Prostate Cancer: Management of Locally Advanced Prostate Cancer

Background

• Definition of locally advanced prostate cancer: stage ≥T3NX/+M0
• Men with locally advanced disease, are at significant risk of disease progression and cancer-specific death if left untreated.

• Fewer men are presenting with locally advanced prostate cancer due to screening

Options

1. Radiation with long-term ADT
2. Radical prostatectomy with extended pelvic lymphadenectomy

Radical Prostatectomy

• Generally reserved for high-risk, low-volume tumors that can be completely excised
  • Prostatectomy alone is often insufficient
    • However, some patients with high-risk disease features achieve cure with radical prostatectomy alone, and the addition of adjuvant and combined therapy may further improve outcomes of surgery alone
    • Modalities other than surgery are increasingly being used for treatment of high-risk prostate cancers.

Prognosis

• 15-year outcomes in patients found to have positive nodes (pN1) following radical prostatectomy
  • Biochemical–recurrence-free survival: 7.1%
  • Metastases-free survival: 41.5%
  • Cancer-specific survival: 57.5%

Neoadjuvant ADT

• See Management of Localized Prostate Cancer Chapter Notes

Adjuvant ADT

• Limited clinical data on the role of ADT in locally advanced tumors, except in N+ disease (see below section on Management of pN1 after radical prostatectomy)

Radiation after prostatectomy

• See 2019 AUA Radiation after Prostate Cancer Treatment Guideline Notes
• Rationale
  • Patients with extraprostatic tumor extension (pT3a), seminal vesicle invasion (pT3b), or positive surgical margins might have retained cancer cells in the bed of the prostate, and postoperative radiotherapy may eradicate these cells.
• Timing of radiation (adjuvant vs. early salvage)
  • The National Cancer Institute defines adjuvant therapy as additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back.
    • In prostate cancer,
      • Adjuvant therapy refers to radiotherapy administered proactively shortly after surgery in patients with undetectable PSA levels.
      • Salvage radiotherapy refers to radiotherapy given to men with detectable postoperative PSA levels
        • Radiation for persistent post-prostatectomy PSA after RP is considered salvage[1], not adjuvant
          • Patients with adverse pathology detected at prostatectomy who have a persistent post-prostatectomy PSA level should be offered post-RP SRT[1]
  • Advantages of adjuvant:
    1. More likely to be successful when the tumor burden is the smallest; waiting to administer RT as a salvage therapy could be less effective, particularly in patients with high-risk disease, and could allow the progression to metastatic disease.
    2. Radiation dose is less than with salvage radiotherapy
    3. Less need for ADT than with salvage radiotherapy
  • Advantages of early salvage:
    1. Avoids overtreatment
       • ART may involve irradiation of some patients who never would have had recurrent cancer, thus exposing them unnecessarily to the risks, toxicity, and QoL impact of RT. SRT avoids overtreatment.
         • Most patients with focally positive surgical margins, with or without extraprostatic tumor extension, are cured by radical prostatectomy.
         • In patients with a limited life expectancy, and especially those with Gleason grade 6 or 7 tumors, PSA levels may be monitored to measure the PSA velocity to help determine whether salvage radiotherapy is necessary
         • Toxicity of adjuvant radiation
           • 5-10% risk of radiation proctitis or cystitis
           • 50% risk of erectile dysfunction
       • Because PSA is a sensitive test for treatment failure, little is lost by delaying with careful monitoring,

Adjuvant radiation

Adjuvant radiation vs. observation (late salvage)

• 3 RCTs have demonstrated improved biochemical recurrence–free and cancer-specific survival with the use of adjuvant radiation compared to observation for locally advanced/positive margin disease:

Southwest Oncology Group (SWOG) 8794

• Initiated in 1987
• Population: 431 men with pT3 prostate cancer and/or positive surgical margins; ≈two thirds had undetectable PSA at randomization.
• Randomized to adjuvant RT vs. observation
• Results:
  • Median follow-up of 12.5 months
  • Median metastasis-free survival was significantly longer in the adjuvant radiation therapy arm compared to the salvage group (14.7 vs.12.9 years) in the salvage group.
  • Overall survival was significantly longer in the adjuvant therapy group compared to the salvage arm (15.2 vs. 13.3 years). The number of men with pathologic T3 disease who must be treated with adjuvant radiotherapy to prevent 1 death at a median follow-up of 12.6 years was 9.1 patients.
• Interpretation: Adjuvant radiotherapy within 18 weeks after radical prostatectomy in patients with T3N0M0 prostate cancer significantly reduces the risk for PSA recurrence, metastasis, and need for hormonal therapy and increases overall survival.
• Thompson, Ian M., et al. "Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial." The Journal of urology 181.3 (2009): 956-962.

European Organization for Research and Treatment of Cancer (EORTC) 22911

• Initiated in 1992
• Population: 1005 men with pT3 prostate cancer and/or positive surgical margins
• Randomized to adjuvant RT vs. observation
• Results:
  • Biochemical progression–free survival rate was improved by 21% at 5-years in the adjuvant radiation arm (74% adjuvant vs. 53% salvage arm)
  • Clinical progression–free survival, defined as no evidence of clinical, sonographic, radiographic, or scintigraphic recurrence, was improved in the adjuvant radiation group compared to the salvage group, as was locoregional failure at 5 years, which was significantly lower in the adjuvant radiation group and 5.4% versus 15.4% in the salvage group.
  • No difference in overall survival
  • Bolla, Michel, et al. "Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)." The Lancet 380.9858 (2012): 2018-2027. https://www.ncbi.nlm.nih.gov/pubmed/23084481 [Original publication 2005]
  • Secondary analyses of EORTC 22911 support the role of immediate RT in the specific subset with positive surgical margin (Van der Kwast et al, 2007). The treatment benefit on biochemical-free survival of adjuvant RT was primarily seen in patients with positive surgical margins (HR 0.38, P < .0001), whereas no benefit was observed in those with negative margins independent of other risk factors.

ARO 96-02

• German study
• Population: 368 patients with pT3 or pT4 but without nodal metastatic disease
• Randomized to adjuvant RT vs. observation
  • A major difference in this trial from the previous two is that all patients had an undetectable PSA level before randomization. Patients in the salvage group underwent salvage therapy with radiation and/or hormone therapy on recurrence.
• Results:
  • Biochemical progression–free survival rate was improved by 21% at 10-years in the adjuvant arm (56% adjuvant vs. 35% salvage) [2014 update, original publication 2009]
  • No improvement in metastasis-free or overall survival
• Wiegel, Thomas, et al. "Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96–02/AUO AP 09/95 trial." European urology 66.2 (2014): 243-250. https://www.ncbi.nlm.nih.gov/pubmed/24680359 [Original publication 2009]

Systematic review and MA of 3 trials

• Immediate RT after RP reduces the risk of recurrence in patients with aggressive PCa. However, immediate postoperative RT is associated with an increased risk of acute and late side effects ranging from 15-35% and 2-8%, respectively.

Early salvage radiation

• Refers to monitoring the PSA levels and avoiding further treatment unless there is convincing PSA evidence of tumor progression.
• Effectiveness is greatest when given at lower levels of PSA
  • Salvage radiotherapy initiated with PSA ≤0.5 ng/mL is associated with improved 5-year biochemical progression-free survival rates compared with patients treated with salvage radiotherapy with a pre-radiotherapy PSA value > 0.5 ng/mL.
• Benefit strongest in those with the shortest PSA doubling times (< 6 months)

Adjuvant vs. early salvage radiation

Evidence

• ARTISTIC Meta-analysis
  • Included 2153 patients from RADICALS, GETUG-17 and RAVES trials which evaluated adjuvant radiation therapy vs. surveillance with early salvage radiation therapy for PSA increase in patients with high-risk localized prostate cancer following radical prostatectomy.
    • Criteria for early salvage therapy was a PSA >0.1 ng/mL or >0.2 ng/mL depending on the trial
    • The proportion of patients in the early salvage therapy groups that received radiation therapy ranged from one third to one half.
  • Results
    • No difference in event-free survival based on meta-analysis of 3 trials (pooled HR 0.95, 95% CI 0.75 to 1.21)
    • Adjuvant radiation was associated with increased risk of genitourinary toxicity
    • Overall, there were few patients with high-risk features
  • Vale, Claire L., et al." Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data." The Lancet (2020).
  • RADICALS
    • 1,396 males from multiple countries that underwent prostatectomy for non-metastatic prostate cancer with undetectable PSA and ≥1 risk factor:
      • pT stage ≥3
      • Grade group ≥2
      • Positive margins
      • Preoperative PSA ≥ 10 ng/mL
    • Randomized to adjuvant radiation vs. early salvage (with second randomization on duration of ADT 6 vs. 24 months)
      • Salvage radiation administered for PSA biochemical progression, defined as either:
        • 2 consecutive rising PSA amounts with a PSA > 0.1 ng/mL
        • 3 consecutive rising PSA
    • Outcomes:
      • Primary: distant metastasis-free survival (though initially was disease-specific survival)
      • Secondary: disease-specific survival, overall survival, initiation of non-protocol hormone therapy, treatment toxicity, and patient-reported outcomes.
    • Results:
      • Median follow-up: 5 years
      • Distant metastasis-free survival outcome data not mature
      • No significant difference in biochemical progression-free survival (85% radiation vs. 88% salvage at 5-years (HR 1.10, 95% CI 0.81-1.49))
    • Parker, Christopher C., et al."Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial." The Lancet 396.10260 (2020): 1413-1421.
  • GETUG-17
    • The French Groupe d’Étude des Tumeurs Uro-Génitales (GETUG-17) trial will evaluate a similar patient population but will randomize patients to immediate adjuvant radiation therapy versus observation patients and treating with salvage radiation when PSA levels reach a level of 0.2 ng/mL.
  • RAVES: Radiotherapy—Adjuvant versus Early Salvage trial
    • A phase III trial randomizing patients with pathologic T3 disease and/or positive margins. Primary end point is biochemical cancer control with secondary outcomes including quality of life, toxicity, anxiety/depression, biochemical failure–free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, time to initiation of androgen ablation, quality adjusted life years, and cost-utility.
    • Trial terminated due to poor accrual

Recommendations

NCCN

• 2023 NCCN (PROS 10, PROS G 5/7)
  • If life expectancy ≤ 5 years, observation
  • If life expectancy > 5 years,
    • Adjuvant RT if pT3a disease, positive margin(s), or seminal vesicle involvement
      • . Patients with positive surgical margins may benefit the most
    • Salvage RT if an undetectable PSA that becomes subsequently detectable and increases on 2 measurements or a PSA that remains persistently detectable after RP
    • PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable levels (PSA persistence) or undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or more determinations (PSA recurrence) or that increases to PSA >0.1 ng/mL
      • Treatment is more effective when pre-treatment PSA is low and PSADT is long.

AUA

• 2023 AUA Guidelines on Clinically Localized Prostate Cancer
  • Adjuvant radiotherapy
    • Should not be routinely recommended
      • Patients should be initially managed with PSA surveillance after radical prostatectomy
    • There may be a role for adjuvant radiation in patients with high-risk features (e.g., Gleason 8 to 10 disease with extraprostatic extension, positive lymph nodes); there were few of these patients in the trials

• 2019 AUA guidelines (published before publication of RCTs comparing adjuvant vs. early salvage)
  • ART should be offered if pT3a disease, positive margin(s), or seminal vesicle involvement
  • SRT should be offered to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease
• 2022 EAU guidelines[2]
  • Only offer adjuvant intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with at least two out of three high-risk features (ISUP grade group 4–5, pT3, positive margins).
  • PSA persistence after surgery
    • Offer a prostate-specific membrane antigen positron-emission tomography (PSMA PET) scan to men with a persistent prostate-specific antigen > 0.2 ng/mL if the results will influence subsequent treatment decisions.
    • Treat men with no evidence of metastatic disease with salvage radiotherapy and additional hormonal therapy.
  • Recommendations for biochemical recurrence (BCR) after radical prostatectomy
    • Offer early salvage intensity-modulated radiotherapy/volumetric arc radiation therapy plus image-guided radiotherapy to men with two consecutive PSA rises.
    • Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has been made, SRT (at least 64 Gy) should be given as soon as possible.

Management of pN1 after radical prostatectomy

• Heterogeneous natural history
  • Up to 30% of patients may remain free of disease long-term following surgery without further therapy.
• Options (3)§
  1. Observation
  2. ADT
  3. EBRT + ADT
  • Observation
    • Retrospective cohort study of 369 patients with pN1 disease found that 28% of males remained free from biochemical recurrence at 10 years.§
  • ADT
    • Eastern Cooperative Oncology Group (ECOG) 7887/3886 (Messing et al. 1999 NEJM)
      • Population: 98 men with pelvic lymph node metastases after RP (cT1-T2 disease) + LND
      • Randomized to immediate (adjuvant) or delayed (detection of distant metastases or symptomatic recurrences) ADT
      • Results:
        • Median follow-up 11.9 years
        • Immediate ADT significantly improved disease-free survival, cancer-specific survival, and OS
      • Interpretation: Adjuvant ADT in patients found to have nodal metastases after radical prostatectomy and pelvic lymph node dissection is associated with improved survival
      • Messing, Edward M., et al."Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy." The lancet oncology 7.6 (2006): 472-479. [Original publication 1999 NEJM]
        • Trial criticisms:
          • Underpowered: the study was designed to enroll 240 patients, yet only enrolled 100
          • Gleason grading was not centralized and the absence of a correlation between histologic grade and survival in the trial suggests an imbalance may exist.
          • Those on delayed ADT experienced disease progression and prostate cancer death that was much more rapid than would have been expected from contemporary N+ patients
      • The magnitude of the difference observed in the ECOG 3886 study has not been seen in larger similar—but not identical—patient populations.
        • EORTC trial (Schröder et al, 2004)
          • Population: 302 pN1-3M0 prostate cancer without local treatment of the primary tumor
          • Randomized to immediate vs. delayed ADT
          • Results:
            • Median follow-up 13 years
            • No significant difference in OS (7.6 vs. 6.1 years)
            • 10-year cumulative incidence of death from prostate cancer was 55.6% in the delayed ADT group versus 52.1% in the immediate ADT group (Schröder et al, 2009); 20.8 patients would need to be treated with immediate ADT to spare one life at 5 years and 28.6 to spare one life at 10 years.
  • EBRT + ADT
    • Retrospective cohort studies from the National Cancer Database found that in patients with lymph node metastases after radical prostatectomy, EBRT + ADT improved biochemical recurrence-free, cancer-specific, and overall survival, compared to ADT alone.
• Patients should be risk-stratified based on pathologic variables (particularly the number of positive nodes identified) and postoperative PSA to guide use of secondary therapy.[3]
  • If undetectable post-operative PSA, consider surveillance with the option of early salvage should the patient experience biochemical recurrence. Adjuvant therapies (e.g. ADT or radiation) are alternatives.
  • If detectable post-operative PSA, salvage therapy with ADT is recommended.
    • The optimal timing (post-operative vs. at biochemical recurrence) of initiating ADT for patients with pN1 remains unknown.

Radiation with long-term ADT

• Radiation with long-term ADT
  • EBRT or EBRT + brachytherapy with concurrent long-term (18 to 36 months) ADT is recommended (2020 NCCN Guidelines PROS-7)
    • EORTC 22863 (Bolla et al. 1997) & RTOG 86-10
      • See Management of Localized Prostate Cancer Chapter Notes
    • The trials above have evaluated the benefit of adding ADT to radiation. It has been questioned whether the benefits of radiation plus ADT are superior to ADT alone for locally advanced disease. These trials have shown that ADT alone is inferior to ADT with radiation.
      • PR3/PR07 trial (Warde et al.) & SPCG-7/SFUO-3
        • See Management of Localized Prostate Cancer Chapter Notes
  • The method of ADT does not affect the outcome of combined treatment with RT.
  • The role of chemotherapy combined with RT is less well studied than that for surgery and chemotherapy.

Primary ADT

• Unlike radical prostatectomy or radiation with ADT, ADT monotherapy has not been conclusively shown to improve overall survival in patients with locally advanced disease
• Bicalutamide Early Prostate Cancer Programme
  • Population: 3,292 men with T1b-4, N0-Nx (N+ not allowed) M0 prostate cancer who had undergone radical prostatectomy or radiotherapy
    • 657 men with locally advanced prostate cancer
  • Randomized to bicalutamide 150mg daily vs. placebo
  • Outcomes: progression-free and overall survival
  • Results:
    • Localized-disease subgroup:
      • No significant difference in progression-free survival (HR 0.93 (0.82–1.06))
      • Almost significantly reduced overall survival (HR 1.15 (1.00-1.32))
    • Locally-advanced subgroup:
      • Significantly improved progression-free survival (HR 0.67 (0.56–0.80))
      • No significant difference in overall survival (HR 0.89 (0.74–1.07))
  • Iversen, Peter, et al."Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow‐up of 9.7 years." BJU international 105.8 (2010): 1074-1081.
• Timing of ADT
  • The most appropriate PSA level at which to institute hormone therapy is unknown
  • MRC Prostate Cancer Working Party Investigators Group trial
    • Population: 934 men with locally advanced or asymptomatic prostate cancer (500 M0, 261 M1, and 173 Mx)
    • Randomized to immediate vs. delayed ADT
    • Results:
      • Immediate ADT associated with significant improved OS and CSS
    • Br J Urol. 1997 Feb;79(2):235-46. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial.
  • EORTC 30891
    • Population: 986 men not suitable for local treatment (refused local treatment; had decreased life expectancy, advanced local tumor stage, and/or severe comorbidities)
    • Randomized to immediate vs.  delayed ADT
    • Results:
      • Immediate ADT resulted in a significant, albeit small, improvement in overall survival but no difference in prostate cancer–specific mortality or overall symptom-free survival
• Compared to castration in men with locally advanced but nonmetastatic disease, both sexual interest and physical capacity were better with bicalutamide (150 mg) monotherapy

Focal ablative therapy

• See Management of Localized Prostate Cancer
• The ability of cryotherapy or high-intensity frequency ultrasound to treat local disease within the prostate may play a role even in men with locally advanced disease, most likely in combination with AD or other systemic therapy.

Questions

1. What is the definition of locally advanced prostate cancer?
2. What are the treatment options for locally advanced disease with proven overall survival benefit ?
3. What is the dose of bicalutamide if used as monotherapy for locally advanced prostate cancer?

Answers

1. What is the definition of locally advanced prostate cancer?
   • T3NX/+M0
2. What are the treatment options for locally advanced disease with proven overall survival benefit ?
   • Radiation with long-term ADT
   • Radical prostatectomy with extended pelvic lymphadenectomy
3. What is the dose of bicalutamide if used as monotherapy for locally advanced prostate cancer?
   • 150mg PO daily

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 118