Radiation Oncology: A Question-Based Review

Low-Risk Prostate Cancer

Russell K. Hales and Justin E. Bekelman

image Background

What is the annual incidence and mortality of prostate cancer in the U.S.?

~230,000 Dx of and ~27,000 deaths from prostate cancer annually in the U.S.

1 in how many American men will develop prostate cancer during his lifetime?

~1 in 6 American men will be diagnosed with prostate cancer during his lifetime.

What are the 4 zones of the prostate?

Zones of the prostate:

1.     Peripheral zone

2.     Central zone

3.     Transitional zone

4.     Anterior fibromuscular stroma

Prostate cancers develop most commonly in which zone?

Two thirds of prostate cancers arise in the peripheral zone.

Benign prostatic hypertrophy (BPH) develops in which zone?

BPH develops in the transitional zone.

What is median lobe hypertrophy?

Median lobe hypertrophy refers to a characteristic transitional zone hypertrophy (BPH) that mushrooms superiorly into the rest of the prostate and bladder. The term does not refer to enlargement of the central zone, which is typically small and compressed in older men.

What is the name for the nerves responsible for penile erections, and where are these nerves located with respect to the prostate?

The neurovascular bundles are paired nerves located along the posterolat edge of the prostate and are responsible for penile erection.

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

Histologic cell types seen in the normal prostate:

1.     Secretory cells (produce PSA and involute with hormonal deprivation)

2.     Basal cells (flattened basement membrane where stem cells that repopulate the secretory layers reside)

3.     Neuroendocrine cells

Describe the Gleason score and what it represents.

The Gleason score is a grade assigned to prostate cancer specimens that reflects the degree of aggressiveness based on the tumor's resemblance to normal glandular tissue. A primary (or predominant) pattern is recorded followed by a secondary or lesser pattern. The Gleason score is the sum of the primary and secondary pattern values and can be between 2 and 10.

1.     Grade 1: small, well-formed glands, closely packed

2.     Grade 2: well-formed glands, but more tissue between them

3.     Grade 3: darker cells, some of which have left the gland and are invading the surrounding tissue

4.     Grade 4: few recognizable glands with many cells invading the surrounding tissue

5.     Grade 5: no recognizable glands; sheets of cells throughout the surrounding tissue

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

One third of cases are higher grade in post-prostatectomy specimens than that diagnosed in Bx specimens.

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

Black men are at highest risk for the development of prostate cancer (and their Dz presents more aggressively [higher Gleason score, 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 between native Asians and black men (Ross R et al., Cancer 1995).

Describe 5 clinical factors associated with the Dx of prostate cancer.

Clinical factors associated with the Dx of prostate cancer:

1.     Advanced age

2.     African American race

3.     Past prostate Bx showing prostatic intraepithelial neoplasia (PIN; especially high-grade PIN)

4.     Obesity

5.     High dietary intake of fats

Is there a causative relationship between vasectomy and subsequent development of prostate cancer?

No. Studies show no consistent trend between vasectomy and subsequent development of prostate cancer. The National Institutes of Health has concluded that information regarding a relationship between them is not convincing and that a causative relationship has not been established. (Healy B et al., JAMA 1993)

Define the incidence of high-grade PIN or adenocarcinoma of the prostate on autopsy studies as a function of age.

Incidental finding of prostate adenocarcinoma on autopsy studies increases with age, with the avg Gleason score between 6 and 7. In 1 study, the following incidence of either high-grade PIN or prostate cancer was found:

1.     Age < 39: 0.6% (cancer: 0.6%)

2.     Age 40–49: 19.2% (cancer: 0%)

3.     Age 50–59: 40.3% (cancer: 23.4%)

4.     Age 60–69: 61.2% (cancer: 34.7%)

5.     Age 70–81: 45.5% (cancer: 45.5%)

(Ming Y et al., J Urol 2008)

Does finasteride decrease the incidence of prostate cancer?

Yes. In a phase III trial comparing finasteride vs. placebo given for 7 yrs to test the role of finasteride as a chemoprevention agent in men age ≥55 yrs (without evidence of prostate cancer), finasteride reduced the incidence of prostate cancer by 25% (30.6% vs. 18.6%) but increased the risk of more aggressive (Gleason 7–10) tumors (37% of tumors on the finasteride arm vs. 22% of tumors on the placebo arm) (Thompson IM et al., NEJM 2003). Follow-up studies suggest that finasteride likely does not affect grade but rather shrinks the prostate, making high-grade Dz more easily detected on subsequent Bx (Lucia MS et al., JNCI 2007).

Describe 5 factors that can increase the level of PSA.

Factors that can increase PSA levels in the body:

1.     Prostate cancer

2.     Prostate manipulation (prostate Bx or DRE)

3.     Infection (prostatitis)

4.     Ejaculation shortly before PSA testing

5.     BPH

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

Prostate cancer risk increases as the total PSA level increases:

1.     PSA < 4: 5%–25%

2.     PSA 4–10: 15%–25%

3.     PSA > 10: 50%–67%

Screening programs for prostate cancer include what 2 clinical assessments?

Screening for prostate cancer includes DRE and a serum PSA.

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

Variants of absolute PSA that identify prostate cancer risk:

1.     PSA as a function of age

2.     PSA velocity

3.     PSA density

4.     ratio of free to total PSA

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

Normal PSA values in men (without prostate cancer) will increase with age.

Upper-limit normal PSA values by age:

1.     40–49 yrs: 1.5–2.5

2.     50–59 yrs: 2.5–4

3.     60–69 yrs: 4–5.5

4.     70–79 yrs: 5.5–7

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

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 (Loeb S et al., Urology 2008).

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

PSAD is the total serum PSA value divided by the volume of the prostate gland (ellipsoid volume = length × width × height × 0.52). A PSAD of ≥0.15 ng/mL/cm3 identifies men with a higher risk of detecting prostate cancer on a screening Bx.

What is the relationship between prostate cancer and the ratio of serum free-to-total PSA?

The end product of normal PSA biosynthesis within the prostate epithelium and ducts is inactive “free PSA”, a fraction 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. Hence, 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.

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

The ACS recommends annual PSA testing and DRE beginning at age 50 yrs in men with a normal risk of prostate cancer. The USPSTF concludes that there is insufficient evidence in men under age 75 yrs to assess the balance between the benefits and risk of screening; the USPSTF recommends against screening men age >75 yrs.

In a recent European-based study, PSA screening has shown what in terms of prostate cancer Dx and deaths?

In a randomized European study comparing PSA screening to no screening, 182,000 men were enrolled. With a median follow-up of 8 yrs, the cumulative incidence of prostate cancer was 8.2% in the screened group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group vs. control group was 0.8 (p = 0.04). 1,410 men need to be screened and 48 prostate cancers need to be treated to prevent 1 death from prostate cancer. (Schroder FH et al., NEJM 2009)

Annual DRE and PSA screening in the American population has shown what in terms of prostate cancer Dx and deaths?

In phase III of the U.S. Prostate, Lung, Colorectal, and Ovarian Cancer screening trial (PLCO), ~76,700 men were screened with annual PSA and DRE. After 7 yrs of follow-up, the incidence of prostate cancer was higher in the screened group (116 cases/10,000 person-yrs vs. 95 cases/10,000 person-yrs). The incidence of death was similar between the groups (screened: 2 cases/10,000 person-yrs vs. 1.7 cases/10,000 person-yrs). (Andriole GL et al., NEJM 2009)

What are some of the critiques of the PLCO screening trial for prostate cancer?

Critiques of the PLCO screening trial for prostate cancer:

1.     40%–52% of the control group were screened with PSA testing and 41%–46% of the control group were screened with DRE.

2.     As of 2009 publication, the study only had a median follow-up of 7 yrs and the complementary European study did not show a divergence in the survival curves until after 7 yrs. (Andriole GL et al., NEJM 2009)

What is the most common presentation of prostate cancer?

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

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

Local Sx that may arise at Dx in men with prostate cancer Sx:

1.     Lower tract Sx such as urgency, frequency, nocturia, dysuria

2.     Hematuria

3.     Sx of rectal involvement, such as hematochezia, constipation, intermittent diarrhea, reduced stool caliber

4.     Renal impairment from bladder outlet obstruction

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

Bone is the most common site of metastatic spread.

What organ is frequently the site of metastatic Dz in other tumors yet almost never harbors metastatic Dz in prostate cancer?

The brain is a frequent site of metastatic Dz in nonprostate carcinoma but almost never is a site of mets in prostate cancer.

image Workup/Staging

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

Important aspects of a focused Hx to include in a pt with newly diagnosed prostate cancer:

1.     GI/GU Sx: may be a clinical presentation of the cancer itself but also may inform the most appropriate type of therapy given the baseline GI/GU function

2.     Comorbid illnesses: such information may inform appropriate types of therapies for the pt; specifically and ascertain a Hx of inflammatory bowel Dz, hernia repair, or previous bowel surgeries (is the pt a surgical candidate; hormone suppression candidate?)

3.     Medications: ask about current use of α-blockers or androgen suppression

4.     New-onset bone pain: should result in a thorough evaluation for bone mets

The lab workup for prostate cancer includes what tests?

Prostate cancer lab workup: PSA, CBC, and BMP. Consider free PSA (if cancer Dx uncertain), alk phos (to assess for bone mets), or LFTS (if androgen receptor blockers will be used, as these are associated with hepatotoxicity).

Describe the AJCC 7th edition (2009) clinical TNM staging of prostate cancer.

Note: Per the AJCC, clinical T staging may use imaging. However, for research purposes, investigators should specify that the staging was based on DRE only or on DRE and imaging.

1.     cT1: clinically inapparent tumor not palpable or visible by imaging

2.     cTla: incidental histologic finding in ≤5% of tumor resected

3.     cT1b: incidental histologic finding in >5% of tissue resected

4.     cT1c: tumor identified by needle Bx

5.     cT2: organ-confined Dz

6.     cT2a: tumor involves less than or equal to one half of 1 lobe

7.     cT2b: tumor involves more than one half of 1 lobe (but not both lobes)

8.     cT2c: tumor involves both lobes of prostate

9.     cT3: tumor extends through prostatic capsule

10. cT3a: ECE

11. cT3b: seminal vesicle involvement

12. cT4: adjacent organ involvement (bladder neck, external sphincter, rectum, pelvic wall or levator muscles

13. N1: regional LN mets

14. M1: DMs

15. M1a: nonregional LNs

16. M1b: bone(s)

17. M1c: other sites

Describe the AJCC 7th edition (2009) pathologic TNM staging of prostate cancer.

1.     pT2: organ-confined Dz

2.     pT2a: tumor involves one half of 1 side or less

3.     pT2b: tumor involves more than one half of 1 side (but not both sides)

4.     pT2c: tumor involves both sides

5.     pT3: tumor extends through prostatic capsule

6.     pT3a: ECE or microscopic invasion of bladder neck

7.     pT3b: seminal vesicle involvement

8.     pT4: involvement of rectum, levator muscles, and/or pelvic wall

Note: Per the AJCC, pathologic assessment is based on evaluation of a prostatectomy specimen, unless a Bx shows involvement of the rectum, seminal vesicles, or extraprostatic tissues.

1.     N1: regional LN mets

2.     M1: DMs

3.     M1a: nonregional LNs

4.     M1b: bone(s)

5.     M1c: other sites

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

Most important clinical and pathologic factors used to risk stratify men with locally confined prostate cancer:

1.     Pre-Tx PSA

2.     DRE-defined clinical T stage

3.     Gleason score

Define the low-, intermediate-, and high-risk groupings according to the D–Amico criteria, and estimate the 10-yr PSA FFS after radical prostatectomy for each group.

Definitions of risk groups and associated 10-yr PSA PFS after prostatectomy (according to D–Amico criteria):

1.     Low risk: T1c-T2a, PSA ≤10, Gleason ≤6 (10-yr PSA FFS: 83%)

2.     Intermediate risk: T2b, PSA >10 but ≤20, Gleason 7 (10-yr PSA FFS: 46%)

3.     High risk: T2c, PSA >20, Gleason ≥8 (10-yr PSA FFS: 29%)

(D–Amico AV et al., J Urol 2001)

Describe the recommended procedure for Bx of the prostate.

Prostate Bx should be performed using a transrectal approach with a 5- to 7.5-MHz transducer in the rectum. A sextant Bx directed at the peripheral zone should result in 12 cores of prostate tissue for Bx.

Describe the appearance of prostate cancer on TRUS.

Prostate cancer on TRUS is usually hypoechoic.

What imaging studies are recommended in the workup of low-risk prostate cancer?

Unless concerning local Sx are present on evaluation of the pt with newly diagnosed low-risk prostate cancer, such as pelvic pain or focal bony pain, no imaging studies are recommended for staging a man with low-risk prostate cancer.

image Treatment/Prognosis

Define the difference between watchful waiting and active surveillance.

Active surveillance is the postponement of immediate therapy, with definitive Tx given if Dz progresses. The goal of care is to cure those with progressive Dz while avoiding unnecessary Tx in pts with clinically insignificant Dz. Watchful waiting forgoes definitive Tx at Dx with the goal of care to provide palliative Tx for symptomatic progression. Watchful waiting is reserved for elderly men or those with substantial comorbidity. (Dall–Era M et al., Curr Urol Rep 2008)

In men with early-stage prostate cancer, what is the benefit in terms of upfront surgical management vs. watchful waiting? Is there randomized data to support an approach?

The role of definitive Tx in men with early-stage prostate cancer is controversial. A Swedish study, SPCG-4, randomized 695 men with T1-T2 prostate cancer (all grades) to radical prostatectomy vs. watchful waiting. Surgery improved 12-yr CSS (12.5% vs. 17.9%) and DMFS (19.3% vs. 26%). Results should be interpreted with caution, as the study was conducted in a pre-PSA screening era and included pts with Gleason 7–10. (Bill-Alexson A et al., J Natl Cancer Inst 2008)

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

A majority of men with low-risk prostate cancer would not have any adverse clinical consequences if their Dz was left untreated. Active surveillance attempts to delay or avoid Tx for the majority of these men while reserving curative Tx for those who exhibit aggressive features.

What follow-up procedures are involved in active surveillance?

At the Johns Hopkins Hospital (JHH), expectant management includes biannual DRE and PSA screening with annual prostate Bx. Pts are referred for definitive management for increasing Gleason score, increasing volume (as estimated by # of cores and % of cores involved), or pt preference.

What group of pts may be most appropriate for watchful waiting?

Groups of pts most appropriate for watchful waiting include those too old or too ill to benefit from Tx or those with asymptomatic metastatic Dz.

What 5 criteria are needed for a pt best suited for active surveillance in early-stage, small-volume Dz?

Although there is no consensus on what group of men, if any, may be appropriate for expectant management in early-stage Dz, in general they should meet the following criteria:

1.     Older age (age >65 yrs) or with comorbid Dz

2.     Clinical T1 Dz

3.     PSAD ≤0.1

4.     Combined Gleason grade ≤6

5.     ≤50% involvement of ≤2 cores of 12

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

In a prospective cohort study at the JHH of men undergoing active surveillance, after median follow-up of 3 yrs, 25% of men underwent definitive management based on Dz progression on Bx or pt preference. Of these men with progressive Dz on Bx, those who opted for surgical management at the time of follow-up had a proportion with curable Dz that was similar to those men who would be qualified for expectant management upfront but instead chose to undergo upfront surgery (Carter HB et al., J Urol 2007). In a prospective, single-arm cohort of 450 men undergoing active surveillance, the 10-yr prostate cancer actuarial survival was 97.2%. Overall, 30% of men were found to have progressive Dz and were offered definitive therapy (Klotz L et al., JCO 2009).

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

Standard Tx options available to an otherwise healthy man with no adverse GI/GU Sx and low-risk Dz (by D–Amico criteria):

1.     Active surveillance (in carefully selected pts)

2.     Radical surgery

3.     RT (brachytherapy [brachy] or EBRT alone)

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

Yes. 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) and the MDACC RCT (Kuban D et al., IJROBP 2008).

Describe the design and outcomes of PROG 9509, which evaluated dose escalation in prostate cancer.

PROG 9509 included 392 men with low-risk prostate cancer (cT1b-T2b, PSA <15 ng/mL, Gleason <7). All men were treated with 50.4 Gy using photon RT and then were randomized to a proton boost to a total dose of 70.2 GyE vs. 79.2 GyE. Dose escalation improved 10-yr biochemical failure (32.2% vs. 16.7%).

Describe the design and outcomes of the MDACC trial that evaluated dose escalation in prostate cancer.

The MDACC dose escalation trial enrolled 301 pts with cT1b-T3 prostate cancer. 21% were low risk, 47% were intermediate risk, and 32% were high risk. Pts were randomized to 70 Gy vs. 78 Gy. Dose escalation improved 8-yr freedom from failure (78% vs. 59%). This improvement was seen in the low- and high-risk subsets but not in the intermediate-risk subset. 8-yr CSS was not significantly different (99% vs. 95%), nor was 8-yr OS (78% vs. 79%). (Kuban D et al., IJROBP 2008)

What RCTs have compared surgery, EBRT, and brachy for low-risk prostate cancer?

Currently, no RCTs have compared surgery, EBRT, and/or brachy for low-risk prostate cancer. Multiple trials comparing definitive modalities for low-risk pts have been attempted, but all have failed due to inadequate accrual. ProtecT is a large UK-based trial designed to address this question and has closed to accrual.

What data support the use of prostatectomy, EBRT, or LDR brachy alone for low-risk prostate cancer?

Numerous retrospective studies suggest similar outcomes for low-risk prostate cancer pts treated with prostatectomy, EBRT, or LDR brachy. D–Amico et al. reviewed low-risk pts treated at the University of Pennsylvania or the Joint Center in Boston and found no difference in 5-yr biochemical FFS (~88%) in men treated with prostatectomy, EBRT, or brachy alone (JAMA 1998). Kupelian et al. reviewed low-risk pts from the Cleveland Clinic and Memorial Sloan Kettering and found similar 5-yr biochemical FFS (~81%–83%) for men treated with prostatectomy, LDR brachy, and EBRT (to total doses >72 Gy). However, in a subset of men treated with EBRT to <72 Gy, 5-yr biochemical FFS was significantly worse (51%) (Kupelian P et al., IJROBP 2004).

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

A pt undergoing CT imaging to plan RT Tx can be simulated in the prone or supine position. Some institutions use a pelvic MRI or a urethrogram to locate the urogenital diaphragm and, hence, the apex of the prostate. The pt is often instructed to have a full bladder and an empty rectum, though techniques vary at institutions.

Describe 4 techniques to verify prostate position in daily RT Tx.

Techniques to verify prostate position in daily RT Tx:

1.     2D-IGRT + fiducials

2.     3D-IGRT +/− fiducials

3.     Implantable radiofrequency transponder

4.     BAT US

image Toxicity

What are the most common side effects after radical prostatectomy?

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

In men with intact erectile function prior to radical prostatectomy, what % retain erectile function after a nerve-sparing procedure?

In men with intact erectile function prior to surgery, at least 50% will retain erectile function after a nerve-sparing prostatectomy, depending on surgeon volume.

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

~33% of men who undergo a radical prostatectomy have significant postop urinary incontinence (Gunderson LL et al., Clinical radiation oncology. 6th ed. 2007). The severity of incontinence after surgery peaks immediately and improves over mos.

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

1.     Most common acute side effects: fatigue, urinary urgency/frequency, proctitis/diarrhea.

2.     Most common late side effects: erectile dysfunction (inability to maintain an erection for intercourse), cystitis, proctitis (frequency/bleeding)

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

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

Estimate the rate of erectile dysfunction in previously potent men 2+ yrs after Tx with definitive prostate RT.

~50% of men who were previously potent will no longer be able to maintain erections for intercourse 2+ yrs after definitive prostate RT. (Robinson JW et al., IJROBP 2002)

What are the current RTOG rectal DVH constraints for RT Tx to the prostate?

For prostate cancer pts being treated in 1.8 Gy/fx, appropriate dose constraints for the rectum (per an RTOG consensus statement):

1.     V70 ≤20%

2.     V50 ≤50%

(Lawton CA et al., IJROBP 2009)

What are the current RTOG bladder DVH constraints for RT Tx to the prostate?

For prostate cancer pts being treated in 1.8 Gy/fx, appropriate dose constraints for the bladder (per an RTOG consensus statement):

1.     V70 ≤30%

2.     V55 ≤50%

(Lawton CA et al., IJROBP 2009)