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MANAGEMENT OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY & RADIATION THERAPY
Evaluation and Management
of Prostate-specific Antigen
Recurrence After Radical
Prostatectomy for Localized
Radical prostatectomy(RP)- the primary curative
procedure for the treatment of localized prostate
Approximately one third of all patients still
demonstrate disease recurrence after surgery.
For the majority, first sign of recurrent disease is a
rising PSA level without either clinical or
radiographic evidence of disease—the so-called ‘PSA
recurrence’ or ‘biochemical failure’.
Rising PSA levels after RP may be due to 1. a local
recurrence in the prostatic bed, 2. occult distant
metastases or 3. a combination of both.
Quite difficult to identify recurrent lesions accurately
at an early stage of PSA recurrence.
Local recurrence may be cured using salvage
external-beam radiotherapy, whereas distant
metastases require systemic hormonal therapy.
Majority of patients with PSA recurrence after RP-
relatively young and healthy; hence treatment for
PSA recurrence should aim not only to improve
survival but also to preserve the quality of life.
PSA is a glycoprotein produced primarily by
epithelial cells lining the acini and ducts of prostate
Serum PSA levels are normally very low.
Elevated serum PSA level-d/t disruption of normal
prostatic architecture- an important marker of many
prostate diseases- BPH, prostatitis, and prostate
• The standard approaches for men with organ-
confined T1/T2 prostate cancer are
– radical prostatectomy (RP)
– external beam radiation therapy (EBRT),
– brachytherapy, and
– active surveillance
Choice of therapy is largely a matter of patient
No evidence that cure rate is different with RP,
EBRT, or brachytherapy when patients are stratified
based upon prognostic characteristics.
Intermediate- or high-risk T1/T2 prostate cancer
For these patients definitive treatment rather than
Intermediate-risk disease- EBRT, brachytherapy, or
High-risk disease- ADT plus EBRT or RP plus
Advantages of main treatment for early prostate
Effective long term control with high dose Rx
Low risk of urinary incontinence
Wide range of ages
When combined with hormonal therapy, offers a
chance of cure in high-risk of disease
Treatments can eradicate extension of tumor beyond
the margins of prostate
Advantages of main treatment for early prostate
Cancer control rate equal to surgery and EBRT for
Quicker than EBRT (one treatment)
Available for cure in a wide range of ages and in
those with comorbidities
Advantages of main treatment for early
prostate cancer: Radical Prostatectomy
Effective long-term cancer control
Prediction of prognosis can be more precise based on
pathologic features in specimen
Pelvic lymph node dissection is possible through the
PSA failure easy to predict
Advantages of main treatment for early
prostate cancer: Active Observation
Avoids or postpones treatment-associated
Has no effect on work or social activities
Contraindications to main treatment options for
early prostate cancer
RP: High operative risk, ‘medical age’ of 70 or more,
neurogenic bladder, morbid fear of surgery
Active observation: High grade tumors, pt
preference, expected survival of 10 or more years.
DEFINITION OF PSA RECURRENCE
PSA usually reaches an undetectable level within 21–
30 days after radical prostatectomy.
Persistently detectable or subsequent rising serum
PSA levels (typical limit of detection is 0.05 ng/ml)
after RP indicate either residual prostate cancer or
AUA Guideline Update Panel recommended using a
cut point ≥ 0.2 ng/mL, with a second confirmatory
level ≥ 0.2 ng/mL, to define surgical failure.
Memorial Sloan-Kettering Cancer Center (MSKCC)
demonstrated best cut point to predict the
probability of metastatic progression was > 0.4
ng/mL, followed by another rise.
EAU guidelines on prostate cancer: serum PSA
level of >0.2 ng/ml- residual or recurrent disease &
major risk of progression when the PSA level
reaches 0.4 ng/ml.
Prostate-Specific Antigen Working Group
recommendation: PSA value ≥ 0.4 ng/mL, 8 weeks
or more after RP and rises on a subsequent
Eight weeks is ample time to allow PSA levels to
clear, given a half-life of 2 to 3 days.
EAU guidelines for follow-up of prostate cancer after
treatment with curative intent, PSA measurement +
DRE at 3, 6 and 12 months after treatment, then
every 6 months until 3 years, and thereafter
45% developed recurrence in first 2 years after RP,
76% within first 5 years, and the remaining 23% >5
years after surgery. Hence a prolonged PSA follow-
up is necessary after RP.
No definite consensus regarding PSA cut-off point
for defining PSA recurrence after RP, a PSA level of
0.2 ng/ml on conventional assays is the most
acceptable cut-off point for PSA recurrence based on
a clinical point of view.
PSA RECURRENCE AFTER RADIATION
Biochemical failure after radiation therapy (ASTRO)
as three consecutive PSA rises, optimally separated
by 3 months between measurements, beginning at
least 2 years after the start of radiation therapy.
Time of failure is midpoint between the nadir and
the first confirmed rise, or any rise significant
enough to trigger therapy.
ASTRO Phoenix Criteria recommend that
biochemical failure be defined as a PSA rise of 2
ng/mL above the post-treatment nadir, whether or
not the patient received hormonal therapy in
conjunction with radiation therapy.
The date at which that level was reached would be
the date of relapse.
FACTORS PREDICTING PSA
RECURRENCE AFTER RP
Local extent of disease on a DRE (T stage), serum PSA
level and Gleason score from prostate biopsy
specimens- all are important factors for predicting
pathological stage (pT stage) for clinically localized
Partin Tables combine clinical stage, Gleason score,
preop PSA level to predict pathologic stage:
1. Organ confined
2. Extracapsular (extraprostatic) extension
3. Seminal Vesicle invasion
4. Lymph node mets
Pretreatment risk stratification for prostate
Using Partin tables, information regarding the
probability of various pathological stages, such as
organ-confined disease, extraprostatic extension,
and seminal vesicle or lymph node involvement, is
Such pathological stages can serve as an excellent
surrogate for outcome after RP.
For majority of patients, biochemical relapse occurs
far earlier than the development of radiographically
evident findings or findings on physical examination
or by biopsy.
Low pretreatment PSA levels, lower-grade tumors,
low clinical or pathologic staging, late time from
definitive local therapy to PSA relapse, and long
PSADTs generally indicate a low likelihood of
developing distant radiographically apparent
Serum PSA level between 10 and 20 ng/ml-
intermediate risk for PSA recurrence, while serum
PSA level >20 ng/ml represent a high-risk for
developing PSA recurrence after RP.
Gleason grade ≥4, or a Gleason score >7 on RP
specimens is predictive of a high-risk for PSA
Histopathological determinants and molecular
markers have been evaluated to predict PSA
recurrence and survival.
p53 tumor suppressor gene expression, bcl-2
protooncogene expression, expression of Ki-67 &
p27, apoptotic index, DNA ploidy and tumor
angiogenesis (microvessel density):- all are possible
predictive factors of PSA recurrence after RP.
TESTS TO DETERMINE SITE OF
Current methods of detecting recurrence whether in
prostatectomy bed, an irradiated gland, or metastatic
sites such as bone or lymph nodes, are of very limited
Bone scintigraphy will only detect metastatic disease
that interferes with normal osteoblast/osteoclast
interactions to produce abnormal bone deposition.
Areas of marrow involvement that do not impact bone
metabolism will remain undetected.
No single PSA value predicts scan positivity,
although PSAs will be well above 20 to 30 ng/mL
before bone scintigraphy reflects metastatic disease.
Tracer uptake in areas of trauma, infection, or
inflammation can easily be mistaken for metastatic
CT scans are not sufficiently sensitive for detecting
local recurrence until increasing rate of PSA becomes
>20 ng/ml per year.
CT is suboptimal for detection of metastasis as it has
a lower limit of detection of 0.5 cm & the scans are
nonspecific, making it difficult to distinguish scar
tissue or fibrosis from tumor.
Sensitivity & specificity of MRI and MR
spectroscopy are improving; most useful for
detecting nodal and bony metastases. But not
sufficiently useful early in the course of PSA
Positron emission tomography (PET-CT
using FDG, 18F choline, 11C choline, 11C acetate), a
biochemical imaging modality, still investigational,
cannot accurately distinguish post-operative scars
from local recurrence.
PROSTASCINT (Antibody based imaging/
Approved by the U.S. FDA to detect occult metastatic
disease in early prostate cancer, also indicated for a
rising PSA and a negative or equivocal standard
metastatic evaluation when there is a high clinical
suspicion of metastatic disease.
Based on a murine antibody, 7E11, combined with
indium-111 to target the internal domain of PSMA, a
transmembrane type II glycoprotein found on normal
prostate tissue and prostate cancers.
PREDICTING LOCAL Vs SYSTEMIC
Combination of Gleason score, pathological stage
and serum PSA velocity 1 year after surgery best
distinguished local recurrence from distant
PSADT and Gleason score are highly prognostic for
TREATMENT OF PSA RECURRENCE
Depends on the site of recurrence: namely local,
systemic or a combination of both.
Treatment options for presumed local recurrence
include external beam radiotherapy and, for
presumed distant metastasis, hormonal therapy.
Observation only is also one of the treatment options
regardless of recurrence site.
Routine tests cannot identify site of recurrence
untilnPSA reaches 20–50 ng/ml, at which level
effectiveness of radiotherapy can no longer be
Therefore, treatment is mainly selected according
to the pathological findings of RP specimen and
post-operative serum PSA parameters.
Natural course from PSA recurrence to development
of metastatic disease or prostate cancer-specific
death is quite long.
Hence observation with delayed hormonal therapy
for symptomatic or metastatic disease can be a valid
Salvage radiotherapy is the recommended
terminology for curative-intended radiation for
post-operative PSA recurrence as opposed to
adjuvant radiotherapy administered shortly after
RP based on adverse pathological findings.
Candidates must have a life expectancy of >10
years, since salvage radiation therapy is sometimes
associated with high morbidity.
Preoperative PSA level, pre-radiotherapy PSA level
and seminal vesicle involvement are significant
risk factors for actuarial biochemical disease-free
survival following post-operative radiotherapy.
ASTRO Consensus Panel demonstrated a serum
PSA level of 1.5 ng/ml as the threshold level for
optimal success rates.
European Consensus Group recommended a PSA
level of 1.0–1.5 ng/ml as appropriate cut-off point
to initiate salvage radiotherapy for presumed local
Dose of radiation:
ASTRO Consensus Panel- 64.8Gy radiation to the
European Consensus group- 64 Gy, with 1.8-2.0 Gy
Predictors of disease progression following salvage
radiotherapy: negative/close margins, an absence
of extracapsular extension, presence of seminal
vesicle invasion, a Gleason score of 8–10, a pre-
radiotherapy PSA level >2.0 ng/ml, a PSA doubling
time of ≤10 months.
Hormonal therapy may increase sensitivity to
irradiation, may be effective for possible distant
metastases in such patients.
But the European Consensus Group mentioned
that hormonal therapy is not standard in patients
receiving salvage radiotherapy.
Androgen deprivation therapy by surgical(B/L
scotal orchiectomy) or medical castration using a
LH-RH agonist or antiandrogens may improve
PSA level at which hormonal therapy should be
initiated remains unclear, though time to
metastatic disease was delayed on starting at PSA
level ≤5 ng/ml than at PSA level ≤10mg/dl.
INTERMITTENT HORMONAL THERAPY- this
concept introduced to avoid the side effects of
Long-term efficacy remains unclear.
Finasteride may have an ability to delay disease
progression patients in PSA recurrence after RP;
long-term studies are required.
Clinical state of “Rising PSA/Biochemical
recurrence” after RP- second in size only to localized
Unique in that patients are characterized by an
absence of symptoms, radiographic findings or
pathologic findings—standard measures of treatment
PSADT is one of the most common elements for
stratifying patients & allocating Rx.
Patients can be divided into three groups based on
low-risk patients are unlikely to develop metastases
or symptoms or die of their disease and should be
intermediate-risk patients receive androgen
deprivation or can be considered for investigational
approaches designed to slow the disease to the point
where the patient dies of other causes; and
high-risk patients (those with PSADTs of ≤9 months)
can be considered for androgen deprivation or ideally,
enrolled in a clinical trial(TAX3503- Docetaxel 10
cycles; Mitoxantrone & Prednisone).