Editing AUA: Clinically Localized Prostate Cancer (2017) (section)

==== Risk stratification ====

* '''Very low risk'''
*# '''PSA <10 ng/ml AND'''
*# '''Grade Group 1 AND'''
*# '''Clinical stage T1-T2a AND'''
*# '''<34% of biopsy cores positive AND'''
*# '''No core with >50% involved AND'''
*# '''PSA density <0.15 ng/ml/cc'''
* '''Low risk'''
*# '''PSA <10 ng/ml AND'''
*# '''Grade Group 1 AND'''
*# '''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.''' In other words, if a man undergoes a 12-core systematic biopsy that finds 4 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.

===== Shared-decision making =====

* Counseling of patients to select a management strategy should incorporate shared decision making and explicitly consider cancer severity (risk category), patient values and preferences, life expectancy, pre-treatment general functional and genitourinary symptoms, expected post-treatment functional status, and potential for salvage treatment.
* Prostate cancer patients should be counseled regarding the importance of modifiable health-related behaviors or risk factors, such as smoking and obesity.
** Smoking and obesity are associated with increased risk of prostate cancer death
** Furthermore, smoking and obesity are associated with increased risk of perioperative complications
* Clinicians should encourage patients to meet with different prostate cancer care specialists (rad/onc, med/onc)
* Effective shared decision making in prostate cancer care requires clinicians to inform patients about immediate and long-term morbidity or side effects of proposed treatment or care options.

#* '''Surgery patients may experience bleeding, infection, and pain in the immediate term and then experience erectile dysfunction, urinary incontinence, urethral stricture and (very rarely) bowel problems.'''
#* '''The same side effects observed after surgery are possible with radiotherapy (RT) approaches, though bowel problems are more common, and sexual and continence side effects take much longer to develop.'''
#* '''Erectile dysfunction and urinary bother beyond 2-5 years may be similar between surgery and RT'''
#* '''RT causes more urinary irritation (brachytherapy more than external beam RT (EBRT)) and modestly more gastrointestinal side effects than radical prostatectomy'''
#* '''RT may be associated with a very small but increased risk for secondary cancer, specifically bladder cancer and rectal cancer. The suspected incidence of radiation-induced second primary cancers is reported to affect between 1-3% of patients in the years following treatment'''.
#* The risk of perioperative death from prostate cancer surgery is <0.1%

===== Treatment Options by Risk-Group =====

* '''Very-low/low-risk'''
** '''Abdo/pelvic CT or routine bone scans should not be performed in the staging of asymptomatic very low- or low-risk localized prostate cancer patients'''
** '''Active surveillance (AS) should be recommended as the best option for very low-risk patients'''
*** Long-term follow up studies of very low-risk patients managed with active surveillance have shown a metastatic progression rate of <1% at 15 years
*** A major risk of active surveillance is serial biopsies. These are recommended at between 3-5 year intervals after the initial confirmatory biopsy. Biopsies are associated with risks of infection, bleeding, and erectile dysfunction.
** '''AS should be recommended as the preferable care option for most low-risk patients'''
*** Men with higher volume disease (i.e. >50% of cores positive or those larger lesions seen on imaging) may be better served with active treatment.
** '''Definitive treatment (i.e. radical prostatectomy or RT) may be offered to select low-risk patients who may have a high probability of progression on AS'''
*** Surgical and radiation treatments do not improve survival within 10 years of follow-up compared to active surveillance for patients with early disease, but has been found to reduce disease progression and development of metastatic disease as shown in the Prostate Cancer Intervention Versus Observation Trial (PIVOT) (10% vs. 5%) and the Prostate Testing for Cancer Treatment trial (ProtecT) (6% vs. 2%).
*** '''Predictors for an increased risk of higher grade disease or reclassification of subsequent biopsy:'''
****# '''PSA density > 0.15'''
****# '''Obesity'''
****# '''African American race'''
****# '''Extensive Gleason 6 cancer on systematic biopsy cores'''
*** Among most low-risk localized prostate cancer patients, tissue based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance
** '''Single modality EBRT or brachytherapy may be offered for patients who elect radiotherapy for low-risk localized prostate cancer.'''
*** '''Options include intensity modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), low-dose rate brachytherapy, and high-dose rate brachytherapy'''
**** Low-dose rate brachytherapy uses radioactive seeds that are implanted based on pretreatment and intraoperative image-guidance according to a computer plan.
**** High-dose rate brachytherapy uses temporary catheters implanted in the prostate to allow for the delivery of a high-activity radiation source.
** '''Androgen deprivation therapy (ADT) should not be added to RT for low-risk disease with the exception of reducing the size of the prostate for brachytherapy'''
*** In RTOG 9408, 1,979 patients were randomized to EBRT with 4 months of ADT versus without ADT and had 9.1 years of median follow-up, OS was not improved with ADT in subgroup analysis of 685 low-risk patients.
*** There is no randomized trial supporting a survival benefit from adding ADT to radiotherapy for low-risk cancer.
*** ADT can be used to reduce the size of the prostate to allow for improved dosimetry brachytherapy, but can cause short-term sexual dysfunction and other associated side effects.
** '''Clinicians should inform low-risk patients considering whole gland cryosurgery that consequent side effects are considerable and survival benefit has not been shown in comparison to AS'''
*** '''Most patients (80-90%) should expect erectile dysfunction after whole gland cryosurgery; should not be offered to patients who desire preservation of potency'''
*** There can be temporary bothersome irritative symptoms in the early recovery period. Urinary retention after cryosurgery can persist for a few weeks and is best managed with a urethral or suprapubic catheter.
** '''Focal therapy or high intensity focused ultrasound (HIFU): not standard of care''' because comparative outcome evidence is lacking
*** The panel felt it was premature to consider partial prostate treatment (focal therapy) outside of a clinical trial.
** '''Observation or watchful waiting should be recommended for low-risk men with a life expectancy ≤5 years'''

* '''Intermediate-risk'''
** '''Routine imaging at diagnosis is not recommended in all intermediate-risk patients; metastasis staging is recommended for men with ≥2 of the following features:'''
***# '''Palpable nodule on DRE (stage T2b/c)''' [Guidelines specify clinical stage T2b/c, despite T2a also being palpable]
***# '''Gleason 7''' (3+4 or 4+3)
***# '''PSA >10'''
*** Most common sites of metastases are pelvic/retroperitoneal lymph nodes and bones. Less common metastatic sites include lung and liver.
*** These recommendations for baseline imaging vary somewhat from NCCN and American College of Radiology
*** '''Bone metastases are evaluated with bone scintigraphy (99mTc-MDP)'''
*** '''Cross sectional imaging is either MRI or CT scan of the abdomen/pelvis'''
** '''Treatment options summary''' (based on AUA summary slides):
*** '''Radical prostatectomy'''
*** '''Radiation'''
**** '''Brachytherapy alone'''
**** '''EBRT +/- 4-6mo ADT'''
**** '''EBRT + brachytherapy +/- 4-6mo ADT'''
***** [AUA guidelines do not specify if ADT should be used with EBRT + brachytherapy but do say that if ERBT is used, ADT should be added and NCCN guidelines supports EBRT + brachytherapy + ADT as an option in intermediate-risk, unfavourable]
*** Radical prostatectomy or RT (EBRT or brachytherapy) should be recommended as standard treatment options for intermediate-risk patients. If ERBT is used, ADT should be added.
**** '''Patients with favorable intermediate-risk prostate cancer should be informed that they can be treated with EBRT alone, but that the evidence basis is less robust than for combining EBRT with ADT'''. Patients with unfavorable intermediate risk disease should be especially considered for the addition of ADT to EBRT.
***** 2 randomized trials (RTOG 9408 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.
**** There are no randomized trials demonstrating a survival benefit from adding ADT to low-dose rate or high-dose rate brachytherapy monotherapy; '''ADT should not be added to brachytherapy [monotherapy] except to reduce the size of the prostate to allow the dosimetry to be optimized'''.
*** '''Clinicians may offer EBRT or brachytherapy alone or in combination for favorable intermediate-risk localized prostate cancer.'''
**** The rationale of combination therapy can be either for the improved coverage of the periprostatic space and/or planned coverage of the pelvic lymph nodes in patients with unfavorable intermediate risk disease.
*** '''Other treatment options such as cryosurgery may be considered in select patients''' (contraindications to surgery/radiation or patient preference)
*** '''Active surveillance 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'''
*** '''Observation or watchful waiting should be recommended for intermediate-risk men with a life expectancy ≤5 years'''
*** '''Focal therapy or HIFU''': '''not standard care options''' because comparative outcome evidence is lacking

* '''High-risk disease'''
** '''High-risk patients should be staged with cross sectional imaging (CT or MRI) and bone scan'''
** '''Radical prostatectomy or radiotherapy (EBRT alone or EBRT combined with brachytherapy) plus ADT (24 to 36 months) should be recommended as standard treatment options for high-risk patients'''
*** Radiation treatment options for high-risk prostate cancer include IMRT, and IMRT plus brachytherapy
*** '''For high-risk prostate cancer patients receiving EBRT and ADT, brachytherapy boost (low-dose rate or high-dose rate) should be offered to eligible patients'''
*** '''In high-risk patients without evidence of nodal metastasis based on imaging, radiation treatment may electively include pelvic nodal areas''' because published nomograms demonstrate that these patients have a risk of harboring micrometastatic nodal disease
*** Two randomized trials have compared EBRT with short-term versus long-term ADT.
**** EORTC 22961 randomized 1,113 men with high-risk prostate cancer to EBRT plus 6 versus 36 months of ADT.
**** RTOG 9202 randomized patients to EBRT plus 4 versus 28 months of ADT.
*** Based on these trials, acceptable ADT durations for radiotherapy patients with high-risk prostate cancer range from 24-36 months.
** '''AS should not be recommended for patients with high-risk localized prostate cancer'''
** '''Watchful waiting should only be considered in asymptomatic men with limited life expectancy (≤5 years)'''
*** '''Active intervention (rather than surveillance) should be pursued in men with high-risk disease unless a patient is expected to die from competing causes within 5 years.'''
** '''Cryosurgery, focal therapy and HIFU: not recommended''' for men with high-risk localized prostate cancer outside of a clinical trial.
** '''Clinicians should not recommend primary ADT for patients with high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms.'''
** '''Clinicians may consider referral for genetic counseling for patients (and their families) with high-risk localized prostate cancer and a strong family history of specific cancers (e.g., breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma).'''
*** The incidence of germline mutation in DNA repair genes in localized prostate cancer is low with estimates of BRCA2 in 1-2%.

* '''Active surveillance'''
** Patients who elect AS should have accurate disease staging including systematic biopsy with US or MRI-guided imaging
*** The 12-core biopsy scheme (sextant template plus laterally directed sampling from each sextant template) has become the most widely accepted method. Some practitioners also take a core from the anterior transition zone on each side since this is a common site for missed cancers.
*** The Panel does not recommend the use of mpMRI in place of prostate biopsy at this time.
** '''Patients undergoing AS should have routine surveillance PSA testing and DRE'''
*** While limited by the subjective nature of the examination, annual DRE remains an important part surveillance.
** '''Patients undergoing active surveillance should be encouraged to have a confirmatory biopsy within the initial 2 years and surveillance biopsies thereafter'''
*** The probability that higher-grade disease will be diagnosed on biopsy during active surveillance is 8-28%. This usually represents a higher-grade component of the original tumor that was not originally sampled rather than evolution to higher-grade disease.
*** '''Current Cancer Care Ontario Guidelines, which have also been adopted by ASCO are:'''
**** '''PSA every 3-6 months'''
**** '''DRE each year'''
**** '''Systematic biopsies within 6-12 months after the diagnostic biopsy, and then every 3-5 years until the patient is ‘switched’ to watchful waiting'''
** '''Multiparametric MRI may be considered as a component of AS for localized prostate cancer patients'''
*** The role of serial MRI for monitoring patients during surveillance has yet to be validated. An interval of 2 years between MRIs in men on surveillance has been suggested.
*** mpMRI has a high negative predictive value (82-95%) for the detection of clinically significant prostate cancer
*** '''mpMRI should be performed on at minimum a 1.5 Tesla magnet MRI and include diffusion weighted imaging (DWI)''' with apparent diffusion coefficient (ADC)''', T2-weighted (T2W) imaging, and dynamic intravenous contrast-enhanced (DCE) imaging.'''
** Tissue based genomic biomarkers have not shown a clear role in AS for localized prostate cancer and are not necessary for follow up.
** '''Clinicians should offer definitive treatment to localized prostate cancer patients undergoing AS who develop adverse reclassification.'''

* '''Prostatectomy for localized prostate cancer'''
** Younger or healthier men (e.g., <65 years of age or >10 year life expectancy) are more likely to experience cancer control benefits from prostatectomy than older men.
** '''Neoadjuvant ADT or other systemic therapy should not be used outside of clinical trials'''
** '''Open and robot-assisted radical prostatectomy offer similar cancer control, continence recovery, and sexual recovery outcomes'''
** '''Robotic/laparoscopic or perineal techniques are associated with less blood loss than retropubic prostatectomy'''
** Nerve-sparing is associated with better erectile function recovery than non-nerve sparing.
** '''Older men experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy compared to younger men.'''
*** '''Post-PCa treatment ED recovery typically occurs over a minimum of 2 (or more) years''' (CUA Post RP ED 2019)
** '''Indications for pelvic lymphadenectomy'''
*** '''NCCN (1)''' (Absolute):
***# '''Predicted probability of nodal metastases ≥2%'''
**** Specific wording in 2.2021 guidlines is "PLND can be excluded in patients with <2% predicted probability of nodal metastases by nomograms..."
*** '''AUA (2)''' (Relative):
***# '''Unfavorable intermediate-risk'''
***# '''High-risk disease'''
**** Specific wording in guidelines is "pelvic lymphadenectomy CAN BE CONSIDERED for..."
*** Counsel patients regarding potential complications of lymphadenectomy
*** About 40% of the primary lymph nodes are contained within a standard dissection limited to the obturator fossa; about two-thirds of the primary nodes are contained within an extended template that includes the obturator fossa and the tissue medial and lateral to the internal iliac vessels.
*** '''Lymphocele is the most common complication of PLND occurring in up to 60% of cases. Most lymphoceles are asymptomatic and require no treatment. Symptomatic lymphoceles''' occur in 0.4-16% of patients, and '''can be managed by placing a percutaneous drain and instilling sclerosing agents''' with resolution between 70–100 %
*** '''In lymphoceles refractory to percutaneous drainage and sclerosis, minimally invasive marsupialization of the lymphocele is recommended'''.
** Clinicians should inform localized prostate cancer patients with unfavorable intermediate-risk or high-risk prostate cancer about benefits and risks related to the potential option of adjuvant radiotherapy when locally extensive prostate cancer is found at prostatectomy.
*** SWOG 8794 randomized subjects to adjuvant radiotherapy or no adjuvant after prostatectomy. Side effects of radiation subsided with time and there was no difference between the treatment arms at 5 years

* '''Radiotherapy'''
** '''Brachytherapy has similar effects as EBRT with regard to erectile dysfunction and proctitis but can also exacerbate urinary obstructive symptoms'''
** Clinicians should inform localized prostate cancer patients that use of ADT with radiation increases the likelihood and severity of adverse treatment-related events on sexual function in most men and can cause other systemic side effects.
** Clinicians should consider moderate hypofractionation when the localized prostate cancer patient (of any risk category) and clinician decide on external beam radiotherapy to the prostate (without nodal radiotherapy).
** '''Contraindications to Radiotherapy for Prostate Cancer'''
*** '''Absolute (2)'''
***# '''Ataxia telangiectasia''' (severe response to ionizing radiation)
***# '''Prior TURP for brachytherapy if the TUR defect precludes adequate placement of seeds'''
*** '''Relative (4)'''
***# '''Inflammatory bowel disease''' (increased risk for treatment-related morbidity)
***# '''History of prior pelvic radiotherapy''' (increased risk for treatment-related morbidity)
***# '''Significant baseline urinary obstructive symptoms''' (can cause acute urinary obstructive and irritative symptoms, risk increased with brachytherapy)
***# '''Large prostate size >60 cc for brachytherapy''' (increased risk of urinary side effects)
** Clinicians should inform localized prostate cancer patients who are considering proton beam therapy that it offers no clinical advantage over other forms of definitive treatment.
*** The predominant forms of EBRT are delivered by photon therapy or electrons. Proton therapy utilizes proton charged particles with superior dosimetric advantages over photons and electrons as they stop depositing dose at an energy-dependent distance from the treatment source; therefore, sparing of tissue beyond this distance can be accomplished.

* '''Whole gland cryosurgery'''
** '''May be considered in low- and intermediate-risk localized prostate cancer patients who are not suitable for either radical prostatectomy or RT due to comorbidities yet have >10 year life expectancy.'''
*** High-risk patients are less suited for this treatment. Moreover, high risk patients may require multimodal/salvage therapy, and clinicians should consider lymph node dissection prior to or in conjunction with cryosurgery.
*** Prostate gland volume is a factor in patient selection in that it can be difficult to achieve uniform cold temperatures throughout the organ. '''Most investigators have not recommended treating glands > 60 g with cyrosurgery.'''
** Similar progression-free survival as non-dose escalated EBRT (also given with neoadjuvant hormonal therapy) in low- and intermediate-risk disease, but conclusive comparison of cancer mortality is lacking.
** '''Defects from prior TURP are a relative contraindication for whole gland cryosurgery due to the increased risk of urethral sloughing'''.
*** The urethral warming catheter may fail to fully contact the urethral mucosa in patients with a TURP defect increasing the likelihood for urethral necrosis, sloughing, dysuria, and urinary retention.
** A third or higher generation, argon-based cryosurgical system should be used for whole gland cryosurgery treatment.
** Unclear whether or not concurrent ADT improves cancer control, though it can reduce prostate size to facilitate treatment.
*** The Panel is unaware of any conclusive studies evaluating whether or how the use of concurrent ADT enhances or mitigates the oncologic efficacy of cryosurgery. Nevertheless, the addition of ADT to cryosurgery is common.
*** '''For glands > 40 g, neoadjuvant ADT (3-6 months) should be considered due to the potential technical challenges from pubic arch interference and increased difficulty in achieving uniform temperatures.'''
** '''Erectile dysfunction is an expected outcome'''
** Adverse events include urinary incontinence, irritative and obstructive urinary problems

* '''HIFU and focal therapy'''
** Focal therapy involves subtotal or zonal destruction of the prostate with cryosurgery, HIFU or other focally ablative techniques with the aim to minimize treatment toxicity.
** '''A prerequisite for focal therapy involves advanced mapping of lesions within the prostate.''' This can be done with a saturation biopsy or, more commonly, with MRI imaging with focused biopsy or a 3D transperineal mapping biopsy to identify appropriate patients with clinically significant disease, to provide an appropriate index target, and to provide an appropriate target for follow-up scanning and biopsies.
** These treatment options lack robust evidence of efficacy.
** Even though HIFU is approved by the FDA for the destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer.
** Tumor location may influence oncologic outcome of HIFU. Limiting apical treatment to minimize morbidity increases the risk of cancer persistence.
*** '''Whole gland HIFU ablation is not optimally suited for men with a prostate >40 g''' due to limited focal length of technology and higher rates of urinary retention.
** As prostate cancer is often multifocal, focal therapy may not be curative and that further treatment for prostate cancer may be necessary.
** '''Men should also be informed that after any focal or ablative treatment, follow up biopsies will still be required'''
** '''If HIFU is offered as an alternative treatment modality for localized prostate cancer, it should be done within the context of a clinical trial.'''

* '''Outcome expectations and management'''
** '''Clinicians should inform localized prostate cancer patients that erectile dysfunction occurs in many patients following prostatectomy or radiation, and that ejaculate will be lacking despite preserved ability to attain orgasm'''
*** 2 years after treatment, poor erections increase by 44% after RP, 23% after EBRT, 21% after brachytherapy
*** Time course of sexual dysfunction differs between radical prostatectomy and radiation treatment (both EBRT and brachytherapy). Radical prostatectomy causes an immediate worsening of sexual function; EBRT and brachytherapy cause a more modest acute decline of sexual function after treatment
** '''Long-term obstructive or irritative urinary problems occur in a subset of patients following observation or active surveillance or following radiation, whereas prostatectomy can relieve pre-existing urinary obstruction.'''
** '''Whole-gland cryosurgery is associated with worse sexual side effects and similar urinary and bowel/rectal side effects as those after radiotherapy.'''
** '''Temporary urinary incontinence occurs in most patients after prostatectomy and persists long-term in a small but significant subset, more than during observation or active surveillance or after radiation.'''
*** Urinary incontinence subsides to be small to no bother for most men by 1 year post-prostatectomy. Beyond 1 year after treatment, urinary continence is moderately (or more) bothersome for 5-25% of men
** '''Temporary proctitis following radiation persists in some patients long-term in a small but significant subset and is rare during observation or active surveillance or after prostatectomy.'''
*** Of patients who received IMRT, the absolute increase in risk from baseline to 2 years for bloody stools is 4%, rectal pain 2%, bowel urgency 13%, frequency 8%, and incontinence 1%.

* '''Post treatment follow-up'''
** '''Clinicians should monitor localized prostate cancer patients post therapy with PSA, even though not all PSA recurrences are associated with metastatic disease and prostate cancer specific death.'''
*** '''Treatment success is defined as nadir PSA'''
**** '''< 0.2 (undetectable) ng/ml after radical prostatectomy'''
**** '''< 2.0 ng/ml for RT +/- ADT (with testosterone recovered if previous ADT)'''
*** '''PSA surveillance after local therapy is recommended for at least 10 years with PSA frequency determined by risk of relapse and patient preferences for monitoring. PSA monitoring beyond 10 years can be considered in men with high risk of relapse and long life expectancy.'''
** '''Salvage therapy after'''
*** '''Prostatectomy includes RT +/- ADT'''
*** '''RT are heterogeneous and include prostatectomy, HIFU, cryosurgery, and repeat radiation. Many of the post-radiation salvage approaches have either high potential for toxicity or low or unclear rates for cure and the pros and cons of localized salvage therapy after radiation should be carefully considered with the patient.'''
** The natural history of relapsed prostate cancer is extremely variable. The important clinical metrics include time to metastasis and death from prostate cancer.
** Clinicians should inform localized prostate cancer patients of their individualized risk-based estimates of post-treatment prostate cancer recurrence.
** Clinicians should support localized prostate cancer patients who have survivorship or outcomes concerns by facilitating symptom management and encouraging engagement with professional or community-based resources.