Treatment/Prognosis

Question 1

What are the Tx options for a man with localized intermediate-risk prostate cancer?

Answer 1

Tx options for a man with intermediate-risk prostate cancer according to 2018 NCCN guidelines include:

EBRT +/– short-term androgen suppression (AS) (4–6 mos) +/– brachytherapy boost

Brachytherapy alone +/– AS

Prostatectomy (consider likelihood of indications for postop RT)

Active surveillance if favorable intermediate risk group
If he has a life expectancy <10 yrs, consider observation.

Question 2

What are the Tx options for a man with localized high-risk prostate cancer?

Answer 2

Tx options for a man with high-risk prostate cancer:

EBRT + long-term AS (2–3 yrs) +/– pelvic node RT +/– brachytherapy boost

Prostatectomy (consider likelihood of indications for postop RT)

Question 3

Estimate the 5-yr biochemical failure-free survival (bFS) for D’Amico intermediate- and high-risk prostate cancer pts treated with prostatectomy alone.

Answer 3

After prostatectomy alone, 5-yr bFS is ∼65% for intermediate-risk and ∼35% for high-risk prostate cancer pts. (D’Amico A et al., J Urol 2001)

Question 4

Estimate the 10-yr bFS for prostate cancer pts with cT2b and ≥cT2c Dz treated with prostatectomy alone.

Answer 4

After prostatectomy alone, 10-yr bFS is ∼62% for cT2b, and ∼57% for ≥cT2c. (Han M et al., Urol Clin N Am 2001)

Question 5

Estimate the 10-yr bFS for prostate cancer pts with Gleason 3 + 4 = 7, 4 + 3 = 7, and Gleason 8–10 Dz treated with prostatectomy alone.

Answer 5

After prostatectomy alone, 10-yr bFS is ∼60% with Gleason 3 + 4 = 7, ∼33% with 4 + 3 = 7, and ∼29% with Gleason 8–10. (Han M et al., Urol Clin N Am 2001)

Question 6

Estimate the 10-yr bFS for prostate cancer pts with a pre-Tx prostate-specific antigen (pPSA) from 10–20 and >20 ng/mL treated with prostatectomy alone.

Answer 6

After prostatectomy alone, 10-yr bFS ∼57% with pPSA 10–20 ng/mL and 48% with pPSA >20 ng/mL are 57% and 48%, respectively. (Han M et al., Urol Clin N Am 2001)

Question 7

What traditionally classied pts as unfavorable vs. favorable intermediate risk?

Answer 7

Factors that may identify an unfavorable intermediate-risk subgroup include primary Gleason 4 Dz, >50% positive cores, or ≥2 intermediate-risk factors. Retrospectively unfavorable pts had higher rates of PSA failure, DM and cause specific mortality. (Zumsteg ZS et al., Eur Urol 2013)

Question 8

What are the benefits of neoadj AS prior to radical prostatectomy?

Answer 8

The benefits of neoadj AS prior to prostatectomy include decreased +margin and LN positivity rates. This has been shown in multiple randomized trials.

Question 9

Why is neoadj AS prior to radical prostatectomy not commonly used?

Answer 9

Despite improvement in pathologic outcomes with neoadj AS prior to prostatectomy, long-term bFS rates do not appear to be improved. This negative result has been found in multiple randomized studies. (Kumar S et al., Cochrane Database Syst Rev 2006)

Question 10

What is the role of adj AS therapy after prostatectomy?

Answer 10

In prostate cancer pts found to have node+ Dz after prostatectomy, immediate adj AS improves OS. (Messing EM et al., Lancet Oncol 2006) There appears to be no OS or CSS in node– men after prostatectomy (Wirth MP et al., Euro Urol 2004), although the RCT evaluating this question used only an antiandrogen instead of a GnRH agonist or total AS with both.

Question 11

What study established the role of adj AS for node+ pts after prostatectomy? What is the main criticism of this study?

Answer 11

Messing EM et al. showed an OS benefit of immediate adj AS vs. observation for node+ prostate cancer pts after prostatectomy (MS 13.9 yrs vs. 11.3 yrs, respectively). The main criticism of this study is that AS was not initiated in the observation arm until clinical Dz progression rather than an elevated absolute PSA or PSA velocity. (Lancet Oncol 2006)

Question 12

Is active surveillance a reasonable approach in intermediate-risk Dz?

Answer 12

Per the NCCN guidelines 2018, active surveillance is an option for men with favorable intermediate-risk Dz.

Question 13

Is LDR brachy alone appropriate for intermediate- or high-risk Dz? Describe 1 study that argues against LDR brachy.

Answer 13

Per the American Brachytherapy Society guidelines, LDR brachy alone is not appropriate for high-risk Dz but may be considered for highly selected pts with intermediate-risk Dz (Davis BJ et al., Brachytherapy 2012). A retrospective study by D’Amico A et al. (JAMA 1998) found that LDR brachy alone was associated with worse 5-yr biochemical progression-free survival (bPFS) compared to prostatectomy and EBRT alone in both intermediate- and high-risk subgroups. However, several single-institution series suggest that well-selected intermediate-risk pts receiving a high-quality implant have excellent outcomes after LDR brachy alone (5-yr bPFS >95%). (Taira AV et al., IJROBP 2009)

Question 14

What is the role of neoadj AS and LDR brachy for pts with intermediate- or high-risk prostate cancer?

Answer 14

Neoadj AS may be used to cytoreduce large prostates (Nag S et al., IJROBP 1999). However, several large retrospective studies have failed to show that AS improves cancer control outcomes in combination with LDR brachy.

Question 15

What randomized evidence exists for brachytherapy boost following EBRT for intermediate- and high-risk pts?

Answer 15

Hoskin PJ et al. (Radiotherapy and Oncology 2012) randomized mostly intermediate/high-risk men to 55 Gy in 20 fx vs. 35.75 Gy in 13 fx + HDR boost (2 × 8.5 Gy) and found a 31% reduced (p = 0.01) risk of recurrence with HDR boost without excess toxicity. ASCENDE-RT (Morris WJ et al., IJROBP 2017) gave high-risk men 46 Gy to the whole pelvis (WP) and then randomized them to EBRT boost to 78 Gy vs. LDR boost to 115 Gy and found a 50% risk of biochemical failure in the LDR boost arm (p = 0.004), but no difference in OS at 6.5 yrs median f/u.

Question 16

What studies support the use of short-course (4–6 mos) AS with EBRT in localized intermediate-risk prostate cancer?

Answer 16

The 1st study to show a benefit to short-course AS in locally advanced prostate cancer was RTOG 8610, although all of these pts were high risk as defined by the D’Amico criteria. None of the published studies of short-course AS specifically studied intermediate-risk pts. RTOG 9408 enrolled all risk group pts (but mainly intermediate risk) and found a 10-yr OS benefit to the addition of short-course AS (Jones CU et al., NEJM 2011). In addition, intermediate-risk pts were included in D’Amico A et al. (JAMA 2004), Laverdiere J et al. (J Urol 2004), and Denham JW et al. (Lancet Oncol 2005; TROG 96.01), all of which showed improved Dz-specific outcomes with the addition of short-course AS to EBRT. It is unclear whether dose escalation mitigates the benefit of short-course AS in intermediate-risk pts.

Question 17

Describe the study design and results of RTOG 8610, which studied the benefit of short-course AS in locally advanced prostate cancer.

Answer 17

RTOG 8610 enrolled 456 men with cT2–T4 (bulky) prostate cancer. N1 pts were eligible if below the common iliac. All were treated with EBRT (65–70 Gy) and randomized to 4 mos of AS (beginning 2 mos prior to EBRT) or observation with AS at relapse. 10-yr OS and MS favored the short-course AS arm (43% vs. 34% and 8.7 yrs vs. 7.3 yrs, respectively) although the difference was NSS. Short-course AS improved 10-yr CSM (23% vs. 36%) and distant failure (35% vs. 47%). (Roach M et al., JCO 2008)

Question 18

Describe the study design and results of RTOG 9408, which studied the benefit of short-course AS in locally confined prostate cancer.

Answer 18

RTOG 9408 enrolled 1,979 pts with T1b–T2b, PSA ≤20, prostate cancer (54% were intermediate risk). Pts were randomized to EBRT alone (66.6 Gy) +/– 4-mo AS (flutamide and LHRH agonist) beginning 2 mos prior to EBRT. 12-yr OS favored the short-course AS arm (54% vs. 61%). AS also reduced the rates of +prostate Bx at 2 yrs (39% vs. 20%). (Jones CU et al., NEJM 2011)

Question 19

Describe the study design and results of TROG 96.01, which studied the benefit of short-course AS in locally advanced prostate cancer.

Answer 19

TROG 96.01 enrolled 818 pts with T2b–T4 prostate cancer treated with EBRT (66 Gy in 2 Gy). Pts were randomized to 0, 3, or 6 mos of AS starting 2 mos prior to EBRT. With only a median f/u of 5.9 yrs, the 3- and 6-mo AS arms had improved LF, biochemical failure, and freedom from salvage Tx compared to the no-AS arm. The 6-mo arm also had improved distant failure and prostate cancer–specific survival (PCSS) compared to the no AS arm. As of yet, there are no OS differences among any of the 3 arms and no consistent cancer control differences b/t 3- and 6-mo arms. (Denham JW et al., Lancet Oncol 2005)

Question 20

Is AS still beneficial with dose-escalated RT?

Answer 20

Two RCTs have evaluated this question. EORTC 22991 (Bolla M et al., JCO 2016) randomized men to intermediate- and high-risk localized prostate cancer pts to 70, 74 or 78 Gy +/– AS and found that AS conferred improved biochemical (HR = 0.53; p < 0.001) and clinical (HR = 0.63; p < 0.001) failure. DART01/05 GICOR (Zapatero A et al., Lancet Oncology 2015) treated intermediate- and high-risk pts with 76–82 Gy and randomized them to 4 mos vs. 28 mos ADT and found long-term ADT improved biochemical and overall survival.

Question 21

When should AS be started in a prostate cancer pt being treated with EBRT and AS?

Answer 21

In prostate cancer pts being treated with EBRT + AS, AS is usually started 2 mos prior to the start of EBRT. Preclinical experiments suggest that neoadj AS may improve prostate cancer RT sensitivity compared to concurrent AS, possibly d/t improved tumor oxygenation with neoadj AS. Furthermore, the RCTs that established the role of short-course AS started it neoadjuvantly (RTOG 8610, D’Amico trial, TROG 96.01). However, RTOG 9413, which compared neoadj/concurrent vs. adj short-course AS, showed no bPFS benefit (or detriment) to neoadj AS.

Question 22

Describe the study design and results of RTOG 9413, which studied the benefit of the sequence of short-course AS and pelvic node RT in locally advanced prostate cancer.

Answer 22

RTOG 9413 had a 2 × 2 factorial design. It randomized 1,323 intermediate- and high-risk pts to 4 mos of AS beginning 2 mos prior to or immediately following EBRT. The 2nd randomization was regarding RT field size: WP RT vs. prostate and seminal vesicles only. After a median f/u of 7 yrs, there was no difference in PFS in the neoadj vs. adj AS arms and no difference in PFS in the WP and prostate and seminal vesicles only arms. Interpretation of this trial is limited by the fact that there was an unexpected interaction b/t the 2 randomizations of this study. (Lawton C et al., IJROBP 2007)

Question 23

What is the appropriate duration of neoadj AS prior to EBRT in prostate cancer pts?

Answer 23

Prostate cancer pts who are treated with neoadj AS usually rcv 2 mos of AS prior to EBRT. 1 RCT enrolled 378 men with localized prostate cancer of any risk group, and all were treated with EBRT (66–67 Gy) without concurrent AS. Pts were randomized to 3 mos vs. 8 mos of neoadj AS. 5-yr freedom from failure (FFF) did not differ b/t the Tx arms. In an unplanned subgroup analysis, 5-yr DFS was improved for high-risk pts (71% vs. 42%) (Crook J et al., IJROBP 2009). RTOG 9910 evaluated 8-wks vs. 28 wks of neoadj therapy in men with intermediate-risk Dz and found no difference in cause-specific mortality, OS, locoregional progression or DM. (Pisansky TM et al., JCO 2015)

Question 24

Which studies support the role of long-term AS in localized high-risk prostate cancer pts treated with EBRT?

Answer 24

An OS benefit of long-term AS in high-risk pts after EBRT was 1st shown in RTOG 8531. Multiple subsequent RCTs have also shown improved prostate cancer outcomes: the Casodex Early Prostate Cancer trial, EORTC 22863, RTOG 9202, and EORTC 22961.

Question 25

Describe the study design and results of RTOG 8531, which studied the benefit of the long-term AS in locally advanced prostate cancer.

Answer 25

RTOG 8531 enrolled 945 men with cT3 (nonbulky), pT3 after prostatectomy, or N1 prostate cancer. All were treated with EBRT (definitive dose: 65–70 Gy; postop dose: 60–65 Gy) and randomized to adj AS indefinitely or observation with AS at relapse. Adj AS improved 10-yr OS (49% vs. 39%), 10-yr CSM (16% vs. 22%), 10-yr LF (23% vs. 38%), and 10-yr distant failure (24% vs. 39%) (WP). On subset analysis, benefits were limited to the subset with Gleason ≥7 and were especially important in the subset with Gleason ≥8. (Pilepich MV et al., IJROBP 2005)

Question 26

Describe the study design and results of EORTC 22863, which studied the benefit of long-term AS in locally advanced prostate cancer.

Answer 26

EORTC 22863 enrolled 412 men with cT3–T4/any grade or cT1–T2/WHO grade 3 prostate cancer. All were treated with EBRT (70 Gy) and randomized to 3 yrs of adj AS (beginning with EBRT) or observation with AS at relapse. Long-term AS improved 5-yr OS (78% vs. 62%), CSS (94% vs. 79%), LF (1.7% vs. 16.4%), and distant failure (9.8% vs. 29.2%). (Bolla M et al., Lancet 2002)

Question 27

Describe the study design and results of RTOG 9202, which studied the benefit of the long-term AS in locally advanced prostate cancer.

Answer 27

RTOG 9202 enrolled 1,541 men with cT2c–T4, PSA <150. All were treated with 2 mos of neoadj AS and 2 mos of concurrent AS + EBRT (65–70 Gy). Pts were randomized to an additional 2 yrs of adj AS or observation with AS at relapse. Long-term AS was not associated with OS in the entire cohort, although it did show improved 10-yr CSS (89% vs. 84%), local progression (12% vs. 22%), and DM (15% vs. 23%). In an unplanned subgroup analysis, long-term AS improved 10-yr OS in pts with Gleason ≥8 (45% vs. 32%). (Horwitz EM et al., JCO 2008)

Question 28

Describe the study design and results of the EORTC 22961 RCT, which compared short-course and long-term AS with EBRT in localized prostate cancer.

Answer 28

EORTC 22961 enrolled 1,113 men with cT2c–T4/N0 or cT1c–T2b/pN1–N2 prostate cancer and randomized to EBRT (70 Gy) with 6 mos vs. 3 yrs of neoadj, concurrent, and adj AS. Men receiving 3 yrs of AS had sup OS (5-yr OS 85% vs. 81%) and CSM (5-yr CSM 3.2% vs. 4.7%). Long-term overall QOL did not significantly differ b/t the 2 arms. (Bolla M et al., NEJM 2009)

Question 29

What is the appropriate duration of long-term AS in localized high-risk prostate cancer pts treated with EBRT?

Answer 29

RTOG 9202 and EORTC 22961 suggested that long-term (2–3 yrs) AS is sup to short-course AS in high-risk pts. However, the optimum duration of long-term AS has not been well studied.

Question 30

What is the role of pelvic nodal RT in localized intermediate- and high-risk prostate cancer?

Answer 30

The major RCTs that established the role of RT in locally advanced prostate cancer generally irradiated pelvic nodes. However, the role of pelvic nodal RT in localized prostate cancer has been specifically studied in 3 RCTs: RTOG 7706, RTOG 9413, and GETUG-01, and none showed a cancer control benefit to irradiating pelvic nodes. Pelvic nodal RT may still be warranted in men at very high risk of harboring nodal Dz, although who these pts are is controversial. RTOG 0924 is currently ongoing to evaluate the role of pelvic nodal irradiation in unfavorable intermediate or favorable high-risk prostate cancer.

Question 31

What is the appropriate EBRT dose for intermediate- and high-risk prostate cancer?

Answer 31

Men with intermediate- and high-risk prostate cancer who do not rcv AS should be treated to total EBRT doses of ≥74 Gy (in 2 Gy/fx). There have been at least 4 EBRT dose escalation studies including intermediate- and high-risk pts: the MDACC dose escalation trial, PROG 9505, the Dutch dose escalation trial, and the MRC RT01 trial. All 4 RCTs have shown at least improved biochemical control with dose-escalated EBRT. The role of high-dose EBRT is less clear in the setting of AS. The Dutch dose escalation trial allowed AS, but only a minority of men rcv it (22%) (Peeters ST et al., JCO 2006). The MRC RT01 trial mandated neoadj and concurrent AS, and 5-yr outcomes favored dose escalation. RTOG 0126 is a phase III trial comparing 79.2Gy in 44 fx or 70.2 Gy in 39 fx powered to examine OS. With a median of 8 yrs of f/u no differences in OS were reported. (Abstract only, ASCO GU 2015)

Question 32

Describe the study design and results of the MDACC RCT that studied the benefit of dose escalation in localized prostate cancer.

Answer 32

The MDACC dose escalation trial enrolled 301 pts with cT1b–T3 prostate cancer. None were treated with AS. 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 FFF (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)

Question 33

Describe the study design and results of the PROG 9509 RCT, which studied the benefit of dose escalation in localized prostate cancer.

Answer 33

The PROG 9509 RCT on dose escalation enrolled 393 pts with T1b–T2b, PSA <15 ng/mL prostate cancer. Pts were randomized to 70.2 Gy or 79.2 Gy. CD RT to the prostate only was given by proton RT prior to 50.4 Gy with photon RT to the prostate and seminal vesicle. Dose escalation improved 5-yr freedom from biochemical failure (80% vs. 61%) and 5-yr LC (48% vs. 55%). In an unplanned analysis, a significant improvement in freedom from biochemical failure was seen in both low- and intermediate-risk subsets. (Zietman AL et al., JAMA 2005)

Question 34

Describe the study design and results of the MRC RT01 RCT, which studied the benefit of dose escalation in the setting of neoadj and concurrent AS for localized prostate cancer.

Answer 34

The MRC RT01 trial enrolled 843 men with cT1b–T3a, PSA <50 prostate cancer. All men were treated with 3–6 mos of neoadj and concurrent AS and randomized to EBRT 64 Gy or 74 Gy. The dose escalation arm improved 5-yr bPFS (71% vs. 60%). LC, freedom from salvage AS, and DMFS favored the dose-escalation arm, although these endpoints were not statistically different. (Dearnaley DP et al., Lancet Oncol 2007)

Question 35

What is the role of primary AS alone for localized high-risk prostate cancer?

Answer 35

AS alone for localized high-risk prostate cancer may be considered for men who cannot tolerate local management.

Question 36

Describe the design and results of the Scandinavian RCT (SPCG-7) that studied the long-term AS +/- EBRT in locally advanced prostate cancer.

Answer 36

SPCG-7 enrolled 875 men with cT1b–T2, N0 WHO grade 2–3 or cT3, any grade, N0 prostate cancer. All men were treated with total AS for 3 mos → an antiandrogen alone (flutamide) indefinitely. Pts were randomized to EBRT (70 Gy) starting after 3 mos of AS or no local therapy. With median f/u of 7.6 yrs, the addition of EBRT improved 10-yr OS (70% vs. 61%) and 10-yr CSS (88% vs. 76%). The 10-yr prostate cancer–specific mortality was reduced by half with EBRT (12% vs. 24%) (Widmark A et al., Lancet 2009). A 2016 update (Fossa SD et al., Eur Urol 2016) showed that the 15-yr prostate cancer–specific mortality was 34% vs. 17% in the ADT vs. ADT + RT arms, respectively.

Question 37

Describe the design and results of the Warde RCT that studied the long-term AS +/- EBRT in locally advanced prostate cancer.

Answer 37

In Intergroup T94-0110 1,205 pts with prostate cancer initially who had cT3–4 Dz (later broadened to include cT2 w/ PSA >40 or PSA >40 and Gleason >8) were randomized to either lifelong AS alone (bilat orchiectomy or LHRH agonist) +/– EBRT (pelvis to 45 Gy → prostate (65–69 Gy) or prostate alone (65–69 Gy). Addition of RT to AS resulted in improved OS (HR 0.70; 95% CI 0.57–0.85) and PCSS (HR 0.46; 95% CI 0.34–0.61) with a median f/u time of 8 yrs. (Mason M et al., JCO 2015)

Question 38

What is the role of definitive prostate RT in men with node+ prostate cancer?

Answer 38

There has been no RCT to determine whether men with node+ prostate cancer benefit from local RT. A retrospective review by Zagars et al. suggested that EBRT in addition to long-term AS confers an OS benefit to node+ pts. (J Urol 2001) Subset analyses from RTOG 8531 suggest that long-term AS + EBRT confer OS benefit compared to EBRT alone in node+ pts. However, long-term biochemical control (PSA <1.5 ng/mL) was still poor (10% at 9 yrs). (Lawton C et al., JCO 2005)

Question 39

What evidence exists for the addition of chemo to ADT for initial Tx in high-risk pts undergoing local therapy?

Answer 39

GETUG 12 (Fizazi K et al., Lancet Oncology 2015) randomized men with ≥1 high-risk feature or positive LNs to local Tx with ADT +/– docetaxel and estramustine and found improved 8-yr RFS in the chemo arm (62% vs. 50%; p = 0.017). The STAMPEDE trial randomized 1,917 men (95% newly diagnosed; 5% relapse post local therapy) to ADT +/– abiraterone and prednisone and found that OS was significantly increased with the addition of abiraterone (3-yr survival 83 vs. 76% with ADT alone, HR 0.63, 95% CI 0.52–0.76).