Radiation Oncology: A Question-Based Review

55
Adjuvant and Salvage Treatment for Prostate Cancer

Jing Zeng and Howard M. Sandler

image Background


What % of newly diagnosed prostate cancers are cT3 Dz or higher?

12%–28% of men with newly diagnosed prostate cancer have cT3 Dz or higher.

In which portion of the prostate is ECE most commonly found?

ECE is most commonly found in the posterolat portion of the prostate, near the prostatic neurovascular bundle.

Name the most important factors in predicting Dz recurrence in pts undergoing local therapy for prostate cancer.

Pre-Tx PSA, Gleason score, ECE, and +margins are the most important factors in predicting Dz recurrence in pts undergoing local therapy for prostate cancer.

What is the American Urological Association (AUA) definition of biochemical recurrence s/p radical prostatectomy?

The AUA definition of biochemical recurrence s/p radical prostatectomy is a serum PSA ≥0.2, confirmed by a 2nd determination also ≥0.2.

What is the mean time to PSA nadir after RT for localized prostate cancer?

The mean time to PSA nadir after RT for localized prostate cancer is ~18 mos. Though there are contradictory reports, it seems that the rate of decline in PSA does not appear to correlate with risk of Dz recurrence.

Is there an absolute threshold for PSA nadir (with respect to Tx failure) after RT for localized prostate cancer?

The PSA nadir after RT for localized prostate cancer is a strong prognostic indicator of Tx success, but there is no absolute level below which the PSA must fall in order to define Tx success vs. failure.

What is the original ASTRO criterion (1996 consensus panel) for defining biochemical recurrence after RT for localized prostate cancer?

In order to be sure that the PSA is truly rising, the original ASTRO criteria for defining biochemical recurrence after RT for localized prostate cancer required 3 consecutive PSA rises following a nadir. The date of biochemical recurrence was defined as halfway between the nadir and date of 1st rise or any rise enough to provoke initiation of therapy.

What is the Phoenix criterion (2005 consensus panel) for defining biochemical recurrence after RT for localized prostate cancer?

Partly to eliminate concerns about the “backdating” associated with the original ASTRO definition, the Phoenix criterion for defining biochemical recurrence after RT for localized prostate cancer is a PSA rise of ≥2 ng/mL above the PSA nadir, regardless of the presence of androgen deprivation therapy (ADT). The date of recurrence is the date of the PSA that triggers the definition. This definition is also considered to be useful for pts treated with EBRT and neoadj hormone therapy.

What is the concept of “PSA bounce” in pts who rcv RT for localized prostate cancer? How should it be managed?

After RT for localized prostate cancer, serum PSA typically falls. However, it can rise transiently, called a PSA bounce, usually around 12–18 mos after Tx. This can occur even without Dz recurrence. The frequency of this occurrence varies depending on the definition of biochemical recurrence. Using the Phoenix definition, it can occur in 10%–20% of pts. There is no definitive method to distinguish a PSA bounce from recurrent Dz. The PSA should be rechecked 3–6 mos later and managed accordingly.

image Workup/Staging


What is the primary purpose of diagnostic evaluation for men with rising PSA after definitive local Tx for prostate cancer?

The primary purpose of diagnostic evaluation for men with rising PSA after definitive local Tx for prostate cancer is to distinguish pts most likely to have isolated local relapse vs. pts with systemic Dz.

For men with rising PSA (and no other Sx of Dz) after definitive local Tx for prostate cancer, what is the utility of imaging studies, such as bone scan, CT, MRI, and ProstaScint?

For men with rising PSA (and no other Sx of Dz) after definitive local Tx for prostate cancer, the likelihood of a positive bone scan is <5% unless the PSA is >40 ng/mL. CT also has limited utility unless the PSA value is relatively high or there is a short prostate-specific antigen doubling time (PSA-DT). MRI may be more sensitive in detecting mets, but its benefits must be weighed against its costs. ProstaScint remains controversial. PET scans are considered investigational, and FDG-PET is problematic b/c of the low metabolic rate of prostate cancer and the excretion of the PET agent into the bladder.

What is the utility of prostate or prostate bed Bx for men with a rising PSA (and no other Sx of Dz) after definitive local Tx for prostate cancer?

For post-RT pts with prostate cancer, TRUS prostate Bx is typically not recommended unless local salvage options are being considered, such as prostatectomy. Bx should be performed at least 18 mos after RT completion, since a positive result <2 yrs after Tx does not correlate well with Dz progression. Utility of the prostate bed Bx is controversial, and most recurrences are at the anastomotic site. Palpable prostate bed nodules should probably be biopsied and perhaps given higher doses of RT.

image Treatment/Prognosis


What is the prognostic significance of PSA-DT after local therapy for prostate cancer?

After radical prostatectomy for prostate cancer, PSA-DT can help predict MFS and cancer-specific survival. PSA-DT <3 mos confers a 20-fold higher risk of prostate cancer death than PSA-DT ≥3 mos. For pts with PSA-DT <3 mos, 5-yr CSM after biochemical failure is 35% and 75% for Gleason ≤7 and ≥8 Dz, respectively.

Name 5 prognostic factors associated with a favorable outcome after salvage RT post prostatectomy.

Prognostic factors associated with a favorable outcome after salvage RT post prostatectomy:

1.     +Margin

2.     Low PSA at recurrence

3.     Long recurrencefree interval

4.     Long PSA-DT

5.     Low prostatectomy Gleason score

(Stephenson AJ et al., JCO 2007)

What are the indications for adj RT after prostatectomy, and what studies support its role?

The indications for adj RT after prostatectomy have been refined due to reports from 3 recent RCTs that included men with pT3N0 prostate cancer or positive surgical margins and showed improved 5-yr biochemical PFS with adj RT compared to observation: SWOG 8794, EORTC 22911, and ARO 96-02. The SWOG 8794 study, which has the longest follow-up, found an OS benefit with adj RT. Subset analyses using centralized pathologic review from the EORTC study suggest that the benefit may be limited to men with +margins after surgery.

Describe the study design and results of the SWOG 8794 RCT that compared adj RT and observation in pts with high-risk features after prostatectomy.

SWOG 8794 enrolled 431 men with pT3N0 prostate cancer or +margin after prostatectomy and randomized to adj RT (60–64 Gy). Adj RT improved MS (15.2 yrs vs. 13.3 yrs). Global QOL was initially worse in the adj RT arm but was similar after 2 yrs of follow-up and superior thereafter. (Thompson IM et al., J Urol 2009)

Is there any evidence that salvage RT post prostatectomy improves survival compared with observation?

Yes. There are no randomized trials comparing salvage RT post prostatectomy against other Tx strategies. However, there is a suggestive retrospective series from the Johns Hopkins Hospital (Trock BJ et al., JAMA 2008) that evaluated 635 pts s/p prostatectomy with biochemical recurrence. Tx included observation, RT alone, or RT + hormone therapy. Adjusted for prognostic factors, cancer-specific survival was prolonged in pts who rcv salvage RT, regardless of hormone therapy (5-yr CSS 96% vs. 88%).

Is there randomized data comparing adj vs. salvage RT in men with locally advanced prostate cancer or biochemical recurrence s/p prostatectomy?

No. There are no published randomized trials comparing adj vs. salvage RT in men with locally advanced prostate cancer or biochemical recurrence s/p prostatectomy. The 3 randomized trials on adj therapy (SWOG 8794, EORTC 22911, and ARO 96-02) compared adj RT vs. observation, without strict salvage guidelines at the 1st sign of Dz recurrence. Nonrandomized series on salvage RT appear to produce results somewhat comparable to adj RT.

What should be the Tx volume in adj and salvage RT post prostatectomy?

The appropriate Tx volume in adj and salvage RT post prostatectomy has not been prospectively determined. Randomized trials in adj RT (SWOG 8794, EORTC 22911, and ARO 96-02) used small-field RT and did not include regional pelvic nodal irradiation. RTOG-0534 is an ongoing trial looking at extent of pelvic RT, but only in men also receiving hormone therapy.

What should be the RT dose in adj and salvage RT post prostatectomy?

There are no randomized studies addressing the issue of dose in adj and salvage RT post prostatectomy. Retrospective series typically report better outcomes when doses are >65 Gy. The ASTRO consensus panel recommends >64 Gy. Often, pts with higher levels of pre-RT PSA or with palpable nodules will rcv higher doses of PORT.

Is there randomized data supporting the addition of hormone therapy to salvage RT post prostatectomy?

No. There are no published randomized trials addressing the addition of hormone therapy to salvage RT post prostatectomy. RTOG-9601, which randomized pts to salvage RT +/− Casodex, has been completed and publication is pending. Based on retrospective series, it is reasonable to recommend hormone therapy for pts with very unfavorable risk factors, such as high Gleason score or high pre-RT PSA.

Is there a role for salvage prostatectomy for biochemical recurrence after RT for prostate cancer?

Yes. For biochemical recurrence after RT for prostate cancer, salvage prostatectomy can provide long-term Dz control in a significant portion of pts. However, salvage prostatectomy is associated with a higher risk of urinary incontinence and rectal injury, though pts treated with modern IMRT may have better outcomes. Careful pt selection is key. Outcome is better with pts with lower preop PSA. Based on retrospective series, 5-yr PFS is up to 86% for a PSA <4, 55% for a PSA 4–10, and 28% for a PSA >10.

Is there a role for cryotherapy for biochemical recurrence after RT for prostate cancer?

This is uncertain. There are no prospective studies comparing cryotherapy against prostatectomy in the salvage setting post-RT with biochemical recurrence. Relative efficacy and safety are uncertain between the 2 modalities. Since cryotherapy can destroy tissue beyond the prostate, it may be an option for pts with extraprostatic extension of Dz.

Is there a role for brachytherapy (brachy) for biochemical recurrence after EBRT for prostate cancer?

This in uncertain. There is not sufficient data to support the widespread use of brachy for biochemical recurrence after EBRT for prostate cancer over the other available modalities, such as prostatectomy and cryotherapy. Small series have shown promise with good Dz control and low levels of toxicity in carefully selected pts, but further study is needed before it is considered a standard approach.

What is the optimal timing of ADT for biochemical recurrence after local therapy for prostate cancer?

Optimal timing of ADT for biochemical recurrence after local therapy for prostate cancer is controversial. In advanced prostate cancer, there is survival benefit to early initiation of ADT. Proponents of early ADT argue that even in the biochemical recurrence setting, early ADT can delay Dz progression and prolong survival. However, there are significant side effects associated with ADT, and there is no clear evidence of survival benefit compared with initiating therapy when there is clinical evidence of mets or Sx. One strategy is to choose early ADT in pts with high-grade Dz, or fast PSA-DT.

image Toxicity


What is the rate of urinary incontinence and anastomotic stricture with salvage prostatectomy for biochemical recurrence after RT for prostate cancer?

The rate of toxicity with salvage prostatectomy for biochemical recurrence after RT for prostate cancer is lower in modern series compared with older series due to decreased fibrosis with modern RT techniques and improved surgical techniques. In modern series, the rate of many acute and late complications are similar to standard prostatectomy. However, there are still significant rates of urinary incontinence (30%–50%) and anastomotic stricture (17%–32%).

Name 5 side effects associated with ADT.

Side effects associated with ADT include hot flashes, loss of libido, decreased muscle mass, mild anemia, and loss of bone density.