Update 'prostate.adoc'

prostate.adoc

@@ -293,7 +293,7 @@ The optimal timing of systemic therapy for BCR is unclear. ADT will lower PSA le
 
 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
+* Nonmetastatic castration-resistant prostate cancer (nmCRPC)
 ** 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
@@ -317,3 +317,155 @@ Nonmetastatic BCR (increasing PSA on ADT) -> confirm castration -> repeat imagin
 * Metastatic (mCRPC)
 
 == 14-2.11: Therapy for Metastatic Prostate Cancer
+
+Treatment of metastatic prostate cancer is palliative, not curative, but with sequential treatments, patients may experience years of disease control.
+
+Compared with ADT alone, the addition of docetaxel, abiraterone plus prednisone, or the AR antagonists apalutamide or enzalutamide to treatment for patients with mCSPC significantly prolongs OS. Docetaxel seems to have the most benefit for patients with high-volume disease (four or more bone metastases with one or more outside the spine and pelvis, or visceral—not nodal—metastases).
+
+* Metastatic castration-sensitive prostate cancer (mCSPC) = metastases on imaging study and noncastration levels of testosterone
+** ADT is standard systemic treatment approach for relapsed prostate cancer
+*** Castrating ADT reduce serum testosterone levels (GnRH agonists/antagonists, estrogens, orchiectomy)
+**** Associated with gynecomastia, impotence, loss of libido, weakness, fatigue, hot flashes, loss of muscle mass, anemia, depression, loss of bone
+**** Conflicting data regarding risk of cardiovascular mortality and dementia
+**** DEXA at baseline and over time to screen for osteopenia/osteoporosis
+***** Usually at start of long-term ADT and after 1 year of ADT
+**** FRAX score
+***** Treat if justified unless testosterone recovery imminent
+**** Response measured by decline in PSA, decrease in size of nodal or visceral metastases, and improvement in cancer-related symptoms
+***** 60%-70% of patients with abnormal PSA would have normalization < 4 ng/mL;
+****** PSA measured at 7 months after initiation is prognostic: dramatically shorter median survival for patients with PSA > 4 ng/mL and a dramatically longer median survival for patients with PSA < 0.2 ng/mL
+***** 30%-50% of measurable tumor masses would regress by ≥ 50%
+***** 60% of patients would have palliation of symptoms
+***** 30%-40% would show improvement on bone scans;
+****** Scintigraphic flare could occur between 3-6 months after initiation of therapy, not to be confused with progression of skeletal metastases
+**** LHRH agonist initially increases serum testosterone level for up to a few weeks, although clinical relevance is debatable
+***** Antiandrogens are sometimes used concurrently to block potential effects of the testosterone surge, starting approximately 2 weeks before LHRH agonist, especially in the setting of high-risk metastatic lesions
+****** Antiandrogen + LHRH analog additionally blocks effects of adrenal androgens, which contribute 5%-45% of residual androgens after surgical castration alone
+****** Nonsteroidal antiandrogens confer a small but significant improvement in 5-year survival over castration therapy alone
+******* Combination treatment is generally not continued after flare period because of additional toxicity
+******* Bicalutamide could paradoxically act as an AR agonist if given long-term
+******** If PSA increases on bicalutamide, bicalutamide should be withdrawn and may result, in 20% of patients, in a decrease in PSA level over 1-2 months
+****** Bicalutamide adverse effects include gynecomastia (treated with tamoxifen 10 mg/day or RT) and elevated transaminases (monitored periodically)
+******* Typical dosing is 50 mg/day, and high doses 150 mg/day should be avoided given evidence of cardiotoxicity (heart failure or cardiac arrest)
+******* Usually used with LHRH analog, but monotherapy could be used in patients who decline castration therapy or are significantly debilitated with other life-limiting comorbidities
+***** GnRH antagonist or surgical castration could be used to avoid testosterone flare
+*** Noncastrating AR blockade block androgen activity at the receptor
+** Chemotherapy
+*** Addition of docetaxel to ADT is standard option (CHAARTED, STAMPEDE, GETUG-AFU 15) for mCSPC, but benefit may be limited to those with high-volume metastatic disease or de novo low-volume disease
+*** Risks of febrile neutropenia (primary prophylaxis G-CSF at investigator's discretion) and edema refractory to diuresis (prevented by steroid prophylaxis)
+** Abiraterone for mCSPC
+*** Similar improvement in OS compared to docetaxel
+** AR antagonists for mCSPC
+*** ADT + enzalutamide improved OS and PFS over ADT alone
+*** ADT + apalutamide improved OS and PFS over ADT alone
+** Prostate-directed therapy
+*** Ongoing studies evaluating local therapies in oligometastatic CSPC
+
+In the setting of mCRPC, abiraterone, enzalutamide, sipuleucel-T, docetaxel, radium-223, and cabazitaxel all prolong OS. Unfortunately, cross-resistance to AR-directed therapies occurs after exposure to abiraterone or enzalutamide for a prolonged period, and the efficacy of enzalutamide after abiraterone or abiraterone after enzalutamide is limited.
+
+* Metastatic castration-resistant prostate cancer (mCRPC) = progression of metastatic disease despite castration levels of testosterone
+** AR signaling continues to play a major role, so castration is maintained
+** Abiraterone and enzalutamide are associated with prolonged survival and improved QoL
+*** Ketoconazole was used previously
+*** Abiraterone causes ACTH-mediated mineralocorticoid excess, and should be used with low-dose prednisone; blood pressure and potassium levels should be monitored
+**** Prednisone 5 mg/day in castration-sensitive disease
+**** Prednisone 5 mg BID in castration-resistant disease
+*** Enzalutamide is highly potent AR antagonist, associated with HTN and seizures
+*** AR splice variant AR-V7 lacks ligand-binding domain and confers resistance to enzalutamide and abiraterone
+**** Taxane could be used
+** New-onset back pain should raise concern for possible spinal cord or cauda equina disease, and an MRI of the spine should be performed if indicated
+** If PSA appears to be disproportionately low for tumor burden, a repeated biopsy may indicate a neuroendocrine or small cell phenotype
+** Chemotherapy for mCRPC
+*** Docetaxel superior to mitoxantrone
+*** Cabazitaxel is second-line after docetaxel
+**** Neutropenic fever grade 3-4 is major serious toxicity, needs primary prophylaxis with G-CSF
+*** Platinum-containing regimens (e.g., cisplatin/carboplatin + etoposide, carboplatin + docetaxel) for small cell histology
+**** ADT should be continued because of tumor heterogeneity
+** Sipuleucel-T
+*** Improved OS in patients with minimally-symptomatic disease
+*** No significant effect on PSA or PFS
+** Immunotherapy
+*** CTLA-4 and PD-1/PD-L1 inhibition had limited efficacy after failure of standard therapies
+*** Small percentage of patients have MSI-H or MMR-D cancer, and may have dramatic response to pembrolizumab
+** Targeted therapy
+*** Olaparib use resulted in response in 33% of patients after docetaxel and one or more AR-directed therapies, more in patients with biallelic somatic or germline BRCA2 loss or ATM aberrations
+*** Addition of platinum to docetaxel may be effective in patients with alterations in DNA repair genes
+** Bone-directed therapy
+*** Radium-223 approved to treat symptomatic bone metastases without known visceral metastases
+**** Associated with increased risk of fragility fractures, to be avoided in combination with abiraterone/prednisone
+*** Bisphosphonates or denosumab for patients on long-course ADT + RT with osteopenia/osteoporosis (zoledronic acid yearly, denosumab 60 mg q6months), or patients with mCRPC and bone metastases (zoledronic acid monthly or q3months, denosumab 120 mg monthly or q3months)
+**** Risks of renal insufficiency, osteonecrosis of jaw, and hypocalcemia
+**** Bisphosphonates should be stopped or given less frequently after 2 years of therapy, due to increased risk of atypical femoral fractures and osteonecrosis of jaw
+**** Denosumab may be continued indefinitely
+**** Both denosumab and zoledronic acid are given with calcium to mitigate risk of hypocalcemia, and sometimes in combination with vitamin D
+* Palliation
+** EBRT
+** NSAID
+** Mitoxantrone and prednisone
+** Radium-223
+
+*Treatment of mCSPC*
+
+|===
+| |High-volume |Low-volume
+|De novo
+a|ADT +
+
+* Docetaxel
+* Abiraterone
+* Apalutamide
+* Enzalutamide
+a|ADT +
+
+* Docetaxel
+* Abiraterone
+* Apalutamide
+* Enzalutamide
+|Recurrent |(rare)
+a|ADT ±
+
+* Apalutamide
+* Enzalutamide
+|===
+
+*Systemic treatment options for mCSPC*
+
+[mermaid, format=svg, opts=inline]
+----
+graph TD
+	Pretreated[Prior local therapy] --> mCSPC
+	Untreated[De novo] --> mCSPC
+	mCSPC --> ADT1[GnRH agonist/antagonist +/- bicalutamide,<br />or single-agent bicalutamide if frail] --> Continue1[Continue ADT] --> |Progression| mCRPC
+	mCSPC --> |Especially if high volume| ADT2[ADT + docetaxel x6 cycles] --> Continue1
+	mCSPC --> ADT3[ADT + abiraterone<br />ADT + apalutamide<br />ADT + enzalutamide] --> Continue2[Continue ADT + ASI] --> |Progression| mCRPC
+----
+
+*Treatment options for mCRPC*
+
+[mermaid, format=svg, opts=inline]
+----
+graph TD
+	ADT[ADT +/- prior docetaxel] --> |Progression| Progression{ }
+	Abiraterone --> |Progression| Enzalutamide --> |Progression| NGS[Biopsy for NGS]
+	Enzalutamide --> |Progression| Abiraterone --> |Progression| NGS
+	Progression --> Docetaxel --> |Progression| Cabazitaxel
+	Progression --> Abiraterone --> |AR-V7| Docetaxel
+	Progression --> Enzalutamide --> |AR-V7| Docetaxel
+	Docetaxel --> |Progression| NGS
+	NGS --> |DDR alteration| PARPi
+	NGS --> |MSI-high| PD-1i
+	Bone1[Bone-predominant mCRPC] --> Radium-223
+	Bone2[Bone metastases in mCRPC] --> BoneTx[Add bisphosphonate or denosumab]
+----
+
+## 14-2.12: Survivorship and Elderly Considerations
+
+* Many men would be cured of prostate cancer by RT or surgery
+* Adverse effects may be particularly pronounced in older men
+* Therapy-related adverse effects include urinary incontinence, erectile dysfunction, and post-treatment psychosocial issues
+* ADT is associated with decreased libido, impotence, decreased lean body mass and muscle strength, increased fat mass, decreased QoL, and osteoporosis
+* Long-term ADT could be associated with metabolic complications such as insulin resistance, hyperglycemia, metabolic syndrome, and potentially an increased risk of cardiovascular events
+* Men on long-term ADT should be monitored for development of diabetes and dyslipidemia
+* Men with previous cardiovascular disease may be at increased risk of cardiovascular morbidity while receiving ADT
+* ADT may be associated with development of depression
+* Risks of ADT are likely justified in the setting of intermediate- to high-disk localized or metastatic disease in which clear survival advantages have been established