Campbell Prostate Cancer + NCCN 2.2021 Flashcards
The American Brachytherapy Society guidelines suggest that prostate glands that are greater than ___ are technically more difficult to implant because of: ___ and ___;
___ can reduce prostate volumes by ___ % to optimize gland before brachytherapy
60cm
- increased frequency of pubic arch interference - large number of seeds required
Cytoreductive ADT
25% to 40%
Prostate volumes in excess of ___ may require ___ before RT to reduce volume of rectum or bladder exposed to radiation.
Neoadjuvant ADT for cytoreduction
Transurethral resection of the prostate (TURP) ____ (before or after?) external radiation, rather than after, may be advisable for men in, or at risk of, retention.
BEFORE radiation!
** post-treatment transurethral resection is performed, there may be a higher associated risk of incontinence (Polland et al., 2017), particularly after brachytherapy with up to 18% of men incontinent after TURP
Contraindications to RT for prostate cancer
Previous radical pelvic irradition
Previous pelvic surgery: potentially trap bowel within pelvic field
PResence of substantial or susceptible bowel (hernia ex.)
Poor tissue healing (chronic steroid therapy)
Risk strat:
Very low
• T1c AND
• Gleason score ≤6/grade group 1 AND
• PSA <10 ng/mL AND
• Fewer than 3 prostate biopsy fragments/cores
positive, ≤50% cancer in each fragment/core AND
• PSA density <0.15 ng/mL/g
Imaging: NOT indicated
Risk strat:
Low
- T1–T2a AND
- Gleason score ≤6/grade group 1 AND
- PSA <10 ng/mL
Imaging: NOT indicated
Risk strat:
Favorable intermediate
- T2b–T2c OR
- Gleason score 3+4=7/grade group 2 OR
- PSA 10–20 ng/mL AND
- Percentage of positive biopsy cores <50%
Imaging:
• Bone imaging: not recommended for staging
• Pelvic ± abdominal imaging: recommended if
nomogram predicts >10% probability of pelvic lymph node involvement
Risk Strat:
Unfavorable intermediate
• T2b–T2c OR
• Gleason score 3+4=7/grade group 2 or Gleason
score 4+3=7/grade group 3 OR
• PSA 10–20 ng/mL
Imaging:
- Bone imaging: recommended if T2 and PSA >10 ng/mL
- Pelvic ± abdominal imaging: recommended if nomogram predicts >10% probability of pelvic lymph
Risk strat:
High
• T3aOR
• Gleason score 8/grade group 4 or Gleason score
4 +5=9/grade group 5 OR
• PSA >20 ng/mL
Imaging:
• Bone imaging: recommended
• Pelvic ± abdominal imaging: recommended if
nomogram predicts >10% probability of pelvic lymph
Risk strat:
Very high
• T3b–T4 OR
• Primary Gleason pattern 5 OR
• >4 cores with Gleason score 8–10/grade group 4
or 5
Imaging:
• Bone imaging: recommended
• Pelvic ± abdominal imaging: recommended if
nomogram predicts >10% probability of pelvic lymph
Observation is most frequently employed in ___ .
General ffu consists of:
Men at low risk of prostate cancer death
Periodic PSA testing, clinical exam, use of imaging to monitor progression
SURVEILLANCE should be recommended as the best care option for ___ and preferable care option for ___ localized prostate cancer.
best for VERY LOW RISK
preferable for LOW RISK
Death in men on active surveillance, most commonly from ___
Cardiovascular disease
** Rarely from prostate cancer
Risk factors:
____ race found be associated withdverse pathologic outcomes such as positive surgical margins, upgrading, or upstaging.
African-American race
A history of ___ is significant and may reflect a germline disposition to prostate cancer.
A history of metastatic disease at a young age (<60) in a first-degree relative
Advising men to ____ is the single most cost-effective health intervention in the entire edifice of medical practice.
QUIT SMOKING!
Patients taking ___ in the SELECT trial had an increased risk of prostate cancer.
Patient consuming >=140 micrograms/day of supplemental ___ had 2.6 times greater disease-specific mortality.
Vitamin E
Selenium
Lifestyle recommendations for active surveillance: ___
- Exercise regularly, and include vigorous activity if possible.
- Maintain a healthy weight.
- Stop smoking.
- Eat a vegetable- and grain-based diet; moderate red meat consump-
tion, especially processed meats; if eating meat, rely on fish and
skinless poultry. - Limit saturated fat intake.
- Take vitamin D, 1000 to 2000 IU/day, especially during periods
of reduced sunlight. - Consider a low-dose statin.
IMRT
Intensity-modulated radiation therapy
IMRT employs more complex, dynamic beam shapes wherein the intensity of radiation is varied across the beam (as opposed to uniform intensity across the beam in 3DCRT)
Low-dose-rate 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
125Iodine emits low-energy x-rays at 27 keV, with a half-life of 59.6 days.
103Palladium was introduced in 1986 because it has an energy spectrum similar to that of 125I, with 21-keV x-rays, but with a significantly shorter half-life of 17 days.
131Cesium, which emits x-rays at 30 keV (thereby offering dose characteristics similar to 125I)
High-dose-rate Brachytherapy
Delivers short but high doses of radiation using temporary catheters
Hollow catheters are placed through the perineum into the prostate using the same procedure as for LDR brachytherapy
iridium-192 (192Ir)
Advantages of HDR vs. LDR Brachytherapy:
The use of catheters allows for more ready inclusion of extracapsular
disease and seminal vesicles, if desired.
• There is greater opportunity for dose optimization by modifying
dwell times and positions of the source within the catheters.
• The use of high doses per fraction has a potential biologic dose advantage for prostate cancer if a low alpha/beta ratio exists.
• No need for personnel to handle the radioactive source during
treatment.
• The use of a single source for all patients using a multipurpose
facility makes HDR brachytherapy potentially more cost-effective.
Potential disadvantages for HDR versus LDR brachytherapy include: • There are potential treatment inaccuracies caused by catheter and organ/patient movement between imaging and time of source insertion (during treatment planning) or between fractions, interobserver contouring variabilities, and effects of edemaThe relatively high activity and energy of the 192Ir source requires
availability of a shielded room for treatment delivery.
• There are less favorable pathologic response results from avail- able post-treatment biopsy studies
Major acute toxicity of brachytherapy is ___
Obstructive and irritative uropathy
Low but non-negligible risk of need for temporary catheterization.
Relative contraindications to brachytherapy:
Large TURP defects, TURP within prior 3-6months
Factors assoc. with poor urinary outcomes or obstruction: Qmax < 10, IPSS >20, large median lobe
Prior pelvic RT
Connective tissue disease or IBD
Pubic arch interference
Lithotomy position
Rectal fistula or lack of TRUS access
The most important pathologic criteria predicting prognosis after radical prostatectomy are:
Gleason score Surgical margin status, Extracapsular extension Seminal vesicle invasion Lymph node involvement
Many men with clinical stage T3 disease have ____ and may not benefit from prostatectomy.
Select (low-volume disease) may benefit because local control may be achieved in most.
Regional spread
The presence of ___ increases progression from 7% to 18-35% at 5 years.
Focal or established extracapsular extension
Radical prostatectomy alone can result in disease-free survival in ___ despite clinically advanced disease.
At least one-half of men at 8 to 10 years
____ therapy before radical prostatectomy does NOT appear to improve DSS or OS.
Neoadjuvant androgen deprivation (NAD)
** For locally advanced tumors (specifically cT3), current data, both retrospective and prospective, do not support a significant benefit of NAD before surgery
The use of adjuvant RT is associated with ___.
Early use of ___ may be beneficial for advanced tumors at the time of biochemical recurrence in select patients.
A range of BDFS (biochemical disease free survival) from 50% to 88% at 5 years
secondary therapy (RT or AD)
Men with seminal vesicle invasion who achieve a low PSA level (<0.3 ng/mL) after prostatectomy or have positive surgical margins may benefit more from ___.
men with more advanced disease never reaching an undetectable PSA level generally constitute a poor prognostic group likely harboring ___.
Adjuvant RT.
Unrecognized lymph node or distant disease.
Postradiation PSA “bounce”
NOT ALL MEN ARE DESTINED FOR BIOCHEMICAL
Varied definition: elevated PSA of 0.1 ng/mL to 0.5 ng/mL over the prebounce PSA with a subsequent decrease in PSA.
Occurred at a mean time of 9 months
Associated with an improvement in biochemical recurrence–free survival compared with those who did not have a bounce
Patients selected for salvage RP must have the ff: ___
Biopsy-proven radiorecurrent prostate cancer
At least 10 years of life expectancy
Lack of identifiable metastasis on imaging
PSA of less than 10 ng/mL
All current forms of hormonal therapy in PCA function by: ___
Reducing the ability of androgen to activate the AR
** by lowering androgen levels, decreasing conversion of testosterone to more potent DHT, or blocking androgen-AR binding
___ is overexpressed in 20-30% of CRPC metastases.
AR gene
** enhances response to low levels of endogenous androgens
AR mutations and splice variants:
___ predominant splice variant has been strongly associated with castration resistance and overall poor patient survival
AR-V7
GnRH agonists
Leuprolide
Goserelin
Triptorelin
SOA: Pituitary
MOA: Stimulates release of LH; feedback loop ultimately decreases LH production
Mainstay of therapy for metastatic disease; leads to increase in FSH; considerable side effects
GnRH antagonists
Degarelix
Abarelix
Cetrorelix
SOA: Pituitary
MOA: Binds to receptors and blocks release of GnRH
Prevents testosterone surge; leads to decrease in FSH; considerable side effects
Adrenal-targeting drugs
Ketoconazole Abiraterone Oreteronel (TAK-700)
Galeterone
SOA: Adrenal
MOA: Decreases androgen production from steroid precursors by blocking cytochrome P450 enzymes
Selective CYP17 inhibitors administered with low-dose prednisone; side effects can include hypertension, edema, and hypokalemia
1st generation AR antagonists
Flutamide Nilutamide Bicalutamide
SOA: Prostate, PCA
MOA: Nonsteroidal antiandrogen inhibits binding of testosterone and DHT to the AR
Monotherapy not indicated; associated with gynecomastia
2nd generation AR antagonists
Enzalutamide Apalutamide
SOA: Prostate, PCA
MOA: Blocks AR, minimizes nuclear translocation of AR, and diminishes AR-mediated transcription
Associated with falls, fatigue, and decreased appetite
5alpha-reductase inhibitors
Finasteride (type II isoenzyme inhibition)
Dutasteride (type I and II isoenzyme inhibition)
SOA: Prostate, PCA
MOA: Inhibits the conversion of testosterone to DHT
Commonly administered for BPH; not indicated for prostate cancer management
Four approaches for androgen blockade:
(1) surgical removal of the testicles (orchiectomy),
2) AR antagonism,
(3) inhibition of LHRH and/or LH, and
(4) inhibition of androgen synthesis
About one-quarter of men on ___ therapy note a delayed adaptation to darkness after exposure to bright illumination.
NIlutamide
** Effects reversible with cessation
Most common side effects of enzalutamide: ___
Fatigue, breast enlargement/tenderness, diarrhea, and hot flashes.
** Seizures were more common in men taking enzalutamide compared with placebo but occurred in less than 1%
Common side effects of apalutamide: ___
25% of men Experienced a rash, 12% experienced falls and fractures, and 8% had hypothyroidism
In a review of 24 trials involving more than 6600 patients, survival after therapy with ___ was equivalent to orchiectomy
An LHRH agonist
*** flare of LH and testosterone levels, resulting in a severe, life-threatening exacerbation of symptoms, almost exclusively occurring in men with metastases in the spine or weight-bearing regions
Aminoglutethimide
Blocks production of aldosterone and cortisol. As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone
*** Side effects include anorexia, nausea, skin rash, lethargy, vertigo, hypothyroidism, and nystagmus.
Abiraterone side effects include: ___ which are due to: ___ and may be prevented by: ___
Hypokalemia, hypertension, and fluid overload
Increase in the mineralocorticoids deoxycorticoste- rone and corticosterone
Co-administration of prednisone (5 mg one to two times daily) suppresses the ACTH increase and lowers the likelihood of mineralocorticoid excess
LATITUDE trial showed that ___ + ___ was superior to traditional ADT by ___.
Abiraterone + prednisone was superior to traditional ADT
Extending median radiographic progression-free survival and overall survival
VERY LOW RISK management
>20 y EPS
AS
OR
EBRT or brachytherapy
OR
RP
- Adverse features: EBRT +- ADT or observation
VERY LOW RISK
10-20 y EPS
AS
VERY LOW RISK
<10 y EPS
Observation
LOW RISK
>=10 y EPS
AS
OR
EBRT or brachytherapy
OR
RP
- Adverse features: EBRT +- ADT or observation
LOW RISK
<10 y EPS
Observation
FAVORABLE INTERMEDIATE
>10 y
AS
OR
EBRT or brachytherapy ALONE
OR
RP +/- PLND if >= 2% prob of LN mets
- AF, no LN: EBRT +- ADT or observation
- LN mets: ADT (cat 1) +- EBRT (cat 2b) or observation
FAVORABLE INTERMEDIATE
5-10 y EPS
EBRT or brachytherapy ALONE
OR
Observation
UNFAVORABLE INTERMEDIATE
>10 y EPS
RPp ± PLND if predicted probability of lymph node metastasis ≥2%
OR
EBRTo + ADTt (4–6 mo)
or
EBRTo + brachytherapyo ± ADTt (4–6 mo)
UNFAVORABLE INTERMEDIATE
5-10 y EPS
EBRTo + ADTt (4–6 mo)
or
EBRTo + brachytherapyo ± ADTt (4–6 mo)
OR
Observation (PREFERRED)
HIGH/VERY HIGH RISK
> 5 y or symptomatic
EBRTo + ADTt (1.5–3 y; category 1) ± docetaxel (for very high risk only)
OR
EBRTo + brachytherapyo + ADTt (1–3 y; category 1 for ADT)
OR
RPp + PLND
HIGH/VERY HIGH RISK
≤5 y and asymptomatic
Observationq
or
ADT
or
EBRT
Active surveillance (AS) components:
• Consider confirmatory prostate biopsy with or without mpMRI and with or without
molecular tumor analysisj to establish candidacy for active surveillancen
• PSA no more often than every 6 mo unless clinically indicated
• DRE no more often than every 12 mo unless clinically indicated v
• Repeat prostate biopsy no more often than every 12 mo unless clinically indicated
• Repeat mpMRI no more often than every 12 mo unless clinically indicated
Observation
involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA that suggests symptoms are imminent
Adverse features
Positive margin(s); seminal vesicle invasion; extracapsular extension; or detectable PSA
PSA nadir
PSA nadir is the lowest value reached after EBRT or brachytherapy
PSA persistence/recurrence after RP
Failure of PSA to fall to undetectable levels (PSA persistence) or undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or more determinations (PSA recurrence).
RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for Therapeutic Radiology and Oncology) Phoenix Consensus
1) PSA increase by 2 ng/mL or more above the nadir PSA is the standard definition for PSA persistence/ recurrence after EBRT with or without HT; and 2) A recurrence evaluation should be considered when PSA has been confirmed to be increasing after radiation even if the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage local therapy who are young and healthy.
REGIONAL RISK GROUP (ANY T, N1,M0)
>5 y or symptomatic
EBRTo + ADTt (preferred) ± abirateroneee,ff
OR
ADTt ± abirateronet,ee
REGIONAL RISK GROUP (ANY T, N1,M0)
≤5 y
and asymptomatic
Observationq or t
ADT
MONITORING: RECURRENCE
After initial definitive therapy
- PSA every 6–12 mo for 5 y,gg then every year
- DRE every year, but may be omitted if PSA undetectable
If with: Radiographic evidence of metastatic disease without PSA persistence/recurrence –> BIOPSY
MONITORING: RECURRENCE
N1 on ADT
or
Localized on observation
- Physical exam + PSA every 3–6 mo
- Imaging for symptoms or increasing PSAf
Check for PROGRESSION: N1, m0 or m1
POST-RP PSA Persistence/recurrence
Risk stratificationjj PSADT Consider: • Bone imagingf,kk • Chest CT • Abdominal/pelvic CT or abdominal/pelvic MRIf • C-11 choline or F-18 fluciclovine PET/CT or PET/MRIf,w,ll • Prostate bed biopsy (especially if imaging suggests local recurrence
IF: Studies negative for distant metastases or imaging not performed –> EBRTo ± ADTt or Observationq –> then monitor for progression
PSA persistence/ recurrencey or
Positive DRE
• Risk stratificationmm PSADT • Bone imagingf,kk • Prostate MRI • Transrectal ultrasound (TRUS) biopsy • Consider: Chest CT Abdominal/pelvic CT or abdominal/ pelvic MRIf C-11 choline or F-18 fluciclovine PET/CT or PET/ MRIf,ll
TRUS biopsy positive, studies negative
for distant metastases –> >10y LIFE EXPECTANCY – > Observationq or p
RP + PLND
or o Brachytherapy or
High-intensity focused ultrasound (HIFU) (category 2B) or cryotherapy
TRUS negative or <10 y EPS: Observation or ADT
M0-CASTRATION NAIVE SYSTEMIC THERAPY
Observation
OR
ADT
Then: Physical exam + PSA every 3–6 mo
• Imaging for symptoms
• Consider periodic imaging for patients with
M1 to monitor treatment response
M1-CASTRATION NAIVE SYSTEMIC THERAPY
ADTt with one of the following: • Preferred regimens:
Apalutamide (category 1)t
Abiraterone (category 1)t,ee
Docetaxel 75 mg/m2 for 6 cyclesuu (category 1)vv Enzalutamide (category 1)t
• EBRTo to the primary tumor for low-volume M1uu
or ADT
Then: Physical exam + PSA every 3–6 mo
• Imaging for symptoms
• Consider periodic imaging for patients with
M1 to monitor treatment response
M0-CRPC
Conventional imaging studies negative
for distant metastases
Continue ADTt to maintain castrate serum levels of testosterone (<50 ng/dL)
PSADT >10 mo: Observation (preferred)q
or
Other secondary t hormone therapy
PSADT ≤10 mo: Preferred regimens: • Apalutamidet (category 1) • Darolutamidet (category 1) t • Enzalutamide (category 1) Other recommended regimens: • Other secondary t
M1-CRPC
CRPC, conventional imaging studies positive
for metastases
• •
•
Metastatic lesion biopsyyy
Tumor testing for MSI-H or dMMR if not previouslyc performed Germline and tumor testing
for homologous recombination gene mutations if not previously performedc
• Continue ADTt to maintain castrate levels of serum testosterone (<50 ng/dL)
• Additional treatment options:
Bone antiresorptive therapy with denosumab (category 1, preferred) or zoledronic acid
if bone metastases
present o Palliative RT for painful
bone metastases Best supportive care
SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMA
NO PRIOR docetaxel/no prior novel hormone therapy
No prior docetaxel/no prior novel hormone therapyfff
• Preferred regimens Abirateronet,ggg (category 1hhh) Docetaxelaaa,iii (category 1) Enzalutamidet (category 1)
•Useful in certain circumstances
Sipuleucel-Taaa,jjj (category 1)
Radium-223kkk for symptomatic bone metastases (category 1)
•Other recommended regimens t Other secondary hormone therapy
SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMA
PRIOR docetaxel/no prior novel hormone therapy
• Preferred regimens Abirateronet, ggg (category 1) Cabazitaxelaaa Enzalutamidet (category 1)
• Useful in certain circumstances
Mitoxantrone for palliation in symptomatic patients who
cannot tolerate other therapiesaaa Cabazitaxel/carboplatinaaa,nnn aaa
Pembrolizumab for MSI-H or dMMR
Radium-223kkk for symptomatic bone metastases (category 1)
• Other recommended regimens Sipuleucel-Taaa,jjj t Other secondary hormone therapy
SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMA
Prior novel hormone therapy/No prior docetaxel
Prior novel hormone therapy/No prior docetaxelfff,lll • Preferred regimens aaa
Docetaxel (category 1)
Sipuleucel-Taaa,jjj
• Useful in certain circumstances mmm
Olaparib for HRRm (category 1) Cabazitaxel/carboplatinaaa,nnn aaa
Pembrolizumab for MSI-H or dMMR
Radium-223kkk for symptomatic bone metastases (category 1) Rucaparib for BRCAmooo
• Other recommended regimens Abirateronet,ggg ggg,ppp
Abiraterone +t dexamethasone Enzalutamide
Other secondary hormone therapy
t
SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMA
Prior docetaxel and prior novel hormone therapy
All systemic therapies are category 2B if visceral metastases are present)
• Preferred regimens
Cabazitaxelaaa (category 1hhh)
Docetaxel rechallengeaaa,eee
• Useful in certain circumstances hhh,mmm
Olaparib for HRRm (category 1) Cabazitaxel/carboplatinaaa,nnn aaa
Pembrolizumab for MSI-H or dMMR
Mitoxantrone for palliation in symptomatic patients who cannot
tolerate other therapiesaaa
Radium-223kkk for symptomatic bone metastases (category 1hhh) Rucaparib for BRCAmooo
• Other recommended regimens Abirateronet,ggg
Enzalutamidet t
An extended PLND
removal of all node-bearing tissue from an area bound by the external iliac vein anteriorly, the pelvic sidewall laterally, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally.
Men with high-volume, ADT-naïve, metastatic disease should be considered
for ___
ADT and docetaxel
Immunotherapy considered for: ___
Men with Asymptomatic or minimally symptomatic mCRPC may consider
immunotherapy.
Sipuleucel-T is only for: ___
nly for asymptomatic or minimally symptomatic, no liver metastases, life expectancy >6 months, ECOG performance status 0–1.
Sipuleucel-T is not recommended for patients with small cell/ neuroendocrine prostate cancer.
Pembrolizumab (MSI-H or DMMR) only as ___.
subsequent Systemic therapy for patients with metastatic CRPC who have progressed through prior docetaxel and/or a novel hormone therapy.
For prevention of SREs in CRPC: ___ and ___
Denosumab (SUPERIOR) and
zoledronic acid have been shown to prevent disease-related skeletal complications, which include fracture, spinal cord compression, or the need for surgery or RT to bone.
Denosumab (preferred) is given subcutaneously every 4 weeks.
Zoledronic acid is given intravenously every 3 to 4 weeks or every 12 weeks.
Zoledronic acid is not recommended for creatinine clearance <30 mL/min.
Osteonecrosis of the jaw (ONJ)
Seen with both agents; risk is increased in patients who have tooth extractions, poor dental hygiene, or a dental appliance. referred
for dental evaluation before starting either zoledronic acid or denosumab.
