Prostate Cancer: Salvage and Adjuvant Therapies

Natural History and Demographics

12% - 18% will have cT3 (ECE or SV involvement) disease at diagnosis. Extracapsular extension is most often found in the neurovascular bundles. For men having undergone local therapy for prostate cancer, the factors most important in predicting recurrence include: 5

• Gleason Score
• Extra-capsular extension
• Positive surgical margins

Determination of Recurrence: Biochemical Evidence of Failure

Determination of recurrence has evolved over time. The AUA definition of biochemical recurrence after radical prostatectomy is a serum PSA ≥ 0.2 ng/ml when confirmed by a second PSA level also ≥ 2 ng/ml. When prostate cancer is treated with primary irradiation, the mean time to nadir is 18 months. There are contradictory reports, but the rate of decline to nadir does not appear to be correlated with the risk of recurrence. For those treated with radiation as primary therapy, the PSA nadir after RT for localized prostate cancer is a strong prognostic indicator of treatment success. There is no absolute level below which PSA must fall in order to define treatment success or failure.

The ASTRO guidelines for defining biochemical recurrence was originally 3 consecutive rises in PSA following a nadir. The date of biochemical recurrence is defined as half way between the first rise and nadir or any levle sufficient to warrant initiation of therapy.

The Phoenix criterion in 2005 for defining biochemical recurrence after radiation therapy for localized prostate cancer was developed to eliminate concerns about "backdating" associted with the original ASTRO definition. The Phoenix consensus criterion define biochemical recurrence as a PSA rise of ≥ 2 ng/ml above the PSA nadir, regardless of the presence of androgen suppression. The date of recurrence is the date of the PSA that triggers the definition. This definition is also considered useful for EBRT patients treated with EBRT and neoadjuvant hormone therapy.

PSA can "bounce" after external beam radiation therapy for localized prostate cancer. Typically the PSA level falls, however, it can exhibit a transient rise around 12 - 18 months after treatment, even without disease recurrence. Using the Phoenix criterion, this can happen in 10% - 20% of all patients. There is no definitive method of distinguishing the PSA "bounce" from recurrence of prostate cancer. PSA should be rechecked in 3 - 6 months and managed accordingly.

PSA doubling time after radical prostatectomy can help predict metastases free survival and cause specific survival times.

• PSA doubling time < 3 months: 20 times higher risk of death from prostate cancer than PSA-DT ≥ 3 months
• PSA doubling time < 3 months: Cause specific mortality after BCF is 35% for Gleason ≤ 7
• PSA doubling time < 3 months: CSM after BCF is 75% for Gleason ≥ 8

Several factors are harbingers of a favorable outcome with salvage radiation therapy post-prostatectomy. These factors are:

• Positive margins post-prostatectomy
• Low PSA at recurrence detection
• Long recurrence free survival
• Long PSA doubling time (PSA-DT)
• Low prostatectomy Gleason score

Workup/Staging

For men with a biochemical evidence of recurrence after definitive local treatment, the primary workup is to determine if the recurrence is localized or distant disease. If the relapse is localized, therapy can be local, accordingly.

For men with localized prostate cancer and rising PSA without other signs of disease, 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 PSA doubling time. MRI may be more sensitive in detecting metastases, but the benefit is not quantified and the study is costly. ProstaScint remains a controversial test and ¹⁸FDG PET scans are less useful because of bladder washout and the fact that prostate cancer has a low metabolic rate.

Biopsy in the bed of the prostate or prostate (in intact prostates) in the setting of biochemical evidence of recurrence/persistence after definitive local treatment should be performed at least 18 months after definitive radiotherapy since a positive result < 2 years after treatment does not correlate well with disease progression. Utility of the prostate bed biopsy is controversial. Most recurrences are at the anastomotic site. Palpableprostate bed nodules should probably be biopsied and consideration of higher radiation doses to those nodules should be given.

Treatment

Adjuvant radiation therapy is indicated after prostatectomy based on the SWOG 8794, the EORTC 22911 and ARO 96-02 trials. These studies demonstrated an overall survival benefit with adjuvant radiation therapy. The SWOG study included pT3N0 or positive margin patients. The EORTC study performed a subset analysis using central pathologic review which indicated the benefit may be restricted to positive margins only.

SWOG 8794 Study: Positive Margins, or pT3N0 Randomized to Adjuvant Radiation or Observation (Thompson J.Urol, 2009. SWOG 8794 found adjuvant radiation therapy, post-prostatectomy improved median survival to 15.2 years from 13.3 years. Global quality of life was initially worse in the adjuvant radiation arm, but normalized after 2 years of follow up and was superior thereafter.

• Enrolled 431 men with pT3N0 or positive margins
• Randomized to Radiation to 60 - 64 Gy or observation
• Improved median survival to 15.2 years from 13.3 years.
• Initial QOL lower but same or better after 2 years

There are no randomized prospective trials demonstrating superiority of radiation therapy to other treatments as salvage therapy after prostatectomy recurrence. There are retrospective studies which provide evidence from Johns Hopkins (Trock, 2008, JAMA) that demonstrated, when adjusted for other prognostic factors, salvage radiation therapy improved cancer specific survival regardless of adjuvant hormonal therapy. CSS₅ was improved to 96% from 88%

There are no randomized prospective trials comparing immediate adjuvant radiation therapy with salvage radiation therapy at the time of biochemical recurrence post-prostatectomy, or in men with locally advanced prostate cancer. The three randomized trials, SWOG 8794, EORTC 22911 and ARO 96-02 compared radiation against observation without strict salvage guidelines at the first indication of disease recurrence. Non-randomized studies on salvage radiation therapy appear to produce results comparable to adjuvant radiation.

Post-prostatectomy Treatment Volumes, Dose and Hormones

Treatment volumes have not been prospectively determined. Generally treatment volumes cover the bed of the prostate and sufficient margin to cover those areas at risk for residual or recurrent disease. Taking into account the pathologic studies of likely areas of pathologic margins, the apex, anastomosis and neurovascular bundle areas are the most likely sites of residual disease. The SWOG 8794, EORTC 22911 and ARO 96-02 used small field radiation therapy not covering pelvic lymph nodes. RTOG 0534 is an ongoing trial looking at the extent of pelvic RT but only in men receiving adjuvant androgen deprivation therapy.

Although there are no randomized studies addressing the dose and fields in adjuvant and salvage radiation therapy, retrospective series typically report better outcomes with a dose > 65 Gy. The ASTRO consensus guideline recommends dose > 64 Gy. Some will offer those with higher levels of pre-radiation PSA or palpable nodules higher doses of radiation.

Likewise there have been no reported prospective studies examining the role of hormonal therapy in post-prostatectomy radiation therapy either adjuvant or salvage. RTOG 9601 randomized patients to salvage radiation therapy ± bicalutamide. This trial has been completed and publicaton is pending but results are not yet available. It may be reasonable to recommend hormoen therapy in patients with very unfavorable risk factors such as high Gleason Score (≥ 8) or high pre-radiation PSA levels.

RTOG 9601 Initial Report of a Phase III trial in Prostate Cancer with Anti-androgen therapy with Bicalutamide in Post Prostatectomy Radiation Therapy in Patients with pT2-3 N0 Disease and Elevated PSA Levels (Shipley, 2010, IJROBP) RTOG 9601 has published an initial report as of late 2010. This study is a double blinded phase III randomized controlled study of radiation therapy alone to a total dose of 64.8 Gy in 36 fractions at 1.8 Gy/fraction or the same radiation dose with the addition of 24 months of bicalutamide at 150 mg QD during and after radiation. The primary endpoint is overall survival.

The study characteristics and preliminary findings are:

• Post radical prostatectomy patients with pT3 (ECE or SV+)NO or pT2N0 with positive surgical margins with elevated PSA
• Randomized: Placebo v. Bicalutamide 150 mg/d x 2 years ± RT to 64.8 Gy @ 1.8 Gy/fx.
• Primary endpoint is OS
• PSA progression is defined as PSA > 0.4 ng/ml whose protocol resulted in undetectable PSA or if PSA remained at detectable levels, a rise to 0.3 ng/ml above entry level PSA
• Enrolled 771 patients median age of 65 years. 33% pT2N0, 67% pT3N0
• 87% had PSA nadir < 0.5 ng/ml.
  • 85% had PSA < 1.6 ng/ml at entry
  • 15% had PSA 1.6 - 3,9 ng/ml
  • Median follow up is 7.1 years
  • Conclusion I: Too few events have transpired to allow a statistical comparision between groups
  • Freedom from PSA progression (FFP) estimated at 7 years was 57% for RT+AAT which was an improvement from 40% with radiation therapy alone.
  • For 226 patients with Gleason Score < 7 FFP in the AAT+RT arm was improved to 63% from 50%
  • For 411 patients with Gleason Score = 7, improved FFP (AAT+RT) arm 55% from 39%
  • For 134 patients with Gleason Score ≥ 8, improved FFP (AAT+RT) 56% from 26%

  The primary observed toxicity of the treatment was gynecomastia, mostly all Grades I and II which increased from 15% to 89%. The preliminary report concludes that the addition of anti-androgen therapy during and after radiation therapy significantly improved freedom from PSA progression and reduced the inidents of metastatic disease without adding significantly to radiation toxicity.

  The authors report that the study, at the present time, is unable to draw conclusions as to overall survival benefit and the significance of these findings with respect to survival. These conclusions must await longer follow up. In addition, while the results of this study appear promising, addition of anti-androgen therapy is not without quality of life affects. The addition of anti-androgen therapy may simply delay the development of progression and longer follow up will help clarify the durability of benefit.

  Salvage Prostatectomy After Radiation Therapy

  There is a role for salvage prostatectomy for biochemical recurrence after radiation therapy. Salvage prostatectomy can provide long term disease control in a significant portion of patients. However, salvage prostatectomy is associated with a higher rate of unrinary incontinence and rectal injury. This is less true in patients treated with intensity modulated radiation therapy (IMRT) and IMRT patients may have better outcomes.

  Based on retrospective studies, careful patient selection is key. Outcome is better with patients with a lower pre-operative PSA. Based on retrospective series:

  • PFS₅ is up to 86% for PSA < 4 ng/ml
  • PFS₅ is 55% for PSA 4 - 10
  • PFS₅ is 28% for PSA > 10

  As with salvage radiation therapy, a key factor is to consider surgery early in the biochemical evidence of recurrence.

  Toxicity associated with post radiation therapy salvage prostatectomy is lower in modern series compared with older (pre-IMRT) series. Fibrosis is decreased in modern IMRT techniques. In modern series the rate of late complications are similar to standard prostatectomy. However, the rates of urinary incontinence remain significantly higher (30% - 50%) as do the rates of anastomotic stricture (17% -32%) in post radiation prostatectomy.

  Cryoablation

  The use of cryoablation has not been proven. The benefit for cryotherapy is uncertain. There are no prospective studies comparying cryotherapy against prostatectomy in the salvage setting post-Radiation with biochemical evidence of recurrence. Relative safety and efficiacy are uncertain between the two modalities.

  Brachytherapy as Salvage Therapy

  As with cryoablation, the role of brachytherapy as salvage treatment is uncertain. There is not sufficient data to support the widespread use of brachytherapy for biochemical recurrence after external beam radiation therapy over other modalities such as salvage prostatectomy. Small series have shown promise with good disease control and low levels of toxicity in carefully selected patients but further study is necessary before this can be considered standard approach.

  Androgen Deprivation Therapy

  Androgen therapy is used commonly after biochemical recurrence after local therapy for prostate cancer. Optimal timing remains somewhat controversial although less so. Recent studies have demonstrated that intermittant androgen deprivation are as effective as continouous ADT. In advanced prostate cancer there is a survival benefit to early initiation of ADT. Proponents arute that even in the setting of biochemical recurrence, ADT can delay disease progression and prolong survival.

  There are significant side effects of long term ADT. These include osteoporosis/osteopenia, loss of libido, muscle wasting and metabolic syndrome. There is no evidence of survival benefit when initiation of ADT is held until there is symptomatic progression rather than biochemical evidence of progression. A commonly used strategy is to choose early ADT in patient with high risk disease or fast PSA doubling times.

Radiation Oncology Synopsis