the short term, this outfield cancer focus likely represents selection failure, and in the intermediate- to long-term, this may represent de novo cancer.
      • This consultation recommended an mpMRI with mandatory targeted biopsy of 4-6 cores in the treated area at 3-6 months, then mpMRI at 1 to 2 years and 5 years with targeted biopsy as needed, especially if a new lesion should become manifest. A systematic biopsy was also recommended at 1 to 2 years and 5 years to provide further histologic evaluation of the untreated zone for potential outfield recurrence.
        • It should be noted that there is limited experience with mpMRI in the post–focal treatment arena, and it is unknown how posttreatment changes interact with mpMRI performance.

Management of High-Risk Localized Prostate Cancer

• 15% of patients with localized disease have high-risk prostate cancer[5]
• Management
  • Historically, treated with ADT alone, radiation, or radiation + ADT
  • Options:
    1. Clinical trial
    2. Radical prostatectomy
    3. Radiation + ADT
  • Radical prostatectomy
    • Potential advantages
      • Local control and debulking may improve the efficacy of sequential therapy (radiation therapy or ADT)
      • Local control and debulking may prevent clinical complications, such as hematuria and obstruction
    • Potential disadvantages
      • Overtreatment and increased morbidity, in patient that will ultimately get radiation + ADT, or already has micrometastatic disease
    • Outcomes
      • Limited data
        • Retrospective cohort studies
          • Population: 176 patients who underwent radical prostatectomy for clinical stage T3 prostate cancer, 36% of which received neoadjuvant hormonal therapy
          • Results
            • Median follow-up: 6.4 years
            • Biochemical recurrence
              • 5-year biochemical recurrence-free survival: 48%
              • 10-year biochemical recurrence-free survival: 44%
              • 17% of patients with BCR treated with salvage radiation
              • 77% of patients with BCR treated with hormonal therapy
            • Cancer-specific survival
              • 5-year cancer-specific survival 94%
              • 10-year cancer-specific survival 85%
          • Carver, Brett S., et al. "Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer." The Journal of urology 176.2 (2006): 564-568.
          • Population: 24,407 high-risk patients from SEER. Using propensity score-matching, 7,363 RP patients compared to 7,363 EBRT patients
          • Results
            • 5-year cancer-specific survival improved in RP compared to EBRT (97.7% RP vs. 95.9% EBRT)
          • Chierigo, Francesco, et al. "Survival after radical prostatectomy versus radiation therapy in high-risk and very high-risk prostate cancer." The Journal of Urology 207.2 (2022): 375-384.
      • Combination therapy
        • Neoadjuvant ADT may improve outcomes
          • Phase II trials demonstrate that pathologic complete response achieved in 4-10% of patients, and minimal residual disease in 17-30% of patients.
          • Phase III trial (PROTEUS) underway
        • Neoadjuvant chemotherapy
          • PUNCH trial evaluated neoadjuvant docetaxel + ADT and found no significant difference in the primary outcome of 3-year biochemical progression-free survival
        • Adjuvant ADT
          • Controversial
          • AFU-GETUG-20 trial evaluating adjuvant leuprolide for 2 years after radical prostatectomy
          • ERADICATE trial will evaluate adjuvant darolutamide after radical prostatectomy
  • Radiation
    • Combination radiation + ADT is a standard of care option for high-risk prostate cancer, with several trials demonstrating improved outcomes with combination therapy compared to monotherapy
    • Optimal duration of therapy not established
      • 2017 AUA Guidelines on Localized Prostate Cancer recommend 24-36 months
    • Combination radiation + second-generation anti-androgen trials underway (ATLAS apalutamide and ENZARAD enzalutamide)

Questions

1. What is the risk of cancer-specific death and the risk of metastasis at 10-years in males on watchful waiting for prostate cancer?
2. Which patients should be considered for watchful waiting as management for their prostate cancer?
3. List the indications for intervention on active surveillance for prostate cancer
4. What are the contraindications to radical radiotherapy for prostate cancer?
5. What is the risk of death from prostate cancer at 10 years of watchful waiting? Risk of metastasis?
6. What are indications for intervention on active surveillance?
7. What are advantages/disadvantages of the perineal vs. retropubic prostatectomy?
8. What are the definitions of biochemical failure following radical radiotherapy for localized prostate cancer?
9. What is the definition of a PSA bounce? Is it more common after EBRT or brachytherapy?
10. What is the optimal timing to perform a prostate biopsy to rule out recurrence after radiation treatment?
11. What is the toxicity profile of radiotherapy for prostate cancer? How does the toxicity differ for EBRT and brachytherapy?

Answers

1. What is the risk of cancer-specific death and the risk of metastasis at 10-years in males on watchful waiting for prostate cancer?
   1. Risk of death from prostate cancer: 15%
   2. Risk of metastasis: 20%
2. Which patients should be considered for watchful waiting as management for their prostate cancer?
   1. Preferred for all males without high-risk disease who have < 5-year life expectancy
   2. Option for those without high-risk disease and a life expectancy < 10 years
3. List the indications for intervention on active surveillance for prostate cancer
   1. Progression in cancer grade
   2. Increased cancer volume on repeat biopsy
   3. Rapidly rising PSA
   4. Patient anxiety
4. What are the contraindications to radical radiotherapy for prostate cancer?
   • ST-LIAR
   1. Size >60g for brachytherapy
   2. Prior TURP for brachytherapy
   3. LUTS
   4. IBD
   5. Ataxia telangiectaisia
   6. Radiation
5. What are advantages/disadvantages of the perineal vs. retropubic prostatectomy?
   • Advantages: reduced blood loss, shorter operating time
   • Disadvantages: inability to do lymph node dissection, potential for rectal injury
6. What are the definitions of biochemical failure following radical radiotherapy for localized prostate cancer?
   • ASTRO: 3 consecutive PSA increases measured 6 months apart, and back-dates the time of cancer progression to halfway between the PSA nadir and the first rising PSA level
   • Phoenix definition: rise of 2 ng/mL or more above the nadir; failure is not backdated
7. What is the definition of a PSA bounce? Is it more common after EBRT or brachytherapy?
   • Definition: a rise in PSA of 0.1-0.5ng/mL above nadir followed by a decline
   • More common after brachytherapy
8. What is the optimal timing to perform a prostate biopsy to rule out recurrence after radiation treatment?
   • After 30-36 months
9. What is the toxicity profile of radiotherapy for prostate cancer? How does the toxicity differ for EBRT and brachytherapy?
   • GI toxicity (urgency, frequency, bleeding), GU toxicity (frequency, hematuria), secondary malignancies, sexual dysfuncion
   • GU toxicity more likely with brachy, GI and ED toxicity more likely with EBRT

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 112
• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 12. Philadelphia, Elsevier, 2020, chap 158
• AUA Update Series (2016) Lesson 14: Multiparametric Magnetic Resonance Imaging for Prostate Cancer