Prostate Flashcards
(140 cards)
1
Q
AJCC T1 scores for prostate cancer:
A
There is no cT1
pT1 is either incidental:
<5% sampled tissue = pT1a
or >5% sampled tissue = pT1b
Or Focal Bx found on investigation of e.g. PSA = pT1b
2
Q
AJCC T2 scores for prostate cancer:
A
T2 = Organ confined
a. Palpable ≤½ of
one lobe or less
b. Palpable >½ of
one lobe, but
not both lobes
c. Palpable both
lobes
3
Q
What is T3 prostate cancer?
How bout T4?
A
T3 = Early extension beyond the date:
a) EPE
b) SV invasion
T4 = invasion - into bladder, external sphincter, rectum, levator muscles, pelvic wall.
4
Q
Low risk prostate cancer is defined as:
A
Both D’amico and NCCN defines as:
T1–T2a, and
GS ≤ 6/grade (ISUP1), and
PSA < 10 ng/mL
5
Q
Very low risk prostate cancer is defined as:
A
Note the very low risk group comes from NCCN. The D’amico staging just defines low risk which is the same as the NCCN. Similary D’amico does not divide int risk into fav/unfav…
T1
GS ≤ 6
PSA < 10 ng/mL
<3 positive biopsy cores
<50% cancer in any core
PSA density <0.15 ng/mL/g
6
Q
Define a general criteria for int risk prostate cancer as a whole:
A
T2
GS 7, or
PSA 10–20 ng/mL
7
Q
Intermediate favourable prostate cancer:
A
T2b–T2c, or
GS 3 + 4 = 7/grade group 2, or
PSA 10–20 ng/mL, and
Percent of positive biopsy cores <
50%
8
Q
Intermediate unfavourable prostate cancer:
A
2 or 3 intermediate risk factors:
GS 3 + 4
PSA 10–20 ng/mL
T2b–T2c
AND/OR
Grade group 3, and/or
>50% cores positive
9
Q
The difference between fav and unfav intermediate PrCa:
A
the addition of:
Grade group 3, and/or
>50% cores positive
10
Q
Low-risk prostate cancer includes organ-confined disease typically detected by:
Standard treatment options include:
A
Low-risk prostate cancer includes organ-confined disease typically detected by:
screening PSA or on DRE (T1-T2a), with a PSA < 10 ng/mL and GS ≤ 6.
Standard treatment options include:
Active surveillance, prostatectomy, EBRT, or brachytherapy.
11
Q
For each standard treatment for low-risk prostate cancer, what is the cancer–specific survival?
Treatment selection is guided by:
Most guidelines recommend treatment only if:
A
Prostate cancer–specific survival is >95% for each.
Therefore, treatment selection is guided by: Side effect profiles and patient preference.
Most guidelines recommend treatment only if life expectancy is >10 years.
12
Q
Is there a role for dose escalation in low-risk PrCa?
A
Dose escalation improves local control compared to conventional doses.
13
Q
What is the watchful waiting approach? For which patient group is this most suited?
A
Watchful waiting:
No further testing = Tx only when
symptoms develop
Target audience:
Patients w/severe comorbidity
and/or limited life span
14
Q
What is (and can be) involved in active surveillance?
A
Regimented follow up with routine PSA tests
and repeat biopsies;
Consider:
genomic testing
MRI guided biopsy
15
Q
A healthy 60yro patient with low risk prostate cancer elects for definitive radiation. Name all the options (there are 5) and give an example dose for each:
A
Targeting the prostate:
1) IMRT/VMAT standard #s = 74Gy/35
2) Hypofractionation: 60Gy/20
3) SBRT (extreme hypofractionation): 35-40Gy/5
4) Brachy LDR (I-125/P-103): 125Gy to 145Gy
5) Brachy HDR (Ir-192): 27Gy/2. RCT evidence suggests 2#s better than 1
16
Q
A healthy 60yro patient with low risk prostate cancer elects for definitive radiation. Name some possible patient concerns that may make this a good choice compared to prostatectomy:
A
In terms of functional outcomes there is no clear benefit of surgery vs radiation. Motivated toward nonoperative intervention - e.g. adverse to operative procedure/anaesthetic risk
Or specific concerns:
Erectile dysfunction 30-90% surgery
Versus 70% radiation (brachytherapy has lower rates)
Incontinence from prostatectomy. Around 5-10% risk.
17
Q
Australian prostate Ca epidemiology:
1) median age at Dx
2) Most common stage at Dx:
3) Chance of being Dx w/prostate cancer before age 86?
A
1) median age 69 (Australia)
2) 46% are Stage II, 36% s are Stage I , 11% are detected at Stage III
3) 1 in 6 chance of Dx before 86
18
Q
The two most significant risk factors for prostate cancer?
A
Most significant:
1) Age (significant increase in risk > 50)
2) Family Hx
19
Q
Risk factors for prostate cancer?
A
1) Age (signif increased risk>50)
2) fam Hx
3) Race (highest rates in Scandinavia)
4) Mutations in genes responsible for DNA repair (e.g., germline BRCA2 mutation) associated with higher GS and worse prognosis.
5) Syndromes associated with
increased risk:
Lynch syndrome,
BRCA2,
Fanconi’s anemia
HOXB13.
20
Q
Syndromes associated with
increased PrCa risk:
A
Syndromes associated with
increased risk:
Lynch syndrome,
BRCA2,
Fanconi’s anemia
HOXB13.
21
Q
Describe the fibromuscular and glandular anatomy of the prostate:
A
Composed of 2/3 glandular elements (divided into 3 zones) and 1/3 fibromuscular.
Glandular divided into 3 zones: peripheral zone (70% of
volume) with the majority of prostate cancer arising from it.
Central zone (25% of
volume) only 5% of cancers.
Transition zone (5% of volumes) rarely site of Ca BUT the site of benign prostatic hyperplasia.
22
Q
Relate the glandular zones to the occurences of cancer and other common pathologies.
A
Glandular divided into 3 zones: peripheral zone (70% of
volume) with the majority of prostate cancer arising from it.
Central zone (25% of
volume) only 5% of cancers.
Transition zone (5% of volumes) rarely site of Ca BUT the site of benign prostatic hyperplasia.
23
Q
Describe the anterior zone of the prostate:
Where are the neurovascular bundles located?
A
1) The fibromuscular stroma (or anterior zone) extends superiorly from the smooth muscle of the bladder neck and inferiorly to the urethra, prostate apex, and external sphincter.
2) Neurovascular bundles located posteriolaterally (thats why they often get invaded from the perif zone).
24
Q
Anatomical relation of the seminal vesicles to the prostate:
A
Position of the pr and SVs varies w/ filling of the rectum and bladder.
SVs are coaxial with the prostate, positioned superiorly and adjacent to the posterolateral aspect of the It.
SV joins the vas deferens to the ejaculatory duct and open into prostatic urethra at the verumontanum.
25
Lymphatic drainage of the
prostate and SVs:
Drainage of prostate:
internal iliac, external iliac, obturator, and presacral lymph nodes, with occasional
drainage directly to the common iliac nodes.
SV lymphatics:
typically to external iliac nodes.
26
What percent of prostate cancers are adenocarcinomas?
Name some of the other histologies and very broadly make a statement about their prognosis:
1) 95%
2) Other histologies (worse prognosis):
- Small cell (neuroendocrine) carcinoma,
- Ductal adenocarcinoma,
- Transitional cell carcinoma,
- Sarcomatoid carcinoma,
- Sarcoma
27
The Gleeson Score is based on:
The most prevalent and highest grade are summed together for the GS since:
The GS is based on the
architectural structure of the malignant cells. Specifically the range from normal small uniform glands (Gleeson 1) to only occasional glands observed.
The most prevalent and highest grade are summed together for the GS since any amount of high-grade
tumor may indicate a more significant amount within the prostate.
28
When may a tertiary grade be given for a prostate cancer - E.g beyond Gleeson = x + y?
Tertiary grades are given
only in RP specimens if there is a component (< 5%) of higher grade tumor than the two predominant
patterns.
29
How common is:
1) ECE
2) SV invasion in setting of risk group
ECE is seen in ~45% of clinically localized disease and is
within 2.5 mm in 96% of cases.
SV involvement increases with risk group:
Low risk ~1%,
Intermediate risk ~15%,
High risk ~30%, with a median 1 cm length of involvement and ~1% risk of SV involvement beyond 2 cm
30
Probability of SV invasion in setting of risk group (just like the last card):
SV involvement increases with risk group:
Low risk ~1%,
Intermediate risk ~15%,
High risk ~30%, with a median 1 cm length of involvement and ~1% risk of SV involvement beyond 2 cm
31
Outline PSA screening approach in Australia and NZ:
Lower grd (C) evidence suggests mortality benefit from early Dx of PrCa due to PSA testing is not seen within less than 6–7 yrs from testing. Therefore PSA testing not recommended for men who are unlikely to live> 7 yrs.
In NZ: men aged 50 and over should discuss testing w/GP or doctor. For Pts w/a FamHx of prCa this discussion should begin at 40.
Australia: Men >50 should be made aware of PSA testing and informed about the pros and cons.
The Australian cancer council advice is supported by RANZCR
32
50yro man elects to have a screening PSA test. At what PSA value should further investigation be discussed?
>=3ng/ml
33
For men without a dx or sx of pr.cancer who wish to undergo regular PSA testing, the following strategy is recommended:
Why is it recommended?
For men without a dx or sx of pr.cancer who wish to undergo regular PSA testing, the following strategy is recommended because it is associated with reduced risk of death from prostate cancer:
PSA testing every 2–4 years from age 50 to age 69, and offer further investigation if the PSA is greater than 3.0 ng/mL
34
Key questions in the Hx of a patient w/low risk Prostate:
1) Life limiting co-morbidities
2) Baseline:
- Urinary function - With IPSS
- Sexual function - E.g IEFS or SHIM score
- Bowel function
3) Fam Hx - may denote higher risk
35
Any benefit to MRI guided prostate Bx?
May decrease the number of cores compared to random. Otherwise same outcomes.
Can see how would be good in setting of active surveillance.
36
Role of imaging in Low-Risk Pr Ca?
No role for routine staging scans in low-risk prostate cancer. Multi-parametric MRI may be
used in patients considering active surveillance as it may detect lesions concerning for GS >7 cancer or ECE.
37
Natural Hx of low-risk prostate cancer:
The risk of death from early-stage, low-risk disease is ~1% at 10 years (active monitoring arm of the ProtecT trial).
Many tumors follow an indolent course for the first 10 to 15
yrs post Dx, but beyond 15 yrs, the PrCa specific mortality rate triples (15/1000 person-years to 44/1000).
BUT recent 15yr ProtecT seems inconsistent with this (active monitoring seems the same).
38
Outcomes for biochemically recurrent PrCa post RRP:
Per the Pound study of pts w/ biochemical failure post RRP:
Mets at a median of 8 yrs after biochemical failure.
Death occurred at a median of 5
years from the development of mets.
39
Is there a role for systemic therapies in patients under active surveillance for low-risk Pr Ca?
use of 5-α-reductase inhibitors to prevent cancer progression in the setting of AS is debatable.
The REDEEM trial shows lower 3-year rates of prCa progression with dutasteride vs placebo (38 vs 48%).
40
Which approach to prostatectomy has the worst outcomes? Which appear equivalent?
A perineal approach omits lymphadenectomy and SV removal, and has with higher rates of biochemical failure/+margins, and
rectal injury. open is 2nd worst. Lapro and robotic are about the same in RCTs.
The +margin rates for open, laparo, and robotic are around
23%, 15%, and 14%, respectively.
41
The most common post prostatectomy adverse side effects?
Impotence and incontinence are the most common (impotence 50-75%, total incontinence 1-2%, ~50% some degree of poor control):
Bilateral nerve-sparing procedure is associated with an estimated ~50%
rate of impotence.
Unilateral nerve-sparing procedure is associated with impotence rate of ~75%.
Around 30% of patients reported have total urinary control,
40% occasional leakage,
7% frequent leakage,
1%–2% no urinary control
42
A standard lymph node dissection involves?
Can outcome be improved with a more aggressive approach?
A standard lymph node dissection involves “sampling” of the obturator and external iliac lymph nodes.
It is uncertain whether an extended lymph node dissection improves outcomes.
43
For low-risk PrCa, give some:
1) Conventional doses:
2) Moderately hypofractionated doses:
2) SBRT/extreme hypofractionated:
1) 78 Gy/39 or 79.2 Gy/44
2) 70 Gy/28 fx or 60 Gy/20 fx
3) 30gy/5 to 40/5
44
Compared to other options, how good is Brachy (LDR or HDR) for low risk prCa?
Brachy is common for low-risk, with comparable outcomes to surg and EBRT, but no RCT has compared these head to head.
45
Dose for LDR brachytherapy is?
Dose for LDR:
144 to 145 Gy for I-125 (D90>145Gy)
125 Gy for Pd-103.
46
In low and favourable intermediate risk PrCa what is the role for combining EBRT with brachy boost or with ADT?
Monotherapy alone is sufficient.
For low-risk and favorable intermediate-risk there is no role for combining EBRT with brachy boost or ADT.
E.g. The ProtecT study suggests outcomes are so good in surveillance arm, would be difficult for any significant difference to be detected in mono vs combined arms.
47
The optimal dose, fractionation and scheduling for HDR brachytherapy?
The optimal dose, fractionation and brachytherapy scheduling has yet to be defined.
RCT data suggests at 5yrs 2 (13.5Gy/#) fractions is superior to 1 (19Gy) in terms of disease-free survival and cumulative incidence of local failure.
48
A suitable HDR dose for low risk PrCa?
Dose should cover?
24Gy, 12Gy/#, fractions at least 6 hours apart.
100% cover target volume, aiming for a minimum of 95% coverage as per ICRU 58
49
The definition of biochemical failure after curative intent radiation is:
As per who?
RTOG-ASTRO Phoenix
Consensus defines biochemical failure as:
A rise of 2 ng/mL above the post-treatment nadir PSA
50
What is a PSA bounce?
A PSA “bounce” may occur in some patients, especially post brachy.
It is not associated with worse outcomes.
51
Acute side effects of brachy:
Perineal bruising and swelling
Fatigue
Irritative or obstructive urinary Sx: Bladder spasms, dysuria, nocturia, frequency, incontinence, urgency.
Urinary retention +/- clots
Proctitis: diarrhoea, increased bowel frequency, rectal urgency, pain and bleeding.
52
late side effects of brachy:
Sexual dysfunction -eg. erectile dysfunction, impotence, dry and/or painful ejaculation, haematospermia and reduction in ejaculate.
Obstructive urinary SX and retention
Perineal discomfort
Rectal ulceration
Urethral stricture
Proctitis
Prostatorectal fistulas very rare, but increased risk in the setting of subsequent rectal biopsies which are contraindicated.
Urinary incontinence
Second malignancy
53
Common SBRT/hypofractionated prostate regime? How does it compare to IMRT?
For SBRT, 36.25 to 40 Gy in 5 fx delivered every second day is common.
Yet to be tested against IMRT in an RCT.
54
How many major PSA screening trials are there?
General themes?
In the PSA era there has been stage migration toward early localized disease and a decrease in metastatic rates.
3 major screening trials.
Methodology suggests that the magnitude of screening may be likely larger than represented.
The ERSPC and Swedish Trial shows a PCSM benefit for PSA screening, while PLCO did not.
It is difficult to keep people in the “observation” arm from being screened, which is one of the criticisms of the PLCO trial.
55
Is extreme hypofractionation via SBRT safe and effective?
Biochemical control and toxicity outcomes are comparable to historical outcomes of dose-escalated 3D/IMRT but longer follow-up is needed.
Patients should be aware of the shorter follow-up and lack of randomized data with SBRT.
Early experience from Stanford found that 2nd daily tx resulted in less toxicity than OD SBRT (nonrandomized) - why most have adopted QOD
56
The potential benefits of moderate hypofraction in low-risk PrCa:
1) Improved convenience
2) lower cost
3) Potentially improved outcomes (low α/β).
Longer follow-up will be helpful to establish noninferiority for clinical effectiveness and toxicity profiles.
57
For low-risk prostate cancer is there a benefit to dose escalation?
Escalated from what?
At least 5 phase III trials support a biochemical control benefit when boosting from around ~ 70Gy/35# to around 78 - 80Gy in 2Gy #s.
There are higher rates of rectal bleeding though.
Current "standard" is 78 - 80Gy w/ 2Gy/#s
58
Does SBRT fractionation schedule effect toxicity?
Prospective date (PATRIOT trial):
Less acute GI, equivalent long-term.
Once weekly: decreased patient-reported acute bowel QOL vs Every 2nd day.
Long-term follow-up = similarly low rates of late GI and GU toxicity with either fractionation.
59
What is the benefit of daily image guidance in prostate cancer EBRT?
Improves biochemical control and reduces toxicity compared to weekly IGRT, with potential increase in second malignancies, though too few events to conclude.
60
Define very High-risk prostate cancer
Very high risk:
T3b–4 or
Primary GS 5 or
>4 cores with GS 8–1
61
Treatment options for high risk prostate cancer:
High risk, and very high risk (T3b–4 or Primary GS 5 or >4 cores with GS 8–1):
* EBRT + long-term ADT (18–36 months)
* EBRT + brachytherapy boost + ADT (12–36
months)
* RP: Consider early salvage RT for adverse features (+margins, SV invasion, EPE) and detectable postop PSA. If node +ve consider ADT + pelvic EBRT
* ADT alone maybe suitable for select patients not candidates for local therapy (e.g.limited life expectancy)
62
Treatment approach to node +ve PrCa
Key recent result
1) RT + long-term ADT (24–36 months)
2) ADT ± antiandrogen (if limited life expectancy)
Stampede era - ADT in all &:
Non-regional nodes - still treat prostate for OS benefit (3yrs 80 vs 73%) (not whole pelvis..)
Regional node +ve: Treat prostate and whole pelvis for failure free survival benefit (2yrs 85 vs 55%)
63
Give a more detailed description of Fam Hx as a risk factor for PrCa:
A father who survived <24 months
from prostate cancer, has been associated with higher risk disease.
64
Which germline mutations seem to have a role in prostate cancer:
What %?
How do they relate to outcomes?
Germline mutations in DNA repair genes occur in ~5% of localized cases, and in particular, germline BRCA2 mutations are associated with a higher GS and a worse prognosis
65
Pelvic nodal involvement has been estimated by both what tables and formula?
Limitations
Pelvic nodal involvement has been estimated by:
Partin tables and
Roach formula (2/3*PSA+[Gleason-6]*10,
Over-estimate risk in the modern era
66
When is imaging indicated in the workup of a patient with prostate cancer? What imaging?
Bone scan for patients at high risk for metastases.
NCCN: Int Unfav, or HR or VHR.
CT or MRI pelvis is indicated for patients with IR or HR and nomogram-indicated probability of lymph node involvement > 10%.
PSMA PET-CT has higher sens and spec for mets, but is not approved for initial wokup yet.
67
Natural history of Gleeson 8 or higher disease:
Connecticut Tumor Registry:
Probability of dying from UNTREATED GS 8 to 10 prCa within 15 years = 60% to 87%.
Pts w/TREATED HR prCa live >10 years, and w/risk of death from other stuff.
68
Beyond the traditional factors, what other methods exist to improve prognostic insight for newly Dx prostate cancer?
Guidelines suggest considering use when?
Molecular biomarkers:
Decipher, Oncotype, or
Prolaris provide prognostic benefit
NCCN: molecular assays be considered for men with Int unfav or High-risk and HR disease and life expectancy >10 yrs.
69
What is Goserelin?
Is there an oral equivalent?
Goserelin is a parenterally administered, gonadotropin releasing hormone (GnRH) agonist which causes an inhibition of estrogen and androgen production.
As yet unavailable in the civilised world (Aus/NZ). Relugolix is an oral GnRH agonist that appears as effective as parential GnRH for long-term castration, with fewer cardiovascular events and the advantage of rapid reversibility.
70
MOA for GnRH agonists (In case name doesnt tell you the answer):
Induce stimulation of LH and an initial testosterone surge, followed by gradual decline to castrate levels over 3–4 weeks.
A testosterone surge can exacerbate pain in patients with metastatic disease.
71
Give detail on the common side effects of GnRH agonists:
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)
72
Less common 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
73
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.
74
When nodal RT is performed, the updated NRG Oncology guidelines recommend including the:
Common iliac (up to L4-L5),
external iliac,
internal iliac,
presacral (S1-S3), and
obturator lymph nodes.
75
MOA for GnRH agonists (In case name doesnt tell you the answer):
Induce stimulation of LH and an initial testosterone surge, followed by gradual decline to castrate levels over 3–4 weeks.
A testosterone surge can exacerbate pain in patients with metastatic disease.
76
What are the classes of antiandrogen? Give an example drug for each. Give at least one brand name...
MOA?
Steroidal antiandrogens (Megestrol acetate, cyproterone acetate):
Inhibition of testosterone and DHT from binding androgen receptors in prostatic nuclei.
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.
77
Key precursors of testosterone
DHEA and androstenedione.
78
MOA for GnRH agonists (In case name doesnt tell you the answer):
Induce stimulation of LH and an initial testosterone surge, followed by gradual decline to castrate levels over 3–4 weeks.
Agonist binds ant pituitary receptors causing a surge in LH release, which stimulates Leydig cells in the testes to produce more testosterone. Surge in testosterone causes negative feedback on hypothalamus GnRH & ant pituitary LH.
A testosterone surge can exacerbate pain
in patients with metastatic disease.
79
MOA Abiraterone:
CYP17A1 inhibitor - decreased formation of DHEA and androstenedione, precursors of testosterone.
80
Indications for Abiraterone (given with what?)
Abiraterone (Zytiga) in combination with prednisone or prednisolone is indicated for the treatment of:
1) high-risk metastatic hormone naïve prostate cancer with ADT
2) newly diagnosed high-risk metastatic hormone sensitive prostate cancer with ADT
3) Metastatic castration-resistant prostate cancer
81
Dose, Side effects and risks of Zytiga:
1 g once daily on an empty stomach + 5mg pred:
Diarrhoea, dyspepsia,
hepatotoxicity (Monitoring requirements),
hypertension,
hypertriglyceridaemia,
heart failure,
angina,
arrhythmia,
atrial fibrillation, tachycardia,
peripheral oedema,
urinary tract infection, sepsis, haematuria, hypokalaemia, fractures, rash;
Less commonly adrenal insufficiency, myopathy, rhabdomyolysis; rarely allergic alveolitis; also reported QT-interval prolongation, torsade de pointes
82
Alternatives to Aniti-androgens/GnRH agonists and/or CYP17A1 inibitors:
1) Orchidectomy
2) 5-α-reductase inhibitors (Suppresses the enzyme that catalyzes the conversion of
testosterone to DHT)
3) Adrenal suppression
83
Common acute effects of prostate EBRT include:
How bout the nodes?
Less common:
Common acute effects of EBRT:
Fatigue, dysuria, urinary frequency, urinary, and
rectal urgency.
If nodes:
diarrhea and cramping are more common.
84
Late effects of prostate EBRT are:
less common and include radiation cystitis, urethral stricture, radiation proctitis, bowel obstruction,
fistula, and secondary malignancies.
Late effects are:
less common and include radiation cystitis, urethral stricture, radiation proctitis, bowel obstruction, fistula, and secondary malignancies. Hip osteoarthritis.
85
Guideline suggest SBRT can be considered for which risk groups?
The 2020 NCCN guidelines endorsed SBRT as an appropriate
option for all risk groups including HR and VHR, to a dose of 36.25 to 40 Gy/5 fx.
86
If brachytherapy boost is planned, what is the EBRT dose is ?
followed by LDR - what dose?
or HDR - what dose?
EBRT dose is 45 to 50 Gy, followed by
LDR (110–115 Gy
for I-125 or 90-100 Gy for Pd-103) or
HDR (15 Gy x 1 fx or 10.75 Gy x 2 fx)
E.g. as opposed to 27Gy/2# (13.5Gy/#) HDR monotherapy
87
Anatomical pathology studies suggest that most ECE is seen at?
The extent of disease outside the prostate was within 4 mm in 90% of cases.
Most of the ECE was at posterolateral sites.
About 30%of T1-T2 demonstrate ECE.
Averaging over both favourable and unfavourable specimens - The extent of disease outside the prostate was within 4 mm in 90% of cases.
88
In the era of dose escalation, does the addition of ADT benefit patients?
RTOG 0815 investigated the role
of ADT in the setting of modern, dose-escalated RT:
79.2Gy + 6 months ADT (or brachy boost and 45Gy) vs 79.Gy alone.
Improved prostate cancer mortality and distant mets, but not OS (the later not surprising as 5yr follow up)
This is consistent with at least 2 other large RCTs demonstrating benefit (PCSM, DM, BF) of ADT to radiation (at lower doses 66- 76Gy).
89
Any role for longer term ADT in intermediate risk prCa patients?
Prospective RCT data (RTOG 9910) neoadj ADT for 8 weeks vs. 28 prior to EBRT (70.2 Gy/39 fx) followed by 8 weeks of concurrent ADT (total 4 vs. 9 months)
No signif diff.
Longer duration of ADT does not improve outcomes in patients
with IR prostate cancer.
90
What is the optimal sequencing of short-term ADT and RT?
Historically, ADT has often been given neoadj for ~2 months prior to RT. Recent prospective 10yr RCT data (Canadian) 6 months of neoadjuvant/concurrent ADT, starting 4 months before RT:
Timing of short-term ADT in relation to RT does not impact biochemical control, OS, or toxicity.
Neoadj ADT is not necessary: RT and ADT can be started concurrently.
91
Is LDR brachytherapy alone sufficient treatment for favourable intermedia prostate ca?
Yes.
Prospective RCT 5yrs data supports HDR alone. The addition of EBRT does not improve outcomes (Progression free surv), but does worsen late toxicity.
92
What is the benefit of ADT in High-risk disease.
How does this relate to duration of ADT?
At least 3 RCTs demonstrate an OS benefit w/the addition of ADT to EBRT.
10yr EORTC data for example suggests 3yrs of ADT has an 18% OS benefit (40 vs 58%)
RTOG RCT data shows no OS benefit if only 4months ADT. Or 3 months (another TROG).
RADAR trial found that 18 months of ADT was superior to 6
months of ADT for HR prostate cancer.
93
What is the optimal duration of hormone therapy for HR prostate cancer?
OS benefit has been demonstrated with long-term ADT (28–36 months) compared to short-term regimens (4–6 months), even in the dose-escalated era (DART trial).
One trial (PCS IV) found similar oncologic outcomes between 18 months and 36 months.
The RADAR trial found that 18 months of ADT was superior to 6
months 4% prCa spec OS 13vs10%
94
How does ADT impact cardiovascular risk?
Role of duration?
Multiple pooled analyses have report mixed results.
Some demonstrated no signif diff in cardiovascular mortality with the use of ADT, others suggest increased cardiovascular death and shorter time to fatal myocardial infarction, particularly in men over 65 years of age.
It has been consistently demonstrated that the duration of ADT does not seem to significantly influence cardiovascular risk.
95
Is there a benefit to elective pelvic nodal RT (ENI) and which patients should be considered?
Historically trial data has been unclear or not supportive (e.g. GETUG, RTOG). More recently the POP RT trial, which studied a population of higher-risk of nodal involvement (>=20% by Roach) demonstrated a 5yr met free, disease free benefit but with higher late GU toxicity. This study used a modern prostate dose (68/25), and 80% of pts had a PET.
A new RTOG study 0924 is recruiting with an aim for higher-power than previous.
96
NCCN guidelines endorse hypofractionation for which risk groups?
NCCN guidelines endorse hypofractionation for all
risk groups.
97
Is hypofractionation safe and effective for IR and HR prostate cancer
Multiple trials involving a range of risk groups generally report similar outcomes as standard fractionation.
Hypro used 64.6 Gy/19 fx and reported higher toxicities (this therefore is probably the dose beyond the upper limit of hypofractionation).
98
Is LDR brachy monotherapy a reasonable option for intermediate prostate cancer?
Yes - for Favorable intermediate:
RTOG 5yr prospective RCT suggests the addition of EBRT (45 Gy/25 to pr and SVs; lymph nodes optional) vs. brachytherapy alone with Pd-103 (125 Gy) or I-125 (145 Gy).
Freedom from progression not improved - B+EBRT group higher grd 3 toxicities.
99
What is the benefit of adding ADT to EBRT for high-risk PrCa?
Prospective RCT trial (EORTC):
Immediate androgen suppression with GnRH agonist for 3yrs + EBRT improves:
bPFS,
DFS,
and OS in patients with HR or locally advanced prostate cancer
100
Is there a role for zolendronic acid in locally advanced PrCa?
TROG RADAR:
18 mnths of ADT + RT is more effective for locally advanced prCa than 6 mnths ADT + RT.
The addition of zoledronic acid is not beneficial.
101
Define "locally advanced prostate cancer":
T3 or T4 - I.e. has broken through the capsule.
102
Role/benefit of brachy boost?
1 RCT, and some prospective data:
Brachytherapy boost is associated with improved biochemical control but increased toxicity. Specifically higher grade III GU toxicity (that is Uf more than hourly, pain requiring narcotics or frank haematuria) - around 18%.
There may be a benefit to combined EBRT and brachytherapy in higher grade patients.
103
ADT prior to prostatectomy?
A meta-analysis demonstrated that neoadj ADT improved surgical margin status.
BUT no diff in PFS or OS
104
Role for chemo in non-metastatic prCa?
RCT (RTOG) study:
Docetaxol for high-risk disease (w/ADT and RT) versus RT+ADT alone = Improved OS and DM at 4 years but not at 10yrs. BUT Improved DFS at 6 years.
A little controversial - i.e if no benefit at 10yrs...
105
Options available for locally recurrent PrCa post radiation?
RP,
cryotherapy (the least late toxicity)
brachytherapy,
SBRT.
Are established w/Meta-analysis sugesting 5yr bRFS around 50% to 60%
High-frequency US ablation also seems reasonable.
RP has the worst toxicity.
106
For any option chosen, the benefit of treating LOCALLY recurrent PrCA post radiation appears to be?
For surgery, EBRT, cryotherapy there appears to be 50-60% biochemical RFS compared to surveillance.
107
MOA zoledronic acid:
Relate this to prostate cancer.
Act predominantly by inhibiting bone-resorbing osteoclasts that are associated with the formation of osteolytic bone lesions.
PrCa is associated with osteoblastic (not osteoclastic) bone lesions, which result in the deposition of calcium in new bone rather than lytic. The rationale for the use of bisphosphonates is that biochemical studies suggest osteolysis may also be present in PrCa bone mets.
108
Indications (population) and rationale for bisphosphantes in prostate cancer:
Bisphosphonates are thought to decrease the level of pain experienced and reduce the risk of skeletal events (e.g. pathologic fractures, hypercalcemia) in patients with bone mets.
ZA can prolong the time to first symptomatic skeletal-related event in people with hormone-refractory metastatic prostate cancer.
The OS benefit for non-castrate pts has probaly been erased by more modern treatments for this group.
109
PrCa is associated with osteo...... (not osteo......) bone lesions.
Prostate cancer is associated with osteoblastic (not osteoclastic) bone lesions.
Results in the deposition of calcium in new bone rather than breaking down of bone.
The rationale for the use of bisphosphonates in the treatment of prostate cancer is that biochemical studies have indicated that osteolysis may also be present in prostate cancer bone metastases.
110
For PSA, give:
The general structure
Function
34Kd glycoprotein. Produced by prostate epithelial cells. Functions as a proteolytic enzyme - Liquifies semen (dissolves coagulum), dissolves cervical mucous.
111
How does ejaculation alter PSA levels
What is free PSA?
Free and total PSA increase after ejaculation and slowly return to baseline over 24hrs.
112
ENZARAD trial
Awaiting results
?enzalutamide mprove survival and QOL in HIGH-RISK pts starting XRT and hormone therapy
113
Roughly how common is gynaecomastia or breast tenderness for anti-androgen patients?
80-90% experience this
114
Again, give an MOA for non steriodal anti-androgens, and older and newer example, and their benefit over steroidal?
Compete with androgen at the receptor level - leaving tesosterone intact (typically raises slightly).
Can be used as a monotherapy alternative to castration.
Liver toxicity requires monitoring.
Benefit:
Cyproterone acetate tends to result in a loss of sexual interest and erectile dysfunction, whereas most men experience this only moderately or not at all during non-steroidal drug treatment. The most common adverse effects of the non-steroidal agents are gynecomastia and breast paigynecomastia and breast pain (mild to moderate in over 90% of cases)
115
ENZAMET trial?
What is a similar trial
LHRH (GnRH) + Enzalutimide (Non-steriodal anti-androgen): Metastatic, hormone sensitive prostate cancer - Improves OS compared to GnRH alone.
The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel.
ENZARAD
116
ADT Sx MX:
1) Hot flushes
2) Sex dysfunction
3)Gynaecomastia
1) Hot flushes:
- Evening primrose oil low grade evidence
- Venlafaxine
- Gabapentin
- Medroxypredisone
2) Sex dysfunction
- Definitive/adj RT - shortest possible time on ADT
- Salvage for relapse.
3) Gynaecomastia (up to 20/5 about 60%RRR)
Prophylactic XRT
Prophylactic tamoxifen
117
SPPORT Trial?
In the the setting salvage RT:
A 3-group RCT:
Added 4–6 months of short-term ADT to PBRT,
OR
BOTH short-term ADT and pelvic lymph node radiotherapy to bed RT.
ADT + nodes + bed is superior to bed RT in terms of OS. Nodal RT can increase the time before ADT is needed.
118
Timing of RT following post prostatectomy biochem failure?
119
Define "locally advanced prostate cancer":
What makes "Very high risk prostate cancer"?
T3 or T4 - I.e. has broken through the capsule.
VHR = T3b or higher
T3b = SV involvement
120
Biochemical failure post prostatectomy is defined as?
Detectable or rising PSA value after surgery that is 0.2 ng/mL or greater with a second confirmatory level of 0.2 ng/mL or greater.
121
ADT Sx Mx:
1) Bone health
- Regular exercise
- Vit D supplimentation - including outdoor activity
- Zoledronic acid
IF Hip # risk>3%
- Denosumab
- Zoledronic acid
- Alendronate
122
MOA Denosumab and benefits
Prevention of the RANKL/RANK interaction: Inhibits osteoclast formation, function, and survival ->
Decreasing bone resorption and increasing bone mass and strength.
Denosumab appears better than zoledronic acid for prevention of skeletal-related events
123
MOA Alendronate
Nitrogen-containing bisphosphonates inhibit protein that promotes attachment of osteoclasts to bone. So osteoclasts detach from bone surfaces, thus inhibiting bone resorption.
124
ADT Sx Mx:
Bone health
- Regular exercise
- Vit D supplimentation - including outdoor activity
- Zoledronic acid
- Smoking cessation
IF Hip # risk>3%
- Denosumab
- Zoledronic acid
- Alendronate
125
MOA Alendronate
Nitrogen-containing bisphosphonates inhibit protein that promotesattachment of osteoclasts to bone. So osteoclasts detach from bone surfaces, thus inhibiting bone resorption.
126
MOA Denosumab and benefits
Prevention of the RANKL/RANK interaction: Inhibits osteoclast formation, function, and survival ->
Decreasing bone resorption and increasing bone mass and strength.
Denosumab appears better than zoledronic acid for prevention of skeletal-related events
127
Key side effects of ADT (examples of Mx):
1) Hotflushes (venlafaxine, gabapentin)
2) Fatigue - exercise (aerobic and resistant)
3) Sex dysfunction - Definitive/Adj XRT in shortest acceptable duration, intermittent ADT. Non-steroidal anti-androgen monotherapy
4) Gunaecomastia - prophylactic XRT, tamoxifen
5) Decreased bone health (Exercise, smoking cessation, ZA, vit D, Alendronate, Denosumab)
7) Metabolic consequences: BSLs/wt/cholesterol monitoring, exercise/diet
8) Cardiovasc - as above
9) Erectile dysfunction - life style, pharmacological (PDE5 inhibitor), injection "therapy", Devices (e.g. time machine)
9) Cognitive changes - Appears significant for Abiraterone
128
Approaches to Mx of erectile dysfunction:
Lifestyle - smoking/wt los/exercise/decrease EtOH
Pharm - PDE 5 inhibitor, penile injection
Device - vacuum or implant/prothesis
Penile rehab - help the penis take control of it's life.
129
Screening PSA result interpretation
PSA >4.0 micro/L has sensitivity of 21% and specificity of 91% for a cancer being detected on Bx. Sensitivity for detecting aggressive prostate cancer is higher, at 51%.
The positive predictive value increases with higher PSA test results or quicker rate of change.
>10 micrograms/L: 67% chance of cancer; values above this level are rarely caused by BPH.
>20 micrograms/L: high likelihood of cancer; prostatitis is an alternative cause
130
General approach to biochemical recurrence post prostate RT
The typical progression (Per the Pound study) of biochemical failure post RRP:
Mets at a median of 8 yrs after biochemical failure.
Death occurred at a median of 5
years from the development of mets.
No clear evidence/guidelines therefore requires discussion of the pros and cons of:
1) Ongoing surveillance
2) ADT - improved DFS - intermittent has improved QOL (8months on, restart at PSA 10)
3) Investigation (PSMA PET) and intervention.
131
Provide a rationale for offering PET in the setting of biochemical recurrence after XRT/RRP:
PET improves sensitivity in detecting earlier disease (e.g 50% chance of detecting recurrence on PET when PSA<=2.0)
Compared to observation, PET may improve time until ADT is needed - STOMP trial: ADT-free survival of 21 months for the metastasis-directed therapy group and 13 months for the surveillance group.
BUT also evidence that treating the bed in BCR post RRP pts who are PET -Ve also improves PFS.
132
What is the benefit of treating oliogomets (define the range) prostate cancer
Generally there is growing evidence (e.g. phase II COMET trial) that SABR in oligometastatic disease of varying histologies (Breast, NSCLC, Pr) may improve PS and OS.
STAMPEDE -
1) OS benefit in treating prostate when when less than 4 BONE mets OR non-regional nodes. No FFS or OS benefit if =>4
2) Docetaxel improves OS in locally advanced, N+, M+
3) At least 4 prostate trials suggest SABR to 3-5 oligomets improves PFS, and may prolong time till ADT is needed, and increase the time that intermittent ADT remains effective (pooled analysis of Oriele and STOMP). There may be an immunogenic benefit (increased marker of T-cell activation).
133
Key studies suggesting role of prostate RT in M1 disease (how many mets is that?):
What is the benefit?
What is the dose?
STOPCAP meta-analysis of STAMPEDE (<5 bone mets):
RT (prostate) + ADT
vs.
ADT
OS benefit at 3yrs 77% vs. 70%
55Gy/20# (1 # a day) or 36/6# (1# a week)
134
Any benefit to "systemic radiation" for metastatic prCa?
Bone-targeting radiopharmaceuticals (eg, 153Sm, 89Sr, and radium-223) have been used for decades to improve symptoms; But fail to deliver radiation to non-bone mets. The alpha emitter radium-223 is only agent in this class to demonstrate a survival benefit in metastatic castration-resistant pr cancer.
There is increasing prospective data supporting Targeted radioligand therapy (e.g. Lu-PSMA-617) with both an OS benefit and progression benefit.
135
For biochemically recurrent PrCa is early or late (how late) ADT better?
Multinational phase III RCT (TOAD/TROG 0306 VCOG) - early ADT improves OS compared to late (91 vs 86%) @5yrs.
Early = immediate on Dx on relapse OR UNFIT for treatment
Late > 2 years after random
136
Intermittent vs continuous ADT.
Define intermittent:
RCT data suggests intermittent is non-inferior in terms of OS, and superior in terms of quality of life.
Intermittent was 8 month cycles if PSA dropd <4, restart when PSA >10.
137
Dose/prescription for salvage EBRT post RRP:
RAVES uses 64/32 to bed,
SPORT (bed+nodes+ 6 months ADT) uses up to 70Gy to bed, 45Gy to nodes.
64/32 and SIB 54/32 (1.8Gy#) to nodes would be my approach with 6 months ADT.
138
Early vs late salvage (AKA?)?
Key studies:
3 key proRCT studies: RAVES (failed to meet criteria), GETUG-AFU17, RADICAL suggest Salvage is non-inferior to Adjuvant radiotherapy in terms of event free survival - but is associated with less late GU toxicity, and some men may be spared radiation entirely.
Salvage being defined as when PSA crosses a defined point (usually 0.2ng/ml).
139
Patient selection for Seed implantation
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