Low-risk prostate cancer

Question 1

What proportion of men will develop prostate cancer and what is the annual incidence and mortality in the United States?

Answer 1

1 in 7 men corresponding to 160,000 Dx of and 26,000 deaths from prostate cancer annually.

Question 2

What are the 4 zones of the prostate?

Answer 2

1. Peripheral zone
2. Central zone
3. Transitional zone
4. Ant fibromuscular stroma

Question 3

Prostate cancers develop most commonly in which zone?

Answer 3

Two-thirds of prostate cancers arise in the peripheral zone.

Question 4

Benign prostatic hypertrophy (BPH) develops in which zone?

Answer 4

BPH develops primarily in the transitional zone.

Question 5

What does median lobe hypertrophy refer to?

Answer 5

Median lobe hypertrophy refers to a characteristic transitional zone hypertrophy (BPH) that mushrooms superiorly into bladder lumen.

Question 6

What tissues likely mediate erectile dysfunction (ED) after prostate RT?

Answer 6

ED likely results from RT injury to the neurovascular bundles, internal pudendal arteries, corpora cavernosa and possibly the penile bulb.

Question 7

Name the 3 histologic cell types seen in the normal prostate.

Answer 7

1. Secretory cells (produce PSA)
2. Basal cells (flattened basement membrane where stem cells that repopulate the secretory layers reside)
3. Neuroendocrine cells

Question 8

Describe the GS and what it represents.

Show

Answer 8

A sum of pathologic grades assigned to prostate cancer that reflect aggressiveness based on the tumor’s resemblance to normal glandular tissue.
A primary (or predominant) pattern is recorded f/b a secondary or lesser pattern, which are summed to give the overall GS (e.g., 3 + 4).

Question 9

How do the Gleason Grade Group definitions correspond to the GSs?

Answer 9

Group 1: GS ≤6
Group 2: GS 3 + 4 = 7
Group 3: GS 4 + 3 = 7
Group 4: GS 4 + 4 = 8; 3 + 5 = 8; 5 + 3 = 8
Group 5: GS 9–10

Question 10

How often is higher-grade Dz diagnosed in a radical prostatectomy specimen (upstaging) than that seen in the initial Bx specimens?

Answer 10

One-third

Question 11

What racial groups are associated with the highest and lowest risks for prostate cancer?

Answer 11

Black men are at highest risk for the development of prostate cancer (and their Dz presents more aggressively [higher GS, more advanced stage]).
Asians are at the lowest risk for the development of prostate cancer. A 30- to 50-fold difference in the incidence of the Dz is observed b/t native Asians
and black men.

Question 12

Define the incidence of adenocarcinoma of the prostate on autopsy studies as a function of age.

Answer 12

Incidental finding of prostate adenocarcinoma on autopsy studies increases
with age, with the average GS b/t 6 and 7. In 1 study, the following
incidences of prostate cancer were found:
Age 50–59: 23.4%
Age 60–69: 34.7%
Age 70–81: 45.5%

Question 13

How does finasteride use impact prostate cancer incidence, aggressiveness, and mortality?

Answer 13

In a phase III trial comparing finasteride vs. placebo, finasteride reduced the incidence of prostate cancer (30.6% vs. 18.6%), but increased the risk of more aggressive (Gleason 7–10) tumors (37% vs. 22%). Finasteride likely does not impact grade, but rather shrinks the prostate, making high-grade Dz more easily detected. There is no impact of finasteride on OS.

Question 14

Describe 5 factors that can increase the level of PSA.

Answer 14

1. Prostate cancer
2. Prostate manipulation (prostate Bx or DRE)
3. Infection (prostatitis)
4. Ejaculation shortly before PSA testing
5. BPH

Question 15

Define the risk of prostate cancer as a function of total PSA level.

Answer 15

Prostate cancer risk increases as the total PSA level increases:
PSA ≤4 ng/mL: 5%–25%
PSA 4–10 ng/mL: 15%–25%
PSA ≥10 ng/mL: 50%–67%

Question 16

Screening programs for prostate cancer include what 2 clinical assessments?

Answer 16

Screening for prostate cancer includes DRE and a serum PSA.

Question 17

Describe 4 variants of absolute PSA that can be helpful in assessing a man’s risk of prostate cancer.

Answer 17

1. PSA as a function of age
2. PSA velocity
3. PSA density
4. Ratio of free to total PSA

Question 18

Describe the upper limits of normal PSA values as a function of age.

Answer 18

PSA values in men without prostate cancer will increase with age:
40–49 yrs: 1.5–2.5 ng/mL
50–59 yrs: 2.5–4 ng/mL
60–69 yrs: 4–5.5 ng/mL
70–79 yrs: 5.5–7 ng/mL

Question 19

What is prostate-specific antigen velocity (PSAV), and how is it used in prostate cancer screening?

Answer 19

PSAV is a measure of the rate of change of the total PSA annually. A PSA velocity ≥2 ng/mL/yr is associated with a higher risk of finding Gleason ≥7 prostate cancer on prostatectomy.

Question 20

What is prostate-specific antigen density (PSAD), and how is it used in prostate cancer screening?

Answer 20

PSAD is the total serum PSA value divided by the volume of the prostate gland. A PSAD of ≥0.15 ng/mL/cm3 identifies men with a higher risk of
detecting prostate cancer on a screening Bx.

Question 21

What is the relationship b/t prostate cancer and the ratio of serum free-tototal PSA?

Answer 21

The end product of normal PSA biosynthesis within the prostate epithelium and ducts is inactive “free PSA,” an fx of which diffuses into the circulation.
In prostate cancer, tumors disrupt the prostate basement membrane and allow precursor forms of PSA to leak into the circulation, which decreases the
relative proportion of free PSA. The ratio of free-to-total PSA will be lower in men with prostate cancer. A ratio of <7% is highly suspicious for prostate cancer, whereas a ratio of >25% is rarely associated with malignancy.

Question 22

What are population-based screening recommendations by the American Cancer Society (ACS) for prostate cancer? U.S. Preventive Services Task
Force (USPSTF)?

Answer 22

The ACS (2010) recommends that physicians discuss screening with men aged (1) ≥50 yrs at avg risk expected to live ≥10 yrs, (2) ≥45 yrs at high risk
(African Americans, 1st-degree relatives diagnosed prior to 65), (3) ≥40 yrs at very high risk (>1 1st-degree relative diagnosed prior to 65 yrs). The USPSTF (2017) acknowledges a small potential mortality benefit with PSA screening that should be discussed with men aged 55–69 yrs of age (C recommendation).

Question 23

Is there evidence of a mortality benefit with prostate cancer screening?

Answer 23

Yes. The European Randomized study of Screening for Prostate Cancer study with 13 yrs of f/u showed an SS 21% decreased risk of prostate cancer mortality with PSA screening. The number needed to screen to prevent 1 death in this study was 781.

Question 24

What has annual DRE and PSA screening in the US population shown in terms of prostate cancer and deaths?

Answer 24

In the U.S. Prostate, Lung, Colorectal, and Ovarian Cancer screening trial, 76,685 men were randomized to (1) annual PSA × 6 yrs + annual DRE × 4 yrs or (2) usual care in which opportunistic screening with PSA or DRE was allowed. After 13 yrs of f/u, the incidence of prostate cancer was higher with PSA testing (108 vs. 97 cases/10,000 person-yrs). The incidence of death
was similar b/t the groups (3.7 vs. 3.4 cases/10,000 person-yrs) (Andriole GL et al., JNCI 2012). However, control group participants reported higher rates of PSA screening (∼90%) than those in the intervention group (Shoag JE et al., NEJM 2016) making it difficult to draw conclusions from this trial.

Question 25

What is the most common presentation of prostate cancer?

Answer 25

In the PSA era, most pts present with an abnl PSA and no associated Sx.

Question 26

In men with symptomatic prostate cancer, what local Sx may arise at Dx?

Answer 26

1. Lower urinary tract Sx such as urgency, frequency, nocturia, and dysuria
2. Hematuria
3. Hematochezia, constipation, intermittent diarrhea, reduced stool caliber
4. Renal impairment from bladder outlet obstruction

Question 27

What is the most common site of metastatic spread of prostate cancer?

Answer 27

Bone is the most common site of metastatic spread. Blastic > lytic lesions.

Question 28

Name 4 important aspects of a focused Hx to include in a pt with newly diagnosed prostate cancer

Answer 28

GI/GU Sx: may inform the most appropriate type of therapy
Comorbid illnesses: especially Hx of inflammatory bowel Dz or previous bowel Sgs (e.g., candidacy for RT, Sg, hormone suppression)
Meds: especially use of α-blockers or androgen suppression
New-onset bone pain: should result in a thorough evaluation for bone mets

Question 29

What are the 3 most important clinical and pathologic factors for risk stratifying men with locally confined prostate cancer?

Answer 29

1. Pre-Tx PSA
2. DRE-defined cT
3. Gleason group

Question 30

Describe the recommended procedure for Bx of the prostate.

Answer 30

Prostate Bx should be performed using a transrectal approach with a US transducer in the rectum. A sextant Bx directed at the peripheral zone should result in 12 cores of prostate tissue.

Question 31

Describe the appearance of prostate cancer on TRUS.

Answer 31

Prostate cancer on TRUS is usually hypoechoic.

Question 32

Define the current NCCN (2018) prostate cancer risk groups.

Answer 32

• Very low: T1c, GS ≤6, PSA <10 ng/mL, <3 Bx cores +, ≤50% cancer per core, PSA density <0.15 ng/mL/g
• Low: T1–T2a, GS ≤6, PSA <10 ng/mL
• Favorable Intermediate: T2b–T2c or GS 3 + 4 = 7 or PSA 10–20 ng/mL and <50% postive cores
• Unfavorable intermediate: T2b–T2c or GS 3 + 4 = 7 or
  PSA 10–20 ng/mL
• High: T3a or GS 8–10 or PSA >20 ng/mL
• Very high: T3b–T4 or primary Gleason pattern 5 or >4 cores with GS 8–10

Question 33

What men should undergo a bone scan per NCCN guidelines (2018)?

Answer 33

T2 and PSA >10 ng/mL; high or very high risk groups

Question 34

What men should undergo pelvic imaging (CT or MRI)?

Answer 34

Per NCCN guidelines (2018) pelvic imaging is indicated for intermediate, high and very high risk groups if nomogram indicated probability of LN involvement >10%. However, developing literature suggests a broader role
for MRI. The PROMIS study was a multicenter randomized trial from 2012 to 2015 in 576 Bx-naïve pts who underwent 1.5T MRI plus Bx and found that
for clinically significant cancer (GS ≥4 + 3 or a max cancer core length 6 mm or longer), MRI was more sensitive (93% vs. 48%; p < 0.0001) but less specific (41% vs. 96%; p < 0.0001) than TRUS-Bx. MRI may also be sup in the identification of Gleason ≥3 + 4. (Rais-Bahrami et al., J Urol 2013) T3 MRI has been shown to be advantageous in predicting ECE at Sg with a sensitivity and specificity of 58.2% and 89.1%, respectively. (Somford et al., J Urol 2013)

Question 35

What is the role of tissue-based molecular assays in decision making for prostate cancer?

Answer 35

A number of tissue-based molecular assays have been developed for treated and untreated men with localized prostate cancer (e.g., Decipher, Oncoptype
DX, Prolaris) and shown in retrospective analyses to provide prognostic information beyond NCCN risk groups regarding outcomes such as risk of biochemical failure, metastatic Dz and mortality. Their exact role remains incompletely defined pending prospective evaluation but current Molecular Diagnostic Services Program recommendations support their post-RP with
adverse features (Decipher), and post-Bx in low-risk Dz (Oncotype DX; Prolaris; ProMark).

Question 36

Describe the AJCC 8th edition (2018) clinical TNM staging of prostate cancer.

Answer 36

cT1: Clinically inapparent tumor not palpable
cTla: Incidental histologic finding in ≤5% of tumor resected
cT1b: Incidental histologic finding in >5% of tissue resected
cT1c: Tumor identified by needle Bx but not palpable
cT2: Palpable organ-confined Dz
cT2a: Tumor involves one-half of 1 side or less
cT2b: Tumor involves more than one-half of 1 side but not both sides
cT2c: Tumor involves both sides
cT3: Extraprostatic tumor that is not fixed or does not invade adjacent
structures
cT3a: ECE
cT3b: Seminal vesicle invasion
cT4: Adjacent organ involvement (bladder, external sphincter, rectum, pelvic
wall, or levator muscles)
N1: regional LN mets
M1: DMs
M1a: Nonregional LNs
M1b: Bone(s)
M1c: Other sites

Question 37

Describe the AJCC 8th edition (2018) pathologic TNM staging of prostate cancer.

Answer 37

pT2: Organ-confined Dz
pT3: ECE
pT3a: ECE or microscopic invasion of bladder neck
pT3b: Seminal vesicle involvement
pT4: Adjacent organ involvement (bladder, external sphincter, rectum, pelvic wall, or levator muscles)

N1: regional LN mets
M1: DMs
M1a: Nonregional LNs
M1b: Bone(s)
M1c: Other sites

Question 38

Define active surveillance, watchful waiting, and observation.

Answer 38

Active surveillance is the postponement of immediate therapy, with active monitoring and definitive Tx given if Dz progresses. Watchful waiting is traditionally defined as forgoing definitive Tx, does not involve active
monitoring, and is typically reserved for those with a short life expectancy. However, in order to disambiguate terms often used interchangeably, current guidelines refer to active surveillance vs. observation. Observation indicates monitoring for progression and offering palliative therapy as needed.

Question 39

In men with early-stage prostate cancer, what is the benefit in terms of upfront surgical management vs. watchful waiting?

Answer 39

A Swedish study, SPCG-4, randomized 695 men with T1–T2 prostate cancer (all grades) to radical prostatectomy vs. observation. Sg improved 18-yr incidence of cause-specific death (17.7% vs. 28.7%) and DM (26.1% vs.38.3%). However, this study was conducted in a pre-PSA screening era and
included pts with GS 7–10. (Bill-Axelson A et al., NEJM 2014)

Question 40

Have any randomized studies compared active surveillance, radical prostatectomy, and EBRT in localized prostate cancer?

Answer 40

Yes, the ProtecT trial (Hamdy FC et al., NEJM 2016) randomized 1,643 men with localized prostate cancer (GS 6–10; T1c–T2) diagnosed by PSA testing
to active monitoring (n = 545), Sg (n = 553), or radiotherapy + short-course ADT (n = 545). The primary outcome was prostate-cancer mortality. At a
median of 10 yrs of f/u there was no difference in prostate cancer–specific deaths or OS. Metastatic Dz was more common in the active monitoring
group (6.3 events per 1,000 person-yrs) than in the Sg (2.4 per 1,000 personyrs) or radiotherapy (3.0 per 1,000 person-yrs) groups (p = 0.004). 27 men require Sg and 33 men require radiotherapy to prevent 1 pt from having
metastatic Dz.

Question 41

What was the active monitoring protocol in the ProtecT trial?

Answer 41

Serum PSA levels were measured q3 mos in the 1st yr and q6–12 mos following. An increase of at least 50% during the previous 12 mos triggered a review. DRE and repeat Bx were not part of the active monitoring protocol. A less comprehensive active monitoring protocol could have contributed to worse outcomes in the active monitoring group (e.g., metastatic Dz).

Question 42

What are the 2 primary surgical approaches for prostatectomy and have any trials compared them?

Answer 42

The 2 primary surgical approaches are robotic-assisted radical prostatectomy and radical retropubic prostatectomy. A trial (Yaxley J et al., Lancet 2016)
randomized 326 men with prostate cancer to robotic-assisted or retropubic radical prostatectomy and found no statistically significant differences at 12 wks regarding urinary function, sexual function, postop complications or margin status.

Question 43

What is the premise underlying active surveillance in prostate cancer care?

Answer 43

A majority of men with low-risk prostate cancer would not have any adverse clinical consequences if left untreated. Active surveillance delays definitive Tx for the majority while reserving curative for those with Dz progression.

Question 44

What f/u procedures are involved in active surveillance? When should pts be referred for definitive management?

Answer 44

PSA no more than q6 mos, DRE no more than q12 mos, prostate Bx no more than q12 mos. MRI may be used to aid in the detection of high-grade Dz. Pts are referred for definitive management for increasing GS, increasing volume (as estimated by # of cores and % of cores involved), or pt preference.

Question 45

Per 2018 NCCN guidelines what prostate cancer risk groups are appropriate for consideration of active surveillance?

Answer 45

Favorable intermediate-, low- and very low-risk groups.

Question 46

Per 2018 NCCN guidelines what individuals are appropriate for consideration of observation only?

Answer 46

Very low–, low-, and intermediate-risk prostate cancer with <10 yrs life expectancy.

Question 47

What % of men with low-grade, early-stage Dz will eventually need definitive management with curative intent b/c of progressive Dz? What is their expected prostate-cancer mortality?

Answer 47

In a prospective cohort study at the JHH of low-risk men undergoing active surveillance, the 10- and 15-yr rates of curative intervention were 50% and 57%, respectively, with a 15-yr prostate-cancer mortality of 0.4% (Tosoian JJ et al., JCO 2015). Similar results were demonstrated in a
prospective study from Toronto that also included favorable intermediate-risk Dz with 98.5% CSS (Klotz L et al., JCO 2015).

Question 48

What 3 standard Tx options are available to an otherwise healthy man with no adverse GI/GU Sx and low-risk group Dz?

Answer 48

1. Active surveillance
2. Radical prostatectomy
3. RT (EBRT and/or brachytherapy)

Question 49

Does dose escalation improve outcomes in men with low-risk prostate cancer?

Answer 49

Dose escalation improves biochemical FFS in men with low-risk prostate cancer. This has been seen in at least 2 randomized trials that included men with low-risk Dz. PROG 9509 (Zietman AL et al., JCO 2010) compared 70.2 Gy vs. 79.2 Gy and found improved 10-yr biochemical failure (32.2% vs. 16.7%). The MDACC RCT (Kuban D et al., IJROBP 2008) compared 70 Gy
vs. 78 Gy and found that dose escalation improved 8-yr freedom from failure (78% vs. 59%). Neither study demonstrated a benefit in causespecific
mortality or OS. RTOG 0126 is a phase III trial comparing 79.2 Gy in 44 fx or 70.2 Gy in 39 fx powered to examine OS. With a median of 7.0 yrs of f/u no differences in OS were reported. (Michalski et al., JAMA Oncology 2018)

Question 50

Have any trials compared Sg to EBRT for localized prostate cancer?

Answer 50

Yes. The ProtecT trial (Hamdy FC et al., NEJM 2016) showed no differences in death d/t prostate cancer with RP vs. RT + ADT. Pt-reported QOL data (Donovan JL et al., NEJM 2016) showed increased urinary pad use in the RP vs. RT groups at 6 mos (46% vs. 5%) and 6 yrs (17% vs. 4%). Bowel function was similar b/t groups except an increase in bloody stools in the radiotherapy group. 17% and 27% of men could obtain erections adequate
for intercourse at 6 yrs in the RP and RT groups, respectively, compared to 67% at baseline.

Question 51

What data support the use of hypofractionation for localized prostate cancer?

Answer 51

The CHHiP trial (Dearnaley D et al., Lancet 2016) randomized 3,216 men from 71 centers with localized prostate cancer (pT1b–T3aN0M0) to 74 Gy in
37 fx vs. 60 Gy in 20 fx vs. 57 in 19 fx. With a median f/u of 62 mos 60 Gy in 20 fx was noninf to 74 Gy in 37 fx. There were no significant differences in side effects at 5 yrs using 3 clinician- and pt-reported outcome measures. RTOG 0415 (abstract only, ASCO 2016) similarly showed that in men with low-risk prostate cancer, 70 Gy in 28 fx is noninf to 73.8 Gy in 41 fx.

Question 52

What evidence supports the use of SBRT for localized prostate cancer?

Answer 52

Data supporting SBRT in the Tx of localized prostate cancer are limited to phase I/II studies. A pooled analysis of phase II trials in 1,100 men undergoing CyberKnife to a median dose of 36.25 Gy in 4–5 fx found 5-yr
BFFS of 93%. Reported GI and GU QOL returned to baseline within 6 mos following Tx, but toxicity grade was not reported (King CR et al.,Radiotherapy and Oncology 2013). A later multi-institutional phase I/II study
(Hannan R et al., Eur J Cancer 2016) of 91 low- and intermediate-risk prostate cancer pts treated with up to 50 Gy in 5 fx found 98.6% BFFS at 5
yrs. 4 grade IV late GU/GI toxicities were observed.

Question 53

Which pts are candidates for primary brachytherapy?

Answer 53

Brachytherapy monotherapy can be considered in low-risk and low-volume intermediate-risk prostate cancer. Intermediate- and high-risk pts are candidates for combining brachytherapy with EBRT.

Question 54

What are the American Brachytherapy Society absolute and relative contraindications for brachytherapy?

Answer 54

1. Absolute: High operative risk, no rectum, limited life expectancy (<10 yrs), DMs, ataxia telangiectasia
2. Relative: High IPSS (cutoff 15–18 in RTOG trials), prior pelvic RT, prior TURP, large median lobe, gland >60 cc, inflammatory bowel Dz

Question 55

Describe the setup of a pt with prostate cancer undergoing CT imaging to plan EBRT.

Answer 55

Techniques vary by institution. One approach is CT simulation in the supine position with knee and foot lock, +/– a pelvic MRI, with a full bladder and
rectal balloon. Fiducials may be placed for daily localization. The use of rectal spacer is an emerging modality to decrease ant rectal wall dose.

Question 56

What are the most common side effects after radical prostatectomy?

Answer 56

The most common significant side effects after radical prostatectomy are ED, urinary incontinence, and urethral stricture.

Question 57

What % of men will be able to maintain erections firm enough for intercourse following definitive Tx for prostate cancer with RT or Sg?

Answer 57

Traditional teaching states that ∼50% of previously potent men will be able to maintain erections for intercourse for both modalities 1–2 yrs post-Tx. In the
ProtecT trial (Hamdy FC et al., NEJM 2016) erectile function was worse at all-time points following Sg compared to RT, including during ADT.

Question 58

What % of men who undergo a radical prostatectomy have significant postop urinary incontinence? Long-term urinary incontinence?

Answer 58

40% of men who undergo a robotic-assisted radical prostatectomy have significant postop urinary incontinence at 12 wks. (Yaxley J et al., Lancet
2016) In the ProtecT trial 17% continued to require pads at 6 yrs (Hamdy FC et al., NEJM 2016) compared to 4% in the RT group.

Question 59

What are the most common acute and late side effects of EBRT and brachytherapy?

Answer 59

Acute: fatigue, urinary urgency/frequency, proctitis/diarrhea
Late: ED, cystitis, proctitis (frequency/bleeding)

Question 60

Estimate the rate of grade 3 or higher late GU or GI RT toxicity with IMRT for prostate cancer.

Answer 60

Numerous retrospective studies suggest that grade 3 or higher late GU or GI
RT toxicity with IMRT for prostate cancer is rare (≤1%).