Prostate Flashcards
Late side effects after Brachytherapy
Sexual dysfunction
-erectile dysfunction (@5yrs 48% experience Gr2 or higher ED)
- impotence,
- dry and/or painful ejaculation,
- haematospermia
- reduction in ejaculate.
Urinary:
- Obstructive urinary SX and retention
- Urethral stricture (8%)
- Urinary incontinence <1%
- Severe late urinary tox 8% at 5years
Perineal discomfort
Rectal:
- Rectal ulceration
- Proctitis
- Prostatorectal fistulas very rare, but increased risk in the setting of subsequent rectal biopsies which are contraindicated.
Second malignancy
Risk factors for prostate cancer
Intrinsic:
Increased age
FamHx
Genetics
- BRCA2
- Lynch syndrome
- HOXB13
- Fanconi Anaemia
Race (African American worse outcomes)
Extrinsic:
Agent orange exposure
What mutations occur in the development of prostate cancer
(CRAB mAPP)
Progressive loss of
Rb
P53
PTEN
CDKNIB
ATM
BRCA
mycAMP
What is the pathogenesis of prostate cancer
Normal prostate –> undergoes proliferative inflammatory atrophy –> prostatic intra-epithelial neoplasia (PIN) –> prostate cancer
What is the Gleason score
Sum of the two most common Gleason grades
What ISUP group does each Gleason score correspond to?
ISUP GG1 = GS 3+3
ISUP GG2 = GS 3+4
ISUP GG3 = GS 4+3
ISUP GG4 = GS 8 (e.g. 4+4, 5+3, 3+5)
ISUP GG5 = GS 9 or greater (4+5, 5+4, 5+5)
what is an advantage of ISUP grade group categories over Gleason score alone?
What is a disadvantage?
GS groups 3+4 and 4+3 together as 7,
and GS 8-10 together.
ISUP grades allow better prognostic stratification of GS 7 and 8-10 (become GG 2, 3, 4 and 5)
disadvantage: doesn’t take into account tertiary score
What is Prostate specific membrane antigen (PSMA)
type II membrane glycoprotein expressed in benign and
malignant prostate
has stronger staining in malignant tissue compared to benign.
correlates with Gleason grade
What is intra-ductal carcinoma of prostate? (IDC-P)
intra-acinar or intra-ductal neoplastic epithelial proliferation that fills large ducts and acini. preservation of basal cells
Uncommon finding on biopsy, presence should be recorded.
- Diagnosis based on:
o Large calibre glands (>2x diameter of normal non-malignant glands)
o Preserved basal cell (i.e. HMWCK and p63 IHC+ve)
o Significant nuclear atypia (enlarged nuclei >6x non-malignant nuclei)
o Comedonecrosis (often, but not always present)
What is the significance of IDC-P
o a/w high volume, high grade disease, early biochemical recurrence and metastatic disease
o presence of IDC-P in biopsy (if invasive carcinoma not identified) mandates immediate repeat biopsy or
definitive treatment
- important to distinguish from HGPIN
- should not be assigned GS/ISUP GG
What microscopic changes are seen in cancer cells after radiation treatment?
Necrosis if have been killed by RT
Very abnormal , usual malignant features if not killed
What microscopic changes are seen in connective tissue after radiation?
glandular atrophy,
stroma fibrosis (if late; inflammatory cells infiltration if acute),
vessels leaky/ hyalinised cytological atypia
What should be reported in the path report for a Prostate biopsy?
What should be reported in the path report for a Radical prostatectomy specimen?
What is the PSA cut off for 40-50yo?
2.5
what is the PSA cut off for 50-60?
3.5
What is the PSA cut off for 60-70yo?
4.5
What is the PSA cut off for >70years?
5.5
What is PSA density?
Ratio of PSA to prostate volume; PSA density>0.15 is suggestive of malignancy
What is PSA velocity?
Changes in PSA over time:
What PSA velocity is concerning
A rise of >0.75ng/ml per year is suggestive of malignancy
What are the 5 points from the Melbourne consensus? (current recommendation on PSA testing)
Murphy DG 2014 BJUI Supp
- For men aged 50-69, Level 1 evidence shows that PSA testing reduces the incidence of metastatic prostate
cancer and prostate cancer specific mortality
* ERSPC showed that PSA screening reduce metastatic disease and PCSM by up to 30% and 21 %
respectively - Prostate cancer diagnosis must be uncoupled from prostate cancer intervention
- PSA testing should not be considered on its own, but rather as part of a multivariable approach to early prostate
cancer detection - Baseline PSA testing for men in their 40s is useful for predicting future risk of prostate cancer and its aggressive forms
- Older men in good health with a >10-year life expectancy should not be denied PSA testing based on their age
Work up- History component
Urinary function (IPSS, flow studies)
Sexual function
FamHx
Medical comorbidities (risks with ADT)
Contraindications to RT
Work up- Physical exam
DRE- cT staging
Work up- Investigations
Labs:
- PSA (free/total ratio, PSA density)
- Testosterone
- calcium
- HbA1C
Imaging:
- Prostate MRI (PIRADS)
- CT C/A/P + bone scan if IR/HR or symptoms
- PSMA PET for HR (ANZUP proPSMA trial for high risk, 85% sensitivity vs 35% (CT))
- DEXA if for ADT
Biopsy:
TRUS vs TPB
* TRUS volume (especially if considering brachytherapy)
* Histopathology: Gleason score, number of cores taken, number of positive, percent of
positive/ maximal length of positive core
Advantages and disadvantages Transrectal biopsy
Advantages and disadvantages of Transperineal biopsy
T1 stage roughly
tumour not palpable on DRE
T2 stage roughly
Organ confined, describes extent throughout prostate
T3 stage roughly
No longer organ confined
T4 stage
Tumour is fixed or invades adjacent structures other than seminal vesicles
such as external sphincter, rectum, bladder, levator muscles, and/ or pelvic wall
How many N classifications are there for prostate cancer
1- N1
regional nodes involved
NCCN Very low risk group
T1c AND
GG1AND
PSA<10 AND
less than or equal to 3 core positive AND
PSA density<0.15ng/mL/g
NCCN low risk stratification
T1-T2a AND
GG1 AND
PSA<10
What is the NCCN favourable intermediate risk stratification?
What is the NCCN unfavourable intermediate risk stratification?
What are the intermediate risk factors for NCCN stratification groups
o T2b-T2c
o GG2-3
o PSA 10-20
What are the features of NCCN high risk straficiation group?
T3a OR
GG4-5 OR
PSA >20
What are the features of NCCN very high risk stratification group?
T3b-4 OR
primary Gleason grade 5 OR
2-3 high risk features OR
4 or more cores with GG4-5
What are the treatment options for very low risk prostate cancer?
What are the treatment options for low risk prostate cancer?
Life expectancy >10years
- active surveillance
- EBRT or BT
- RP
Life expectancy <10years
- observation/watchful waiting: no further testing, test only when symptomatic
What are features of active surveillance?
- Consider mpMRI or prostate biopsy to confirm candidacy for AS
- PSA not more frequent than every 6 months
- DRE not more frequent than every 12 months
- Repeat biopsy not more frequent than every 12 months
- Repeat mpMRI not more frequent than every 12 months
What are the treatment options for favourable intermediate risk prostate cancer?
What are the treatment options for unfavourable intermediate risk prostate cancer?
What are the treatment options for high and very high risk prostate cancer?
What are the treatment options for isolated prostate recurrence after definitive RT
Salvage RP
Salvage brachytherapy (interstitial/seed)
Salvage re-irradiation/SBRT
Other investigational options
- cryotherapy
- High-intensity focused ultrasound (HIFU)
- Irreversible electroporation (IRE)
What is the PROMETHEUS trial
Australian trial
Population: intermediate and high risk prostate cancer
Single arm dose-escalation study:
19Gy/ 2# SBRT boost + EBRT 46Gy/ 23#
* SBRT boost escalate 1Gy at a time to 22Gy
Assessing safety, efficacy and feasibility
What is the NINJA trial
TROG trial
Population: intermediate and high risk
- arm 1: SBRT alone 40Gy/5# over 2 weeks
- arm 2: SBRT ‘virtual HDR’ boost 20Gy/2# + EBRT 36Gy/12#
Primary outcomes: 5-year biochemical control
Currently recruiting (Jan 2024)
What studies inform the management of oligometastatic prostate cancer?
- STOMP
1-3 mets randomised to Metastasis directed therapy (RT or surgery) vs observation
Increased ADT free survival and castrateRes free survival
- STAMPEDE: shows OS benefit for patients with low metastatic burden who received RT to prostate primary, and improved FFS in all who had RT
- ORIOLE
1-3 mets randomised to SABR vs observation.
Improved progression free survival with SABR group - SABR COMET
Tumour agnostic- 16 with prostate cancer
1-5 mets
Increased PFS and OS - POPSTAR
single arm prospective trial on safety and efficacy of SABR 20Gy/1# to oligo mets (1-3)
Safety established and >1/3 of patients did not progress and were free of ADT at 2 years
What were the findings of the STAMPEDE trial with regards to RT to prostate in patients with metastatic prostate cancer?
randomised comparison of more than 2000 patients with metastatic prostate cancer showed that local radiotherapy to the prostate did not improve overall survival for unselected patients.
However,a prespecified analysis showed that prostate radiotherapy did improve OS (from 73% to 81% at 3 years) in those with a low metastatic burden, which represented 40% of the comparison population.
High met burden defined as:
4 or more bone metastases with one or more outside the vertebral bodies or pelvis, OR visceral metastases,
OR both;
all other assessable patients were considered to have low metastatic burden.
What is the definition of high metastatic burden as per STAMPEDE trial?
High met burden defined as:
4 or more bone metastases with one or more outside the vertebral bodies or pelvis, OR visceral metastases,
OR both;
all other assessable patients were considered to have low metastatic burden.
What were the doses used in STAMPEDE for prostate RT
55Gy/20#/5 or 36Gy/6#/1
What were the STOMP and ORIOLE trials?
two prospective phase II trials of stereotactic ablative radiation versus observation
in metachronous oligometastatic castration-sensitive prostate cancer
Describe the STOMP trial and main findings
- Randomised prospective phase II trial
- biochemical relapse with three or fewer extracranial metastatic lesions on choline positron emission tomography-computed tomography, and serum testosterone levels > 50 ng/mL
- assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy)
- At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11).
Describe the ORIOLE trial and main findings
- Randomised prospective phase II trial
- 1-3 mets in hormone sensitive prostate cancer
- Randomised 2:1 to SABR vs observation
- Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002).
Describe the POPSTAR trial and main findings
- Single arm prospective trial of 33 patients with oligomer prostate cancer (1-3 mets)
- received 20Gy/1# to each lesion
- Twenty patients had bone only, 12 had node only, and one had mixed disease.
- The 1 and 2-yr Local PFS was 97% (95% confidence interval [CI]: 91–100) and 93% (95% CI: 84–100), and Distant PFS was 58% (95% CI: 43–77) and 39% (95% CI: 25–60), respectively.
- In those not on androgen deprivation therapy (ADT; n = 22), the 2-yr freedom from ADT was 48%.
Limitations
- small sample size
- short follow up of 2 years
- lack of control arm
What is the rationale for treating oligo met disease in prostate cancer
- sensitive and specific imaging now available (PSMA PET) so can reliably detect mets
- Early detection possible due to PSA testing and this allows us to monitor for relapse
- Long natural history with prostate cancer, may give reasonable length of time to patient
- provides local control and symptom benefit
- delays treatment lines and their side effects
What is the PEACE-V-STORM trial
Currently underway.
Superiority trial in oligorecurrent nodal prostate cancer (5 or fewer pelvic nodes identified on PET)
Randomised to Metastasis directed therapy + 6mo ADT vs
MDT + Elective nodal irradiation 45Gy/25# + 6mo ADT
What two studies inform practice for oligoreccurent nodal mets?
PEACE-V-STORM
Oligopelvis GETUG p07
Describe OLIGOPELVIS GETUG P07 trial
phII efficacy study of pelvic irradiation and 6 months ADT in prostate cancer nodal recurrence with 5 or fewer nodes.
2yr PFS 81%
3yr PFS 58%
Median PFS 45.3mo
progression = 2 consecutive PSA tests above baseline at entry to study
What is the CHAARTED trial and its key results?
Phase III randomised trial of metastatic hormone sensitive prostate cancer
Randomised to 2 arms
1. ADT alone
2. ADT + 6C x Docetaxel 75mg/m2
Findings:
High volume metastatic disease had improved OS with docetaxel (51 months vs 34 months).
No OS benefit seen in low volume met disease
High volume defined as visceral mets and/or
4 or more bone mets with at least one outside of the vertebral column or pelvis
What were the results of the STAMPEDE trial re Docetaxel
(Lancet 2016)
STAMPEDE assessed the efficacy of standard of care (at least 2 years of ADT)
vs SOC + docetaxel 75mg/m2 x 6C
vs SOC + zolendronic acid
vs SOC + ZA + docetaxel
Findings:
Improves OS in docetaxel group cf ADT alone
(median OS 81 months vs 71 months)
No survival advantage to zolendronic acid
Docetaxel should be started when long term ADT is being started.
What trials support the use of docetaxel in metastatic hormone sensitive prostate cancer?
CHAARTED
STAMPEDE
What trials support the use of abiraterone in metastatic hormone sensitive prostate cancer?
LATITUDE
STAMPEDE
What was LATITUDE study and its key findings?
randomised double blind phase III trial
1199 men randomised to 2 arms:
1. Abiraterone + predisone + ADT
2. Placebo + ADT
Findings:
Improves OS In abiraterone group cf placebo (median OS 53.3mo vs 36.5mo)
What were the results of the STAMPEDE trial re abiraterone in met hormone sensitive prostate cancer?
Randomised to ADT alone or ADT + Abiraterone + prednisolone in men previously not treated with hormone deprivation.
52% were metastatic
20% had Node positive disease
Findings:
improves OS (HR 0.63) and FFS in abiraterone arm
What was the ENZAMET trial and its main findings
randomised phase III trial run by ANZUP
patients with met hormone sensitive prostate cancer randomised to ADT + Enzalutamide 160mg OD vs
ADT + non steroidal antiandrogen e.g. bicalutamide.
Docetaxel given at physician discretion (65% in enzalutamide arm and 76% in control arm)
OS benefit with enzalutamide (3yr OS 80% vs 72%)
PSA PFS benefit too (@3yeears 67% vs 37%)
Describe the titan trial and its key findings
randomised double blind phIII trial in metastatic castrate sensitive prostate cancer.
randomised to ADT + apalutamide vs
ADT + placebo
Findings:
OS benefit in apalutamide group (@2years 82% vs 73%)
Radiographic PFS benefit in apalutamide (@24 months 68% vs 47%)
What are the treatment options in metastatic hormone sensitive prostate cancer?
If oligometastatic»_space;
ADT +
RT to prostate +
Metastases directed therapy
Not Docetaxel (no OS benefit per CHAARTED)
If high burden of metastatic disease:
- ADT +
Docetaxel or
Abiraterone or
Enzalutamide or
Apalutamide
What are the treatment options for metastatic castrate resistant prostate cancer?
ADT + one of:
Docetaxel
Abiraterone
Enzalutamide
Describe the COU-AA-301 trial and its key findings
randomised blinded phase III trial in metastatic citrate resistant prostate cancer in patients who HAD ALREADY HAD DOCETAXEL
1195 patients randomised to abiraterone + prednisone vs placebo + prednisone
OS benefit in Abi group (14.8 months vs 10.9months)
PFS and PSA response benefit seen as well
Describe the COU-AA-302 trial and its key findings
randomised double blind phase III trial of abiraterone in chemotherapy naive metastatic castrate resistant prostate cancer
1088 patients randomised to abiraterone 1000mg OD + prednisone 5mg BD VS
placebo + prednisone 5mg BD
Findings:
Improves OS in Abi group (34 months vs 30 months)
4% more gr3-4 cardiac events in Abi group
What is the definition of castrate resistant prostate cancer
Prostate cancer that has progressed despite castrate levels of androgens (<50 ng/ml) is termed castration-resistant prostate cancer (CRPC).
clinical manifestations include rising PSA concentration in 90%, bone metastases in 90%, substantive pain in 35%, and soft-tissue/lymph node metastases in 20% of patients
What two trials established 3 weekly docetaxel as standard in MCRPC?
TAX327
SWOG 99-16
Both of these showed improved OS for 3 weekly docetaxel vs Mitoxantrone vs weekly docetaxel
What trials support the use of Enzalutamide in MCRPC?
AFFIRM: MCRPC previously treated with chemo
OS benefit for enzalutamide vs placebo (median OS 18.4 mo vs 13.6mo)
increased seizures in Enza group
PREVAIL: chemo-naive
(OS benefit for enzalutamide vs placebo (36mo vs 31months)
increase in fatal cardiovascular events in treatment group
When is docetaxel started in MCRPC?
When there is progression (e.g PSA rise) despite secondary androgen deprivation therapy
What agent can be used after progression in MCRPR after Docetaxel?
What evidence supports this
3weekly Cabazitaxel + prednisolone
Supported by TROPIC and PROSELICA trials
TROPIC showed improved OS compared to mitozantrone
PROSELICA established the non inferiority of 20mg/m2 vs 25mg/m2 dose
What is the role of olaparib in MCRPC?
30% have mutations in BRCA1, or ATM
Trial in NEJM 2020 of MCRPC with BRCA or ATM mutation
randomised to olaparib vs physicians choice of enza or Abi.
Improves imaging based PFS in olaparib group
80% of control crossed over which may have diluted survival benefit.
What is the ARASENS trial and its key findings
Trial in HSMPC
Patients randomised to Daralutamide vs Placebo (also with ADT and Docetaxel)
OS benefit at 4yrs (62.7% vs 50.4%)
What is the benefit of bisphosphonates in preventing skeletal related events in MCRPCA?
Are there any better agents available?
Randomised trial evidence supports zolendronic acid 4mg q3weekly for 15 months vs placebo in reducing incidence of skeletal related events and delaying time til their onset.
SRE = path #, surg or RT to bone, MSCC, change in antineoplastic treatment due to bone pain
ZA on above schedule reduced SRE at 2 years to 38% vs 49% with placebo.
also time to first SRE with ZA was 6 months longer than in placebo group.
Describe the principle behind why androgen deprivation is used in prostate cancer?
Prostate cells are physiologically dependent on androgen to stimulate growth, function and proliferation.
Testosterone (not tumorigenic) is essential for the growth and perpetuation of tumour cells.
If prostate cells are deprived on androgenic stimulation, they undergo apoptosis.
Describe how testosterone is regulated/produced
- Regulated by the hypothalamic-pituitary-gondal axis
- Hypothalamic luteinising hormone-releasing hormone (LHRH) stimulates anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH)
- LH stimulates Leydig cells of testis to secrete testosterone
- Within the prostate cell, testosterone is converted to 5-a-dihydrotestosterone (DHT) by enzyme 5-a-
reductase - Circulating testosterone aromatized peripherally and converted to oestrogen – exert negative
feedback control on hypothalamic LH secretion
What are different types of ADT?
- Surgical castration
- LHRH agonist
- LHRH antagonist
- Steroidal anti-androgen
- Non-steroidal anti-androgen
No convincing evidence to choose between LHRH agonist/ LHRH antagonist/ orchidectomy
Describe surgical castration and pros and cons of this ADT option.
Bilateral Orchidectomy
- Leads to decline in testosterone level and induces a hypogonadal state
- Definition: testosterone <20ng/dL (0.1nmol/L)
- Quickest way to achieve a castration level (usually <12 hours)
- Cons: negative psychological effect; irreversible; does not allow intermittent treatment
What is a GnRH agonist in ADT?
- Synthetic analogues of LHRH
- Currently the ‘standard of care’ in hormonal therapy
- Delivered as depot injection on a 1-, 2-, 3-, 6-monthly or yearly basis
What are some examples of GnRH agonists?
o Goserelin acetate (Zoladex® (AstraZeneca) S/C) – 3.6mg monthly, 10.8mg 3-monthly
o Leuprorelin acetate (Lucrin® (Abbvie) IM; Eligard®(Mundipharma) S/C) – 7.5mg monthly, 22.5mg
3-monthly, 30mg 4-monthly, 45mg 6-monthly
o Triptorelin (Dipherelin® (Ipsen) IM) – IM; 3.75mg monthly, 11.25mg 3-monthly, 22.5mg 6 monthly
What is the mechanism of action of GnRH agonists in how it reduced testosterone levels?
o Chronic exposure to LHRH agonist → down-regulation of LHRH receptors (through negative feedback)
→ suppressing LH and FSH secretion and testosterone production
o Testosterone level decrease to castration level within 2-4 weeks
What % of patients do not reach castration levels of testosterone with GnRH agonist?
approx 10%
What occurs after the first injection of a GnRH agonist and how is this managed?
o Stimulate pituitary LHRH receptors
o Induce a transient rise in LH and FSH release → lead to a ‘testosterone-surge’ or ‘flare-up’ phenomenon
can cause escalation of pain in metastatic patients
o (begins 2-3 days later, lasts approx. 1 week)
o Anti-androgens (e.g. Bicalutamide) should be started on the same day as LHRH agonists and
continued for a 2-week period to suppress flare-up phenomenon
How does a GnRH antagonist work?
Mechanism: Binds immediately and competitively to LHRH receptors in the pituitary glands
o Leads to rapid decrease in LH, FSH, and testosterone without any flare
What serious side effect can GnRH antagonists cause?
Potential serious and life-threatening histamine-mediated side effect
What are examples of GnRH antagonists?
o Abarelix (Plenaxis®)
o Degarelix acetate (Firmagon® (Ferring) S/C)
▪ Monthly s/c (240mg first month, followed by 80mg monthly)
▪ 95% patients achieve castrate level at day 3, and quick decline in PSA (as early as day 14)
▪ S/E: painful injection
Common Side effect of GnRH agonist
Most common
Top 3 -
- Hot flashes
- Impotence,
- decreased libido
Fatigue,
Weight gain
Osteoporosis (NZ data, suggest more than double risk of fracture - risk higher for orchidectomy or complete blockade)
Uncommon side effects of GnRH agonists
Uncommon/lower risk:
Cognitive changes/decreased motivation
Depression,
Sarcopenia,
Cardiovascular disease (risk has been questioned by meta-analysis).
Tumors of the liver, liver cancer, or peliosis hepatis (a form of liver disease) have occurred during long-term, high-dose therapy with androgens
MOA Abiraterone
CYP17A1 inhibitor - decreased formation of DHEA and androstenedione, precursors of testosterone.
Role of a bone density scan for patients on ADT
Some other advice?
Evidence supports a significant reduction in fracture risk.
Has been recommend at the start of ADT, and every 2 years if on long-term ADT.
Also consider vit D supplementation and calcium
- Pts should also be encouraged to get these through diet and sunlight exposure
- Smoking cessation very important.
- Exercise is protective for loss of bone density and counteracts other side effects of ADT.
What are the classes of anti androgen ADT?
Steroidal and non steroidal
Give examples and MOA of steroidal anti androgen
Steroidal antiandrogens (Megestrol acetate, cyproterone acetate):
Inhibition of testosterone and DHT from binding androgen receptors in prostatic nuclei.
Abiraterone also in this class but different MOA
Give examples of non steroidal anti androgen and MOA
Non-steroidal (e.g. Bicalutimide = Cosudex):
Competitive inhibitors of androgen binding to androgen receptors.
Next-generation antiandrogens prevent nuclear translocation of androgen receptors and binding of androgen receptors to DNA response elements.
What side effects do non steroidal anti androgens have?
Liver toxicity so need to monitor LFTs.
Does not suppress testosterone so doesn’t cause side effects related to this (competes with it at receptor level)
Bicalutamide: gynaecomastia and breast pain
What are the doses for bicalutamide in complete androgen blockade vs mono therapy?
CAB: 50mg OD
Monotherapy: 150mg OD
Do steroidal anti androgens suppress testosterone levels? how?
Yes
Pro-gestational properties leading to central inhibition – lower testosterone level
Therefore S/E: loss of libido, erectile dysfunction, gynaecomastia (rare)
Why does abiraterone need to be given with a glucocorticoid?
Because of CYP17A1 inhibition which can cause adverse events related to mineralocorticoid excess e.g
hypokalemia, hypertension, and fluid retention
Glucocorticoid administration prevents this by preventing the rise in ACTCH
Management of ADT side effects:
Hotflushes
- Venlafaxein
- Gabapentin
- Medroxyprogesterone
Management of ADT side effects: Fatigue
- Exercise (aerobic and resistant)
Management of ADT side effects: Gynaecomastia and breast pain
Prophylactic radiation
Prophylactic tamoxifen
Management of ADT side effects: Sexual dysfunction
PDE5 inhibitor (Sildenafil)
Penile injection therapy
Vacuum erection device
Penile implant/prosthesis
Penile rehab
Lifestyle:
Quit smoking
Healthy diest
regular exercise
reduce alcohol intake
weightless
Management of ADT side effects: decreased bone health
Calcium 1000 daily Vitamin D
Hip fracture risk > 3%
* Denosumab (increased BMD and decreased fracture)
* Zoledronic acid
* Alendronate
Management of ADT side effects: cholesterol, diabetes, cardiovascular events
- Optimise cardiovascular risk factors
- exercise (aerobic and resistant)
- regular BSL and cholesterol monitoring
What components
contribute to sexual dysfunction after prostate cancer treatment?
- Erectile dysfunction (neurovascular damage)
- Reduced ejaculate volume, dry ejaculation (from reduced seminal fluid)
- Retrograde ejaculation (from sphincteric dysfunction
What factors are associated with Erectile dysfunction?
Non-treatment related:
* Medical condition – diabetes, cardiovascular disease, hypertension
* Lifestyle – smoking, excessive alcohol, obesity
* Psychosocial – stress, anxiety, depression
Treatment related:
* Radical prostatectomy
o Damage to neurovascular bundle
* Radiotherapy – neuronal damage, reduced blood flow into penis with fibrotic changes
* Androgen deprivation therapy
o Reduce libido
What is the pathogenesis of Erectile dysfunction?
Neuronal damage:
* Radiation to the cavernous nerve → inflammation and reduction in neuronal nitric oxide
synthase (nNOS) which is signalling molecule in vasodilation
* Late RT mediated effects on cavernous nerve can lead to ED after 3-5 years
Vascular damage:
- RT-induced fibrotic changes in blood vessels resulting in reduced blood flow into penis
Muscular damage:
* RT-induced smooth muscle fibrosis of penile bulb
* Corpus cavernosa undergoes atrophy from lack of erection similar to other muscles when
unused
Name studies which provide evidence for Active surveillance
PIVOT 2012
PROTECT 2016
What did the PIVOT study show? (Active Surveillance Trial)
RP did not significantly reduce all-cause/ PC-specific mortality
- Study period: 1994-2002
- 731 men with localised prostate cancer (T1-T2N0, PSA<50, any Gleason), <75 y/o, life expectancy? 10 years
- 2 arms: surgery vs. observation
- Primary outcome: all-cause mortality (ACM); secondary outcomes: prostate cancer specific mortality (PCSM)
- Median follow-up 19.5 years
What did the PROTECT trial show?
PCSM low at ~1% regardless of treatment arm;
disease progression/ mets lower in RP/RT vs. observe
- Study period: 1999-2009
- Population: 1,643 men with diagnosis of localized prostate cancer
- 3 arms: Active monitoring (AM) (n=545) vs RP (n=553) vs RT (n=545)
o Compliance within 9 months: AM 88%, RP 71%, RT 74%
o 291 (55%) of AM eventually had radical treatment (142 RP, 124 EBRT, 22 BT, 3 HIFU)
- Primary outcomes: prostate cancer specific mortality (PCSM)
- Secondary outcomes: disease progression, metastases, all-cause mortality (ACM)
- Median follow-up: 10 years
Who may be offered active surveillance as a management strategy?
Very low risk
Low risk
Favourable intermediate
Must be compliant with follow up
What trials support dose escalation in prostate RT?
PROG/ACR-9509 (Zietman 2010 JCO)
CKVO96-10
MRC-RT01 (Dearnaley 2014 Lancet Oncol)
RTOG-0126 (Michalski 2018 JAMA Oncol)
What does dose escalation mean in terms of RT prostate?
> 74Gy in conventional fractionation
What were the overall findings of the dose escalation studies in prostate cancer?
That increasing dose from approx 70Gy to 80Gy improves biochemical control but not OS.
In some trials there was worsened late GI and GU toxicity in the dose escalated arm.
What trials support the use of moderately hypo fractionated RT in definitive RT for prostate cancer?
PROFIT (Catton 2017 JCO)
CHHIP (UK) (Dearnaley 2016 Lancet Oncol)
RTOG 0415 (Lee 2016 JCO)
What did the PROFIT trial show?
PROFIT (Catton 2017 JCO) – for intermediate risk PCa, 60Gy/20# not inferior to conventional RT 78Gy/39#, no increased tox
5yr BCF 85% in both
- Ph3 RCT, Canada/ Australia; non-inferiority trial, 2006-2011
- Population: all Intermediate risk PCa
- 2 arms: 78Gy/39# (n=598) vs. 60Gy/20# (n=608); ADT not allowed
- Primary outcomes: BCF
- Median follow-up: 6 years
What did the CHHIP trial show?
CHHIP (UK) (Dearnaley 2016 Lancet Oncol) – 60Gy/20# not inferior to 74Gy/37# (57Gy/19# not proven to be non-inferior to 74Gy/37#)
- Ph3 RCT, 2002-2011
- Population: 3216 men localised PCa (15% low risk, 70% intermediate risk, 15% high risk)
- 3 arms: 74Gy/37# (n=1065) standard arm vs 60Gy/20# (n=1074) vs. 57Gy/19# (n=1077); most had 3-6 months ADT
- Primary endpoint: biochemical failure
- Median follow-up: 62.4 months
What trials support ADT in HR prostate cancer patients?
Bolla et al. EORTC22991
EORTC22863
- RT vs RT + 36months ADT
- 10yrs OS and PCSM much better in combined group
- OS approx 20% better in combined arm
RTOG8531
- RT +indefinite ADT vs RT alone
- 10yr OS improved by 10% in ADT arm (49% vs 39%)
RTOG 8610
- EBRT vs EBRT + 4mo ADT
- improved DFS and PCSM in combined group
- OS improved in GS2-6 but not GS>7 suggesting 4mo insufficient in HR patients)
TROG9601
- EBRT vs EBRT + 3mo ADT vs EBRT +6mo ADT
- 6mo ADT improved EFS, PSA progression, distant progression, PCSM, ACM
Should ADT be given in HR prostate cancer
Definitely
What is the optimum duration of ADT in HR patients?
Supported by what?
18months
RADAR- 18mo better than 6mo in terms of PCSM
Nabid, PCS IV
- 36mo not superior to 18mo in terms of OS, similar DFS
- QOL better in 18mo (sexual function and hot flushes)
What did the RTOG 0415 trial show?
hypofractionated RT is not inferior to conventional RT for DFS, but increased late GI/ GU tox
- Ph3 RCT non-inferiority study, 2006-2009
- Population: 1092 men low risk prostate cancer
- 2 arms: 73.8Gy/41#, 1.8Gy/# (CRT) (n=542) vs. 70Gy/28#, 2.5Gy/# (HRT) (n=550)
- Primary endpoint: 5-yr disease free survival
- Median follow-up 5.8 years
Late GI and GU tax increased by about 1% in the 70Gy/28# arm
What did the PACE-B trial show?
SBRT does not increase acute GU/GI toxicity compared to conventional/ hypofractionated RT
* Ph3 non-inferiority study, UK/ Ireland/ Canada, 2012-2018
* Population: 874 men low-intermediate risk PCa
* 2 arms: ADT not allowed
o Arm 1: 78Gy/39#, 2Gy/#, 5#/ week, or 62Gy/20#, 3.1Gy/#, 5#/ week (n=441)
o Arm 2: SBRT 36.25Gy/5#, 7.25Gy/#, 3#/ week (n=433) * Co-primary outcomes:
o Freedom from biochemical failure (results pending)
o Acute RTOG G2+ GU/GI toxicities up to 12 weeks post RT
difference in toxicity not stat sig between arms (but lower in sabr arm)
Who is appropriate for watchful waiting approach?
- Life expectancy <10years
- treat on symptomatic progression
- aim is to avoid toxicity, not cure cancer
What was the result of the POP-RT/Tata memorial trial?
pelvic RT improve BFS, DFS, but not OS compared to prostate alone RT
- Study period: 2011-2017
- Study population: high risk prostate cancer (80% PSMA PET staged; risk of LN involved >20% by Roach
formula) - 2 arms: prostate alone RT (68Gy/ 25#) (N=114) vs. whole pelvic RT (68Gy/25# to prostate and 50Gy/25# to
pelvic nodes including common iliac) (N=110) - Primary endpoint: 5-year BFS
- Secondary endpoint: Disease free survival (DFS) and OS
- Median-follow-up: 68 months
What is significant about the RTOG1260 trial for dose escalation?
Only RCT where some patients were treated with IMRT
biochem control 70% vs 55%
Describe why free/total PSA level is raised in malignancy
- pro-PSA is secreted by epithelial cels and converted to free PSA before entry to blood stream
- cancer basement membrane is more leaky and so more bound PSA is leaked into blood stream
- hence, bound PSA is a higher proportion of total
For men with equivalent PSA (4-10)
>25% PSA free is unlikely malignant
<10% free more likely malignant
What is an explanation for a PSA density <0.15ng/mL?
BPH
very LR prostate ca
What is considered a relatively rapid/very rapid PSA doubling time?
<12months relatively rapid
<6 months very rapid
What is the Gleason grade
Histological pattern on H + E staining
Grades based on major and minor criteria
What would be an appopriate surveillance paradigm for active surveillance?
DRE q6/12
PSA q3/12
Biopsy and MRI q6-12-12
re assess in 2-3 years or if PSA DT <2-3years or DRE progression
What are the approaches used in radical prostatectomy?
retropubic vs laparoscopic/robotic
Do you know any evidence supporting robotic RP?
Phase III RCT published in lancet 2016.
Performed out of Royal Brisbane and Women’s Hospital (Brisbane, QLD
Randomised to (1:1) to receive either robot-assisted laparoscopic prostatectomy or radical retropubic prostatectomy.
These two techniques yield similar functional outcomes at 12 weeks (urinary, sexual function).
Positive margin status not stat sig different
Longer FU is awaited
What are the proposed benefits of robotic RP?
Less blood loss
Shorter hospital stay
Less post op pain
What are peri op complications of RP?
Mortality <1%
Rectal injury <1%
Wound infection
VTE 1-3%
MI 1-8%
Pelvic pain
>1L blood loss
What is done in the lymph node dissection portion of RP?
Sampling of obturator and external iliac nodes
Ideally >10 nodes taken
What are the risks of impotence aw RP?
50% with bilateral nerve sparing
75% with unilateral nerve sparing
What are the risks of incontinence with RP?
30% total control
40% have occasional leakage
7% frequent leakage
3% no control
What did the DART trial show?
Showed that long term ADT (28months) is better than short term ADT (4mo) in terms of OS, MFS and bDFS in HR patients even when dose escalated RT is used.
OS benefit was in HR not IR patients
so dose escalation doesn’t compensate for shorter ADT course
What trials support intermediate/long term ADT is better than short term in HR patients?
EORTC 22961
RTOG9202
DART
RADAR (TROG 03.04)
Statement on dose escalation in definitive RT for prostate ca
Conventional fractionation with dose escalation (>74Gy) is recommended for all risk groups as it reduces biochemical recurrence.
It has not been shown to improve OS.
Subnotes:
- OS benefit was seen in HR patients in one meta analysis (Kalbasi)
Statement on hypo fractionated RT in definitive RT for prostate cancer
Hypofractionated RT has been shown to be non inferior to conventional fractionated dose escalated RT in 3 large RCTs.
Subnotes:
- most of the data is for IR patients
- 1 trial showed worse late GI and GU toxicity but this hypofractionated dose was higher BED/EQD2 than the other trials (this was the HYPRO 2016 trial)
Should ADT be given to LR prostate patients
Nope.
ADT is not recommended for LR prostate cancer patients because of its lack of benefit and potential for harm from SE
Is there benefit to dose escalation for low and intermediate risk prostate cancer?
Yes
Zaorsky et al meta-analysis supports this.
for IR 7.2% improvement in 10yr freedom from biochemical failure
no OS or PCSM advantage
SSPORT trial
What trials support ADT in intermediate risk prostate cancer?
RTOG 9408
- 4mo ADT
- improves 10yr OS in ADT group, improved disease specific mortality, improved incidence of DM
D’Amico randomised controlled trial 2008
- 6mo ADT
- Improved 8yr OS with ADT by 13%
EORTC 22991(75% IR patients)
- 6mo ADT
- Improved biochemical and clinical PFS with ADT
- OS data not mature
Network meta-analysis of 6 RCTs
Jackson et al. published 2020
- OS benefit to addition of ADT to RT for IR patients (HR 0.73)
Statement on ADT in IR prostate cancer patients
Multiple randomised trials show improvement in OS and cancer specific mortality with short term ADT (4-6mo) in IR patients.
Is there evidence for adding ADT after RP?
No
a meta-analysis concluded that there was limited survival benefit for adjuvant ADT after RP even in the highest risk patients
What trial showed that longer ADT was not better for IR patients?
RTOG 9910
4mo ADT vs 9mo ADT in IR patients
no difference in 10yr OS, DSS, DM or Local failure between arms
Recommendation for IR is short term ADT 4-6mo
