Update 'prostate.adoc'

prostate.adoc

@@ -1,6 +1,6 @@
 = 14-2 Prostate Cancer
 
-== 14-2.1 Epidemiology
+== 14-2.1: Epidemiology
 
 Prostate cancer is a common diagnosis, and although metastatic disease develops in a small percentage of affected patients, this translates into a large absolute number of deaths due to prostate cancer.
 
@@ -15,7 +15,7 @@ Whether black men tend to have biologically more aggressive prostate cancer than
 
 There is no clear causal link between vasectomy and prostate cancer, nor does testosterone supplementation appear to increase the risk of aggressive prostate cancer.
 
-== 14-2.2 Heredity
+== 14-2.2: Heredity
 
 Prostate cancer is one of the most hereditable cancers. Clinicians should take a full history of malignancies in the family and be familiar with the link between prostate cancer and germline alterations in BRCA2 and mismatch repair genes, which are enriched among men with metastatic prostate cancer.
 
@@ -46,7 +46,7 @@ Guidelines for referral to genetic counseling are frequently changing, but at mi
 ** two or more relatives with colorectal, endometrial, gastric, ovarian, pancreatic, small-bowel, urothelial, kidney, or bile duct cancer (suggesting Lynch syndrome)
 ** Ashkenazi Jewish ancestry, which could also prompt genetic testing
 
-== 14-2.3 Anatomy
+== 14-2.3: Anatomy
 
 Prostate cancer is typically diagnosed via TRUS biopsy using a standard 12-core template to sample the posterior peripheral zone.
 
@@ -62,7 +62,7 @@ Anatomic location can help predict pattern of spread and treatment-related risks
 * Apical disease poses the problem of having a higher rate of positive surgical margins, harboring an anterior tumor, and incontinence
 ** Patients with a bulk of positive specimens from the apex may not be optimal candidates for prostatectomy
 
-== 14-2.4 Pathology and molecular pathogenesis
+== 14-2.4: Pathology and molecular pathogenesis
 
 Prostate cancer can be characterized by its typical IHC profile: cytokeratin 7/20-negative, PSA-positive, AR-positive, and NKX3.1-positive.
 
@@ -102,7 +102,7 @@ Small-cell prostate cancer is a rare subset and classically occurs with rapid vi
 *** Neuroendocrine prostate cancer is associated with amplification of AURKA and MYCN, offering the opportunity for targeted therapy
 *** Clinically, emergence of neuroendocrine differentiation and small cell transformation should be considered in men who develop castration-resistant disease after ADT for high-grade cancers, especially when visceral involvement is diagnosed and radiographic progression occurs in the absence of an increase in PSA
 
-== 14-2.5 Prevention
+== 14-2.5: Prevention
 
 There are no universally accepted protocols for prostate cancer prevention or screening.
 
@@ -127,7 +127,7 @@ When clinicians have adopted MRI-targeted biopsies thus far, it has typically be
 * Abnormal DRE necessitates referral to urologist for additional diagnostic evaluation (i.e. TRUS biopsy)
 * MRI guidance may be useful as first diagnostic step
 
-== 14-2.6 Tumor staging
+== 14-2.6: Tumor staging
 
 * Clinical T stage is assigned by DRE
 * Pathologic T stage is assigned based on examination of a radical prostatectomy specimen
@@ -136,7 +136,7 @@ When clinicians have adopted MRI-targeted biopsies thus far, it has typically be
 * T3 tumor extends through the prostate capsula (T3a) or invades the seminal vesicles (T3b)
 * T4 tumors invade adjacent structures or organs
 
-== 14-2.7 Risk stratification
+== 14-2.7: Risk stratification
 
 Patients with localized prostate cancer can be risk-stratified on the basis of three clinical factors: T stage, Gleason score, and PSA level. Genomic testing of the cancer specimen may provide additional information about risk and progression, but this is not yet prospectively validated for decision-making.
 
@@ -164,7 +164,7 @@ Patients with localized prostate cancer can be risk-stratified on the basis of t
 *** PSA concentration > 10 ng/mL
 ** High-risk disease: all patients
 
-== 14-2.8 Management of Prostate Cancer by Risk
+== 14-2.8: Management of Prostate Cancer by Risk
 
 Prostatectomy, RT, and ADT all have unique adverse effect profiles. Prostatectomy can lead to urinary incontinence and erectile dysfunction, but it can help improve significant obstructive symptoms. Radiation tends to lead to irritative urine and bowel symptoms. ADT can cause vasomotor symptoms, fatigue, loss of libido, weight gain, muscle loss, and bone thinning, most of which reverse after discontinuation of ADT and recovery of testosterone.
 
@@ -185,7 +185,7 @@ Prostatectomy, RT, and ADT all have unique adverse effect profiles. Prostatectom
 *** Definitive radiotherapy to prostate and pelvic nodes + long-course ADT
 *** Prostatectomy + extended lymphadenectomy + adjuvant radiotherapy + adjuvant ADT
 
-== 14-2.9 Treatment modalities
+== 14-2.9: Treatment modalities
 
 Patients with low-risk disease may be offered active surveillance, which uses serial PSA measurements, DREs, and biopsy specimens to detect any presence of higher-risk disease, at which point definitive therapy can be offered. Sequential MRI may also be helpful. This strategy results in less treatment-associated morbidity and similar long-term cancer survival compared with immediate therapy.
 
@@ -240,7 +240,9 @@ Patients with preexisting urinary symptoms should avoid brachytherapy and may ex
 
 There is little to no advantages for robotic prostatectomy versus other surgical approaches and for proton therapy versus conventional RT for clinically localized prostate cancer.
 
-== 14-2.10 Therapy for recurrent or advanced disease
+== 14-2.10: Therapy for recurrent or advanced disease
+
+Detectable PSA after radical prostatectomy or increase in PSA concentration by 2 ng/dL or more above PSA nadir after RT is an indicator of recurrent prostate cancer. In the absence of evidence of metastatic disease on standard bone scan and CT imaging, this is termed BCR or biochemical relapse.
 
 * Pathologic node-positive disease
 ** Positive lymph nodes at time of prostatectomy indicates aggressive disease at high risk of recurrence
@@ -263,4 +265,55 @@ There is little to no advantages for robotic prostatectomy versus other surgical
 **** MCSPC
 **** Metastasis-directed therapy ± ADT ± ASI
 
-== Next: 14-2.10.3: Local Failure
+Salvage RT may be used for patients who experience BCR after radical prostatectomy, typically combined with 6 months of ADT. Conversely, salvage prostatectomy is less commonly performed after primary RT.
+
+* Local failure
+** Adjuvant and salvage RT
+*** Adjuvant RT for advanced pathologic features (pT3a or pT3b) improves biochemical PFS and OS
+*** To avoid risk of overtreatment, reserve adjuvant RT for very high risk pathology (e.g., seminal vesicle involvement, positive margins) and early salvage RT in more ambiguous cases (1-2 mm positive margin)
+*** Salvage RT may increase prostate cancer-specific survival in men with PSA doubling time < 6 months
+** Endocrine therapy
+*** High-dose bicalutamide 150 mg/day ×24 months provided an OS benefit bit was associated with cardiotoxicity and gynecomastia
+*** ADT with LHRH analog ×6 months, based on benefits seen in the primary treatment setting
+** Salvage prostatectomy
+*** Was surgical candidate at time of diagnosis, treated with RT, has life expectancy > 10 years, has no metastatic disease, has biopsy-proven persistent disease
+*** Incontinence rates are high, virtually all patients are impotent after surgery
+**** Also consider cryotherapy and brachytherapy
+*** MRI most useful for detecting recurrence after RT
+*** Prostate biopsy done to confirm diagnosis
+**** Biopsy should not be done for several months after RT because of prolonged radiation effect and persistence of residual cancer cells
+
+The optimal timing of systemic therapy for BCR is unclear. ADT will lower PSA level in this setting but its impact on OS relative to ADT at the time of metastatic disease is still unknown.
+
+* Systemic therapy
+** ADT is standard
+** In patient with increasing PSA and no evidence of metastasis, intermittent androgen suppression may be reasonable alternative to continuous androgen suppression
+*** Suppress for 8 months each cycle, restarting ADT when PSA > 10 ng/mL
+*** Goal is to minimize adverse effects including hot flashes, loss of libido, bone loss, and muscle atrophy
+
+Patients with BCR who are treated with ADT and whose PSA levels increase without evidence of metastases on standard bone scan and CT imaging have disease that has progressed to nmCRPC. The addition of the second-generation AR antagonists apalutamide, darolutamide, or enzalutamide prolongs metastasis-free survival in this setting.
+
+* Nonmetastatic castration-resistant prostate cancer
+** In nmCRPC (increasing PSA despite castration-level testosterone levels without radiographic evidence of metastasis by bone scan and CT), addition of second-generation AR antagonists delays onset of radiographic metastatic disease (metastasis-free survival)
+*** Enzalutamide (also for mCSPC and mCRPC); risk of HTN, MI, fatigue, fall, fracture
+*** Apalutamide (also for mCSPC); risk of rash, hypothyroidism, fracture
+*** Darolutamide; risk of fatigue
+** Metastasis-free survival is strong surrogate for OS in localized prostate cancer
+*** Not clear if early ADT prolongs survival relative to ADT at time of metastasis
+* Local therapy outside the prostate for oligometastatic recurrence
+** Targeted RT, cryoablation, or RF ablation may delay need for systemic therapy
+** Earlier detection by more sensitive imaging
+*** Fluciclovine PET when CT, MRI, and bone scan are negative
+**** After primary RT, residual prostate takes up fluciclovine, limiting detection of local recurrence
+**** Use MRI to evaluate for local recurrence
+
+Nonmetastatic BCR (increasing PSA on ADT) -> confirm castration -> repeat imaging ->
+
+* Nonmetastatic (nmCRPC)
+** Continue ADT until metastatic
+** Or add apalutamide or enzalutamide
+* Oligometastatic
+** Consider targeted RT ± ADT ± ASI
+* Metastatic (mCRPC)
+
+== 14-2.11: Therapy for Metastatic Prostate Cancer