Gurdarshan S. Sandhu, MD
Gerald L. Andriole, MD, FACS
BASICS
DESCRIPTION
• Biochemical recurrence following radical prostatectomy is a clinical state characterized by a detectable and increasing serum prostate specific antigen (PSA) after radical prostatectomy in the absence of detectable disease based on current imaging modalities
• Men with a biochemical recurrence fall into 3 groups
– Those with a PSA that fails to fall to undetectable after surgery (persistent disease)
– Those with an initially undetectable PSA after surgery that subsequently increases on 2 or more tests (recurrent disease)
– Those with stable but low PSA levels (rare)
Attributed generally to residual benign disease
• Generally defined as detectable or rising PSA value after surgery that is ≥0.2 ng/mL with a 2nd confirmatory level ≥0.2 ng/mL
EPIDEMIOLOGY
Incidence
Up to 30% of men will develop a biochemical recurrence after radical prostatectomy in large, institutional, long-term follow-up series (1)
Prevalence
Based on the estimated probability of relapse after surgery OR radiation therapy, more than 50,000 American men have biochemical recurrence without other detectable disease (2)
RISK FACTORS
• Biochemical recurrence is predicted by several factors:
– Advanced pathologic tumor stage (3)
Adverse features include positive surgical margins, non-organ confined disease, seminal vesicle invasion, and lymph node metastases
– High Gleason score
– High preoperative PSA
• In addition to the risk factors above, risk factors for the development of clinical metastases and prostate cancer related mortality include:
– Time to biochemical recurrence
– PSA doubling time (PSADT) after recurrence
Genetics
See “Prostate cancer, general considerations”
PATHOPHYSIOLOGY
• In a patient with biochemical recurrence, it is important to try to distinguish local from systemic
– In general, low preoperative PSA, lower Gleason grade, lower tumor stage, prolonged time from surgery to biochemical recurrence and long PSADT are more suggestive of local recurrence
– Conversely, higher stage, higher Gleason score, shorter (<2 yr) time to biochemical recurrence and shorter (<3–6 mo) doubling time suggest distant disease
ASSOCIATED CONDITIONS
• Biochemical recurrence of PSA after surgery when the PSA after surgery was initially undetectable generally precedes metastatic progression and prostate cancer specific mortality by a median of 8 and 13 yr, respectively (4)
– Importantly, not all men with biochemical recurrence will develop metastases or die of prostate cancer (1)
– PSADT after recurrence is an important factor in assessing the risk of subsequent metastases and prostate cancer mortality
GENERAL PREVENTION
Although proper surgical technique can limit the risk of PSA recurrence it cannot be guaranteed to do so due to varying tumor biology
DIAGNOSIS
HISTORY
• Preoperative PSA
• Time since surgery
• Pathologic information from the radical prostatectomy
• Postoperative continence and erectile function
– Timing of adjuvant/salvage therapy after surgery may be affected by the patient’s functional recovery
PHYSICAL EXAM
Digital rectal exam to palpate for local recurrence in the prostate bed
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Serial surveillance of PSA after biochemical recurrence is necessary to monitor disease progression and response to additional treatment if offered
– PSADT assessment (can be calculated using widely available online calculators)
– PSA level can vary depending on the lab assay used so use of the same laboratory recommended for serial follow-up
• Baseline testosterone to guide future therapy
Imaging
• Imaging evaluation is necessary to determine if distant metastases are present under some circumstances (eg, short time to recurrence, short PSADT, rapid rise in PSA)
– Computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen/pelvis
Identify local recurrence or lymphadenopathy
Multiparametric MRI has an emerging role in this setting and appears to be more sensitive than CT in detecting local recurrence
– Bone scintigraphy to evaluate for bony metastases
Unlikely to be positive unless the PSA is generally >20 ng/mL
– ProstaScint is approved by the US Food and Drug Administration (FDA) to detect occult metastatic disease in patients with early prostate cancer
Is associated with a significant number of false positive and false-negative results
– Positron emission tomography/computed tomography (PET-CT), with choline
Approved by the FDA in September 2012
Falsely positive PET scans can be observed in 15–47% so confirmatory tissue sampling of abnormalities detected with PET-CT is required
Diagnostic Procedures/Surgery
Transrectal ultrasound guided biopsy of the prostate bed may be helpful only if imaging or digital rectal exam suggest local recurrence
ALERT
“Blind biopsies” of the prostate bed in the absence of evidence to suggest locally recurrent disease have a low yield, often do not affect decision making, poorly predict the efficacy of salvage radiation and should not be a standard of care.
Pathologic Findings
Dictated by pathology from the radical prostatectomy. Often positive surgical margins or seminal vesicle invasion is noted
DIFFERENTIAL DIAGNOSIS
• PSA elevation due to residual benign epithelium after prostatectomy
• Local recurrence of adenocarcinoma
• Systemic recurrence of adenocarcinoma
• Local and systemic recurrence of adenocarcinoma
TREATMENT
GENERAL MEASURES
• Close monitoring of the serum PSA postoperatively. NCCN Guidelines recommend PSA every 3 mo if high risk or 6–12 mo up to 5 yr, then annually thereafter; annual DRE
• Follow up treatment decision primarily based on pathology, imaging, and PSA dynamics
• Can include observation, androgen ablation, or pelvic radiation
• Careful observation can be considered with slow PSADT, in older patients with other comorbidities
MEDICATION
First Line
• Androgen deprivation therapy (ADT)
– ADT drug classes include Gonadotropin-Releasing Hormone(GnRH) agonists (eg, goserelin, histrelin, leuprolide, and triptorelin) and antagonists (Degarelix)
– Depot injections of the GnRH agonists allow dosing to extend from 28 days up to 1 yr
– GnRH antagonist dosing is every 28 days
– See “Prostate Cancer, metastatic” for more information on drug classes
• No data are available on the optimal PSA value at which to initiate treatment
– ADT is potentially detrimental to cognitive function, quality of life, sexual health, cardiovascular risk, and bone integrity
– Timing of initiation of ADT should be based on a patient’s risk of metastatic progression and risk of death from disease as opposed to absolute PSA levels
– When ADT is initiated, in the absence of metastases, intermittent ADT is preferred to continuous ADT given the side effects of this treatment and the non-inferior overall survival of intermittent ADT (6)
– With the benefits that have been observed with adjuvant/salvage radiation, the role of ADT as monotherapy may be somewhat limited
Second Line
See “Prostate Cancer, metastatic” and “Prostate Cancer, rising PSA following androgen ablation” for more information on additional drug classes
SURGERY/OTHER PROCEDURES
• Scrotal orchiectomy
– Can be used instead of ADT
Is more cost effective than ADT
Does not allow for intermittent androgen deprivation
– Quickly achieves castrate levels of testosterone (<50 ng/mL) within 24 hr
– Subcapsular scrotal orchiectomy can also be offered in lieu of ADT
May help avoid the psychological consequences of an empty scrotum
ADDITIONAL TREATMENT
Radiation Therapy
• Patients with demonstrable disease in the prostate bed or those with suspected local recurrence may be considered for adjuvant/salvage radiation
– Favorable responses to adjuvant/salvage radiation are associated with low PSA levels prior to radiation(<1 ng/mL), long PSADTs, lower Gleason scores, longer time to biochemical recurrence and positive surgical margins
– Adjuvant or early salvage radiation (based on a lower PSA trigger value) should be considered for patients with positive margins, extraprostatic extension, and seminal vesicle invasion (3)
Such therapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer (3,7)
The impact on subsequent metastases, prostate-cancer specific mortality, and overall survival is less clear (3,7). The survival benefit was established in one randomized trial but was refuted in another randomized trial, which was not powered to look at this outcome (3,7)
Adjuvant/early salvage radiation is well supported by randomized trials for patients with adverse pathology at the time of prostatectomy and is endorsed by AUA/ASTRO Guidelines
Additional Therapies
Clinical trials should be available and offered
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Prognosis is dictated by several variables including:
– Preoperative PSA
– Pathologic Gleason score
– Pathologic tumor stage
– Time to biochemical recurrence
– PSADT: <3–6 mo associated with the development of metastatic disease
• For those patients that progress after biochemical recurrence, in general, metastatic progression and prostate cancer specific mortality occur at a median of 8 and 13 yr after biochemical recurrence (4)
COMPLICATIONS
• Patient anxiety
• Complications are dictated by adjuvant and salvage therapy offered
– Either radiation or ADT
FOLLOW-UP
Patient Monitoring
• Monitoring of serum PSA is necessary to diagnose biochemical recurrence and the response to treatment when/if it is offered
• For patients on ADT, baseline and periodic assessment of bone density is recommended
– If PSA begins to rise on ADT, serum testosterone should be assessed to ensure a castrate level
Patient Resources
• NCCN. http://www.nccn.org/patients/patient_guidelines/prostate/index.html
• American Cancer Society. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-recurrence
REFERENCES
1. Roberts WB, Han M. Clinical significance and treatment of biochemical recurrence after definitive therapy for localized prostate cancer. Surg Oncol. 2009;18(3):268–274.
2. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163(6):1632–1642.
3. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: ASTRO/AUA guideline. J Urol. 2013;190(2):441–449.
4. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281(17):1591–1597.
5. Alfarone A, Panebianco V, Schillaci O, et al. Comparative analysis of multiparametric magnetic resonance and PET-CT in the management of local recurrence after radical prostatectomy for prostate cancer. Crit Rev Oncol Hematol. 2012;84(1):109–121.
6. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367(10):895–903.
7. Stephenson AJ, Bolla M, Briganti A, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol. 2012;61(3):443–451.
ADDITIONAL READING
• NCCN Practice Guidelines Version 1.2014 http://www.nccn.org./ (Accessed January 6, 2014).
• Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190(2):441–449.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, General
• Prostate Cancer, Locally Advanced (Pathologic T3, T4)
• Prostate Cancer, Metastatic (Clinical and Pathologic N+, M+)
• PSA elevation, General Considerations
• PSA, General Considerations
• Reference Tables: TNM: Prostate Cancer
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 790.93 Elevated prostate specific antigen [PSA]
• V45.77 Acquired absence of organ, genital organs
ICD10
• C61 Malignant neoplasm of prostate
• R97.2 Elevated prostate specific antigen [PSA]
• Z90.79 Acquired absence of other genital organ(s)
CLINICAL/SURGICAL PEARLS
• Distinguishing local from systemic disease recurrence dictates adjuvant/salvage therapy options.
• Adjuvant/early salvage radiation is supported by randomized trials for patients with adverse pathology at the time of prostatectomy and is endorsed by AUA/ASTRO Guidelines.