AUA & ASTRO & SUO: Salvage Therapy for Prostate Cancer (2024)

See Original Guidelines

Literature search up to July 2023

Background

Definitions

• Biochemical recurrence (BCR)
  • Post radical prostatectomy (RP): detectable or rising PSA level ≥0.2 ng/mL on 2 separate determinations after reaching a nadir PSA <0.2 ng/mL and no evidence of metastatic disease on conventional imaging
  • Post radiotherapy (RT): rise in PSA ≥2 ng/mL over nadir (Phoenix criteria) and no evidence of metastatic disease on conventional imaging

Natural history of BCR

• Heterogenous and often prolonged after RP
• High-risk features (9):
  1. Short PSA doubling-time
     • Consistently associated with higher rates of metastases and mortality
  2. Short interval from primary therapy to PSA recurrence (including persistent detectable PSA after prostatectomy)
  3. Grade group 4-5
  4. Stage pT3b-4
  5. Surgical margin status
     • Positive surgical margins has been associated both with an increased likelihood of BCR as well as a lower risk of disease progression after salvage radiation
       • Mixed evidence regarding associations between surgical margin status with metastases and mortality among patients with BCR.
  6. Node-positive disease
  7. Higher post-prostatectomy PSA
  8. Genomic classifier risk
     • A tissue-based genomic score from RP specimens is associated with metastasis risk
  9. PET imaging findings
     • A retrospective study of 302 patients with BCR after surgery found that a positive (11C choline) PET scan was associated with worse survival outcomes
• Several prognostic models have been developed to assess the risk of death from prostate cancer among patients with BCR by combining clinicopathologic variables
  • These models do not provide information regarding the likelihood of response to salvage therapy.
  • Critical to consider competing risks of mortality and the potential adverse health-related quality-of-life impacts of salvage therapy

Diagnosis and Evaluation

UrologySchool.com Summary

• Recommended (2):
  1. History and Physical Exam
  2. Imaging
     • PSMA-PET
       • If PSMA not available, non-PSMA PET recommended over conventional imaging
  3. Other
     1. Prostate biopsy in patients with BCR after radiotherapy or focal therapy
• Optional (2)
  1. Labs:
     • Ultrasensitive PSA in patients with BCR after radical prostatectomy
  2. Imaging
     • Pelvic MRI

Recommended

History and Physical Exam

History

• Assess urinary, bowel, and sexual function prior to salvage treatment using standardized instruments, such as
  • Expanded Prostate Cancer Index Composite [EPIC]-26
  • Functional Assessment of Cancer Therapy Prostate [FACT-P]
  • International Index of Erectile Function [IIEF]
  • Sexual Health Inventory for Men [SHIM]
  • European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-PR25

Imaging

Next generation molecular PET imaging

Rationale

• Detection of disease outside the typical fields covered by salvage radiation (prostate bed and pelvic node fields) may influence salvage therapy approach
  • In patients with BCR after RP, PET imaging has improved sensitivity compared to conventional imaging and results in changes in management
    • Conventional imaging is typically defined as diagnostic CT, multiparametric MRI (mpMRI), and bone scan with technetium-labeled radiotracers.
    • 68Ga-PSMA-11 and 18F-PSMA-1007 PET/CT detected disease in ≈85% with newly diagnosed BCR (mean PSA level of 1.96 ng/mL), compared to ≈50% of disease detected by conventional imaging.
    • 18F-piflufolastat- PET/CT detected disease in ≈45% with newly diagnosed BCR (at a lower median PSA level (0.32 ng/mL), compared to ≈15% with contrast-enhanced CT chest, abdomen, and pelvis.
    • The benefit of PSMA PET/ CT appears to be detecting tumor harboring in nonenlarged lymph nodes and bone metastases and disease outside the pelvis.
  • In patients with BCR after RT or prior ablative therapy, the performance of PET/CT imaging for diagnosis of local recurrence remains undefined

Technique

• PET tracers
  • Classification (2)
    • Non-PSMA agents
      • Options (2):
        1. 18F-fluciclovine
        2. 11C-choline
    • PSMA-targeted agents
      • Differ in physical properties (e.g., radioisotope, radiochemistry, and biodistribution)
      • Options (3):
        1. 68Ga-PSMA-11 or gozetotide
        2. 18F-piflufolastat (formerly 18F-DCFPyL)
        3. 18F-flotufolastat (formerly 18F-rhPSMA 7.3)
      • Test characteristics
        • Positive predictive value (compared to histopathology) ≈85%
        • More specific for prostate cancer than 18F-fluciclovine or 11C-choline
        • Most sensitive for detecting biochemically recurrent prostate cancer, especially outside the prostate bed
        • Detection rates increase with increasing PSA levels
          • PSA <0.5 ng/mL: 30-40%
          • PSA ≥0.5 to <1 ng/mL: 45-55%
          • PSA ≥1 to <2 ng/mL: 55-85%
          • PSA ≥2 to <5 ng/mL: 75-85
          • For PSA ≥5 ng/mL
            • 68Ga-PSMA-11 or gozetotide and 18F-piflufolastat had detection rates of ≈95%
            • 8F-flotufolastat had detection rates of ≈60% between PSA ≥5 to <10 ng/mL and ≈85% for PSA ≥10 ng/
          • A meta-analysis of a very limited number of studies reported a PSMA-PET positive rate of 40% at PSA levels <0.2 ng/mL;  however, few were with pathologic correlation.

Indications

1. Should be performed in patients with BCR following RP in whom salvage radiation is being considered
2. May be obtained instead of conventional imaging or after negative conventional imaging for further evaluation of clinical recurrence for patients with a BCR after local therapy
3. In the absence of PSMA-PET/CT or with known PSMA-negative disease, 18F-fluciclovine-PET/CT is an alternative and preferred over conventional imaging alone.
   • A subset of prostate cancer may not produce PSA or express PSMA, for example poorly differentiated or neuroendocrine prostate cancer. In these instances, 18F-fluciclovine-PET/CT or FDG-PET may be useful to detect and localize recurrent disease.

Prostate Biopsy if BCR after RT or focal therapy

Rationale

• Given the potentially significant side effects from any local salvage therapy, confirming the presence of recurrent prostate cancer is recommended for patients with BCR following primary RT or ablative therapy who have no evidence of metastatic disease and are candidates for local salvage therapy
  • Details of prostate biopsy are important to guide the choice and extent of local salvage therapy
    • If diffuse bilateral cancer recurrence versus isolated to a lobe or region, or if there is positive seminal vesicle involvement
• Local salvage therapy should only be performed after pathologic confirmation of prostate cancer and should not be attempted based solely on positive imaging findings.

Technique

• Biopsy should include the seminal vesicles and targeted biopsy of suspicious areas that may be identified on imaging

Optional

Labs

Ultrasensitive PSA in patients with BCR after RP

• Can provide PSA levels below 0.1 ng/mL (some down to 0.001 ng/mL)
  • A higher detectable ultrasensitive PSA is associated with a greater risk of ultimately progressing to a PSA of 0.2 ng/mL or above
• May identify some patients with residual, benign prostate tissue as well as indolent low PSA recurrence

Indications

• May be obtained in patients who are at high risk of recurrence following RP and in whom salvage RT would be considered.
  • May be helpful in patients at high risk for recurrence in whom early salvage RT (e.g., at levels below 0.2 ng/mL) would be considered given the association of improved outcomes for patients treated with early salvage RT for BCR after prostatectomy
    • See above for high risk features
• Not routinely recommended over standard PSA for surveillance after primary local therapy
  • Unknown if this earlier detection of a detectable PSA, and subsequent treatment for such patients, results in superior oncologic outcomes compared to treatment when the PSA meets the BCR definition of ≥0.2 ng/mL.

Imaging

Pelvic MRI

Rationale

• Many PET tracers are excreted in the urinary tract, which consequently makes prostate bed/bladder neck recurrences hard to identify
• Several observational studies demonstrate that combination of PET and MRI resulted in superior detection of prostate bed recurrences for patients with BCR
  • A study of patients with rising PSA level after RP and/or primary RT (median, PSA 2.27 ng/mL; range, 0.2 to 27.45 ng/mL) and negative conventional imaging found that for prostate bed recurrences, sensitivity was higher with MRI (83% versus 57%) than 18F-DCFPyL PET/CT imaging, while specificity and PPV were higher with PET/CT (only specificity was statistically significant, p=0.02). The combination of 18F-DCFPyL and MRI improved PPV for detecting prostate bed recurrences by 30%.
  • Similar results have also been obtained with a 68Ga-PSMA-based tracer.

Indication

• May be obtained in addition to a PET/CT for evaluation of local recurrence in patients with BCR following RP, RT, or focal therapy.

Not recommended

Labs (1)

1. Genomic testing
   • The Panel does not recommend reflexive use of genomic testing in all patients with BCR being considered for salvage RT.

Management

• Cure is still possible for many of these patients

Non-Metastatic BCR after Primary RP

Patient counselling

• Use prognostic factors (e.g., PSADT, Gleason Grade Group, pathologic stage, surgical margin status, validated postprostatectomy genomic classifier and/or PET imaging results) to counsel patients with a detectable PSA about their risk of clinical progression.
• Inform patients that salvage radiation for a detectable PSA after RP is more effective when given at lower levels of PSA
• Inform patients of the potential harms of salvage radiation after RP.
  • These risks must be considered in the context of the risks posed by recurrent cancer along with patient life expectancy, comorbidities, and preferences to facilitate a shared-decision making (SDM) approach to management.

Timing of salvage therapy

• Engage the patient using SDM when discussing the timing of salvage RT, communicating the potential impact of salvage RT on continence and potency as well as the risk of disease progression associated with delaying additional local therapy
• For patients with a detectable PSA after RP in whom salvage RT is being considered, salvage radiation should be provided when the PSA is ≤0.5 ng/mL.
• For patients with a detectable PSA after RP who are at high risk for clinical progression, salvage radiation may be offered when PSA values are <0.2 ng/mL.
• Salvage prostate bed RT should not be withheld in the setting of a negative PET/CT
  • The detection rate of PET/CT, particularly at low PSA levels, is not high enough to determine that patients would not benefit from salvage RT in the setting of a negative PET/CT
  • Withholding salvage prostate bed RT in patients without detectable lesions on PET/CT may miss a “window” of opportunity to more effectively treat a minimal amount of recurrent disease.

Concurrent Therapy

Androgen deprivation therapy

Indications

• Should be offered if any high-risk feature (6)
  1. Postprostatectomy PSA ≥0.7ng/mL
     • An optimal threshold of PSA to identify patients most likely to benefit from adding ADT has not been rigorously defined
     • There remains uncertainty about the use of concurrent ADT with salvage radiation in patients with PSA values <0.7 ng/mL
  2. Gleason Grade Group 4 to 5
  3. PSADT ≤6 months
  4. Persistently detectable post-operative PSA
  5. Seminal vesicle involvement
  6. Positive findings on PSMA-PET
• For patients with BCR following RP without any high-risk features or extracapsular extension, clinicians may offer radiation alone.
  • AUA Guidelines explicitly mention extracapsular extension for this context, which is not included in the list of high-risk features.
• Randomized trials that compared salvage RT plus ADT versus salvage RT alone (3):
  1. GETUG-AFU 16
  2. RTOG 9601
  3. NRG/RTOG 0534 SPPORT

Adverse Events

• Discuss treatment side effects and the impact of medical comorbidities when patients are being considered for ADT (as well as duration) with salvage RT, utilizing an shared-decision making approach
• Risks of ADT (risks increase with longer-term use)
  1. Cardiac events (coronary heart disease, myocardial infarction, sudden cardiac death
     • Patients with coronary risk factors starting ADT may be referred for comanagement with a cardiologist
  2. Sexual dysfunction
  3. Hot flashes
  4. Gynecomastia
  5. Metabolic syndrome
  6. Diabetes
  7. Weight gain
  8. Grade ≥2 hypertension
  9. Bone mineral density loss and fracture risk
  10. Dementia
• No significant differences between RT versus RT + ADT in terms of urinary or bowel symptoms.

Duration

• A minimum of 4-6 months of hormonal therapy should be provided when providing ADT to patients undergoing salvage RT
  • Different forms and durations of ADT were used in the 3 trials that compared salvage RT with ADT versus salvage therapy alone following RP
    • The shortest durations of ADT across these 3 trials ranged from 4 to 6 months.

• For patients with high-risk features, clinicians may extend ADT to 18 to 24 months
  • Stratified analyses of RTOG 9601 found that longer-term duration of ADT was associated with lower likelihood of progression and death in patients with high-risk factors, including Grade Group 4 to 5 cancer, positive surgical margins, and higher PSA at the time of RT

Timing

• ADT could be initiated concurrently or up to two months prior to initiating salvage RT

Expanding radiation fields to include pelvic lymph nodes

Indications (3)

1. Positive pelvic nodal disease on PET/CT
2. Clinical situation warrants consideration of including elective pelvic nodal irradiation, despite negative PET/CT
   • Sensitivity of nodal involvement with PET/CT at low PSA levels is not high enough to determine patients would not benefit from this treatment.
3. BCR following RP and undergoing salvage RT with ADT
   • NRG/RTOG 0534 SPPORT found 5-year freedom from progression increased by 6% with the addition of pelvic lymph node RT to prostate bed RT + short-term ADT but no significant difference in overall survival

Adverse events

• Gastrointestinal: diarrhea
• Blood or bone marrow: lymphopenia

Other

Docetaxel

• Not recommended in patients undergoing salvage RT and ADT
  • No studies have reported comparative outcomes of docetaxel with standard ADT versus ADT alone in patients undergoing salvage RT
  • Two RCTs have compared docetaxel plus ADT versus ADT alone in patients with BCR after RP and found to significant improvement outcomes

Intensified AR suppression

• Indications
  • For pN0 patients, intensified AR suppression with salvage RT only should only be used within a clinical trial setting
• Several ongoing studies are assessing the role of intensified AR suppression (defined as newer AR pathway inhibitors such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide) with salvage RT

Special scenarios

Detectable PSA but do not meet the AUA definition of BCR after RP (PSA ≥0.2 ng/mL)

• Diagnosis and Evaluation
  • Confirm a rising trend (either two consecutive rises with PSA ≥0.1 ng/mL or consecutive rises at any PSA level) in PSA before proceeding with therapy.

pN1 disease

• Optimal management for patients with pN1 disease post-RP remains to be defined
  • The only randomized trial in this specific patient population is ECOG 3886, which reported that adjuvant lifelong ADT was associated with improved cancer specific survival and OS, albeit in a relatively limited number of patients and with the reference comparator arm consisting of what would today be considered very late salvage therapy
• ADT should be included with post-operative RT, rather than treating with RT alone
  • In several more recent retrospective series, the addition of RT to ADT in this patient population has been associated with improved outcomes

Non-Metastatic BCR after Primary RT

• For patients who demonstrate isolated local recurrence after prior definitive radiation treatment or following partial or whole-gland ablative therapy, local salvage therapy may be a more effective management option than observation or ADT
• Options
  1. Salvage radical prostatectomy
  2. Salvage reirradiation
  3. Salvage ablation (cryoablation or HIFU)
     1. Efficacy between treatments is largely similar at two-year and five-year follow-up
• Counseling regarding local salvage therapy after primary RT should emphasize that there are likely to be higher risk of treatment-related adverse events, particularly impacting patients’ urinary, sexual, and bowel function compared to initial local treatment applying these same therapies in the primary setting
• Salvage RP
  • Can be performed via an open or robotic approach
  • Should incorporate lymphadenectomy to provide complete pathologic staging
  • Technically challenging operation even in the hands of experienced surgeons and is associated with greater risk for urinary incontinence compared to other local salvage treatments
  • Similar severe urinary function toxicity with HIFU, slightly less with cryoablation, and significantly less with reirridation
• Salvage ablation
  • Traditionally have been applied as whole-gland treatments, although these may also be performed as partial gland ablation or focal ablation
• Salvage reirradiation
  • Most common approaches: low-dose-rate (LDR) brachytherapy, high-dose-rate (HDR) brachytherapy, or SBRT
    • Salvage RT approach chosen is generally different from the original radiation treatment
  • Rates and severity of complications for these salvage local treatments are similar

Non-Metastatic BCR after partial or whole-gland ablative therapy

Indications (2)

• Biopsy-proven Grade Group 2 and higher local recurrences
• Life expectancy greater than 5 to 10 years

Options

1. Salvage radical prostatectomy
2. Salvage reirradiation
   • Based on the multifocal nature of prostate cancer, whole gland treatment by RP or RT should be offered in patients for whom salvage local therapy is being considered following focal ablation

Evaluation and Management of Regional Recurrence

• In patients with pelvic nodal recurrence following primary
  • RP, salvage RT to the prostate bed and pelvic lymph nodes should be offered
  • RT who did not receive prior pelvic nodal RT, salvage RT to the pelvic lymph nodes plus ADT should be offered
    • Options in patients that received prior pelvic nodal RT (3):
      1. Salvage lymphadenectomy
      2. Re-irradiation (e.g., with SABR])
      3. ADT alone
• Salvage pelvic lymphadenectomy
  • May be offered for patients with evidence of pelvic lymph node recurrence after RP or RT
  • Patients should be counseled regarding the uncertain oncologic benefit from surgery in this setting.

Management for Molecular Imaging Metastatic Recurrence

• The standard treatment for metastatic prostate cancer includes intensified systemic therapy in addition to ADT based on high-quality evidence.
• In patients with evidence of regional or metastatic oligorecurrence following primary therapy (RP or RT), SABR metastasis-directed therapy (MDT) may be performed but should consider the risk of toxicity versus benefits.
  • The definition of oligometastatic varies, and generally means limited skeletal or nodal metastases, but there is no defined number of metastases that is universally accepted.
  • Clonal evolution studies demonstrate that metastases are capable of spreading not only from the primary tumor but also from other metastatic sites
  • In this oligometastatic setting, there have been attempts to incorporate MDT in order to minimize or delay the need for systemic therapy and prolong PFS, with the ultimate intent to improve OS.
    • MDT may be offered to patients with oligorecurrent disease who are motivated to achieve time off of systemic therapy
• In patients with BCR who have non-regional disease seen on PET/CT but no visible disease on conventional imaging, salvage RT to the prostate bed may be omitted and the uncertain role of systemic therapy in this setting should be discussed
  • Historically, patients with BCR after RP and negative conventional imaging received salvage RT with curative intent as standard of care. A portion of these patients had subclinical metastatic disease that would be visible with PET/CT today. Whether these patients with conventional imaging negative, but PET/CT positive metastatic disease benefit from salvage RT is unknown. It may be reasoned that patients with metastatic prostate cancer are unlikely curable with local therapy; therefore, omitting salvage RT is reasonable.
  • Treating these patients using an oligometastatic disease paradigm, which could include salvage RT to the prostate bed and metastatic areas, remains a reasonable approach
  • Meanwhile, the benefits of systemic therapy, including treatment intensification beyond ADT with the use of chemotherapy and androgen receptor signaling inhibitors (ARSIs), has been demonstrated in clinical trials for patients with metastatic disease on conventional imaging.
  • Whether these benefits exist for patients with conventional imaging negative and PET/CT only detected disease has not been proven to date. Simply applying clinical trial data to conventional imaging negative patients risks potential overtreatment of many of these patients

Questions

1. What is the definition of biochemical recurrence?
2. What are the high-risk features associated with worse clinical outcomes in patients with BCR?
3. What are the randomized trials that have evaluated the benefit of ADT in patients with BCR after radical prostatectomy undergoing salvage radiation?

Answers

1. What is the definition of biochemical recurrence?
   1. Post radical prostatectomy (RP): detectable or rising PSA level ≥0.2 ng/mL on 2 separate determinations after reaching a nadir PSA <0.2 ng/mL
   2. Post radiotherapy (RT): rise in PSA ≥2 ng/mL over nadir Phoenix criteria)
2. What are the high-risk features associated with worse clinical outcomes in patients with BCR?
   1. Short PSA doubling-time
   2. Short interval from primary therapy to PSA recurrence (including persistent detectable PSA after prostatectomy)
   3. Grade group 4-5
   4. Stage pT3b-4
   5. Surgical margin status
   6. Node-positive disease
   7. Higher post-prostatectomy PSA
   8. Genomic classifier risk
   9. PET imaging findings
3. What are the indications for concurrent ADT with salvage radiation?
   1. Postprostatectomy PSA ≥0.7ng/mL
   2. Gleason Grade Group 4 to 5
   3. PSADT ≤6 months
   4. Persistently detectable post-operative PSA
   5. Seminal vesicle involvement
   6. Positive findings on PSMA-PET

References

• Morgan, Todd M., et al. "Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline part I: introduction and treatment decision-making at the time of suspected biochemical recurrence after radical prostatectomy." Journal of Urology 211.4 (2024): 509-517.