Prostate carcinoma- biochemical recurremce

MANAGEMENT OF BIOCHEMICAL RECURRENCE
AFTER DEFINITIVETHERAPY FOR LOCALISED
PROSTATE CANCER
DEPT OF UROLOGY
GOVT ROYAPETTAH HOSPITALAND KILPAUK MEDICAL COLLEGE
CHENNAI
Dept of Urology, GRH and KMC, Chennai.
1

MODERATORS:
Professors:
• Prof. Dr. G. Sivasankar,M.S., M.Ch.,
• Prof. Dr.A. Senthilvel,M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan,M.S., M.Ch.,
• Dr. R. Bhargavi,M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam,M.S., M.Ch.,
• Dr. D.Tamilselvan,M.S., M.Ch.,
• Dr. K. Senthilkumar,M.S., M.Ch.
2

BIOCHEMICAL RECURRENCE AFTER
• RADICAL PROSTATECTOMY
• RADIATIONTHERAPY
• CRYOTHERAPY
• HIFU
3

RADICAL PROSTATECTOMY
Radical prostatectomy(RP)- the primary curative procedure for the treatment of localized
prostate cancer.
Approximately one third of all patients still demonstrate disease recurrence after
surgery.
F o r 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’.
4

• A significant portion of men will have a detectable PSA level that plateaus and does not
progressively rise.
• 1. Residual benign disease is left in the prostatic bed
• 2. PSA is produced at very low levels by cells of nonprostatic origin
• 3. PSA elevation is a result of residual low-grade prostate cancer destined to follow an indolent
course
5

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.
6

DEFINITION OF PSA RECURRENCE AFTER RP
PSA usually reaches an undetectable level within21–30 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 recurrence.
7

AUA Guideline Update Panel recommended using a cut of 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 of point
to predict the probability of metastatic progression was > 0.4 ng/mL, followed by
another rise.
8

E AU 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 AntigenWorking Group recommendation:PSA value ≥ 0.4
ng/mL,8 weeks or more after RP and rises on a subsequent measurement.
8 weeks is ample time to allow PSA levels t
to clear, given a half-life of 2 to 3
days.
9

PREDICTION OF BIOCHEMICAL RECURRENCE AFTER PROSTATECTOMY
ONLINE RISK STRATIFICATION NOMOGRAMS FOR PROSTATE CANCER
10

11

12

IMAGING IN PATIENTSWITH BIOCHEMICAL RECURRENCEAFTER
RADICAL PROSTATECTOMY
• Bone scan in patients with PSA levels less than 10 ng/mL is of limited value because
only 4% will demonstrate a positive scan
• CT is unlikely to be positive in patients with PSA levels less than10 ng/mL
13

• TRUS - reasonable sensitivity at low PSA levels, especially with masses at the
vesicourethral anastomosis
• TRUS followed by biopsy - 100% sensitivity in patients with a PSA level of 2.0 ng/ mL or
greater.
14

PROSTASCINT
• Indium-111 capromab pendetide scanning ( Cytogen,Princeton, NJ ) incorporates an immunoglobulin G
monoclonal antibody that binds to PSMA
• Its use in biochemical recurrence - limited because sensitivities and specificities are 60% to 70%
• Another limitatioin - the monoclonal antibody has been found to bind to intracellular domains exposed
only at apoptosis or necrosis
• Newer generation antibodies such as J591,which are more specific to the external components of PSMA,
are promising for both prostate cancer detection and potential therapy
15

POSITRON EMISSIONTOMOGRAPHY (PET)/CT SCAN
• Gained popularity in the recurrent prostate cancer population
• 18F-fluoro-2-deoxy-D-glucose (FDG) - limited by low sensitivity secondary to modest glucose
consumption in prostate cancer cells, similar uptake in benign tissue or postoperative scar, and high
urinary excretion limiting anatomic delineation
• Acetate, choline, and fluorocholine – high sensitivity
16

• U.S. Food and DrugAdministration approved choline PET for the detection of prostate cancer
recurrence
• Two radiotracers for choline
• 11C-choline - advantage of low urinary excretion and quality pelvic imaging.
• 18F-choline - higher urinary excretion but has a longer half-life
17

• The validity of choline PET has been seen at PSA levels below 2.5 ng/mL,because up to 90% of patients
will demonstrate positive scans with a specificity of 50%
• PET scan with choline may be limited in patients with very low levels of PSA recurrence,because only
half will be positive in patients with PSA levels less than 1.0 ng/mL
18

• C11-acetate PET scans - sensitivity as high as 75% with a median PSA level of 2.0 ng/mL
• 18F-Fluciclovine PET/CT - Higher sensitivity than choline PET/CT in detecting site of relapse
• 18F-Fluciclovine has been approved in the US and Europe,
• Currently, the only Pca specific radiotracer widely commercially available
19

• PSMA PET/CT ( 68Ga-PSMA-11,18F labelled PSMA ) – More sensitive than Choline
PET/CT especially for PSA < 1ng/ml
20

• PET/CT has demonstrated promise in the detection of prostate cancer
recurrence;
• its clinical utility is still questionable because salvage therapies are most
effective at lower levels of PSA and awaiting the conversion of PET scans to
positive may delay potential curative therapy
21

• MRI can be used in the detection of local recurrence after biochemical failure
• Compared to PET/CT,multiparametric MRI performs better in identification
of local recurrence, especially at low levels of biochemical failure
22

EAU GUIDELINES FOR IMAGING
23

TREATMENT OPTIONS
• Salvage RadiationTherapy
• Concurrent Androgen DeprivationTherapy with Salvage Radiation
• Adjuvant RadiationTherapy
• Androgen DeprivationTherapy
24

SALVAGE RADIATION THERAPY
• Salvage radiation therapy remains the clearest choice and best chance for
long-term freedom from progression.
• At least 66 Gy to prostatic fossa ( depending on pathological stage after RP)
• Failure after salvage radiation therapy can be due to persistent local disease, recurrence
of local disease, persistence of metastasis, or development of metastatic disease.
25

CONCURRENTANDROGEN DEPRIVATIONTHERAPYWITH
SALVAGE RADIATION
• Theoretically, the use of systemic therapy with androgen deprivation may sterilize
micrometastatic disease, shrink tumor burden making it more amenable to local salvage
therapy,and potentially work in synergy with radiation therapy to treat remaining cancer
cells.
• only the patients in the high-risk group (Stage- >pT3 , Gleason score >/=8 or PSA level
>/=20 ng/mL ) benefited from the addition of androgen deprivation
26

ADJUVANT RADIATION THERAPY
• After radical prostatectomy,patients at high risk for local recurrence are offered
radiation therapy to prolong the disease-free interval
• Typically, this is administered 4 to 6 months after radical prostatectomy when the PSA is
still undetectable and when patients have regained urinary continence
27

• Recent AUA guidelines
• “Physicians should offer adjuvant radiotherapy to patients with adverse pathologic
findings at prostatectomy including seminal vesicle invasion, positive surgical
margins, or extraprostatic extension because of demonstrated reductions in
biochemical recurrence, local recurrence, and clinical progression”
28

ANDROGEN DEPRIVATIONTHERAPY FOR BIOCHEMICAL FAILURE
AFTER RADICAL PROSTATECTOMY
• Patients at the highest risk for local and systemic recurrence are most likely
benefit from adjuvant hormone therapy.
• GS >7, PSADT <12months
29

GUIDELINES FOR SECOND LINETHERAPYAFTERTREATMENTWITH CURATIVE INTENT
30

PSA RECURRENCE AFTER DEFINITIVE RADIOTHERAPY
31

• ASTRO DEFINITION (American Society forTherapeutic Radiology and Oncology)
- After 2 yrs of treatment, 3 consecutive rise in PSA at 3-4 months apart
- Date of failure is half way between nadir & 1st failure rise.
• PHOENIX DEFINITION
Any rise in PSA value of >/= 2 ng/ml above the NADIR value,irrespective of whether either
of these treatments[EBRT/BT] was accompanied by androgen deprivation therapy
32

POSTRADIATION PSA BOUNCE
• An elevated PSA of 0.1 to 0.5 ng/mL over the prebounce PSA level, with a subsequent
decrease in PSA level
• Occurs secondary to post-treatment prostatitis or even from the delivery of a sublethal
dosage of radiation with associated delayed cellular death.
• Decreases after 6 to 9 months
33

BIOPSY AFTER RADIOTHERAPY
• The goals - to identify the presence or absence of locally residual or recurrent disease
and to identify the grade of remaining disease.
• Biopsies to be performed at least 2 to 3 years after the completion of radiation therapy
to decrease the rates of false-positive and false-negative biopsies.
34

• Biopsy based on ultrasound or MR guidance should target abnormal lesions, the seminal vesicles, and a
systematic sampling of the entire prostate gland
• Tumor architecture is altered after radiation therapy and may represent dedifferentiation of cancer cells
• Gleason grading after radiation therapy may or may not be accurate and its utility is controversial
35

IMAGING AFTER BIOCHEMICAL RECURRENCE
FOLLOWING RADIOTHERAPY
• Challenging with traditional modalities because of fibrosis and shrinkage of the prostate
• TRUS has limited ability to identify suspicious lesions of the prostate and has a sensitivity
and specificity profile no better than that of rectal examination
36

• CT is useful in patients with significantly elevated PSA levels (>20 ng/mL) for the
detection of bone and lymph node metastasis, the ability to identify recurrent cancer
after radiotherapy is limited.
• MRI - identifying recurrent tumors of the prostate in biochemical recurrence.
37

• T2-weighted MRI of the prostate is capable of excellent soft tissue differentiation;
• its use in postirradiated tissue is limited by diffusely decreased signal intensity in the
prostate
• Sensitivity ofT2-weighted MRI is as low as 27%, with limited positive predictive value of 32%
• Dynamic imaging studies - to better identify potential recurrent lesions amenable for salvage
therapy.
38

• DCE gives the ability to identify vascularization of the prostate and tumor along with
angiogenesis and capillary permeability characteristics
• When comparing DCE-MRI withT2-weighted MRI, DCE-MRI had better sensitivity (72% vs.
38%), positive predictive value (46% vs. 24%),and negative predictive value (95% vs 88%).
• The addition of MR spectroscopy to T2-weighted imaging significantly improves the detection
of locally recurrent prostate cancer after radiation therapy
39

EAU GUIDELINES FOR IMAGING
40

TREATMENT OPTIONS
• Salvage Radical Prostatectomy
• Salvage Cryotherapy
• Salvage Brachytherapy
• Salvage High-Intensity Focused Ultrasound
• Androgen DeprivationTherapy
41

SALVAGE RADICAL PROSTATECTOMY
• Most definitive way to eradicate localized radiorecurrent prostate cancer.
• 10-year cancer-specific survival - 70% to 83%
• Robotic-assisted laparoscopic prostatectomy - Preferred
42

• survival outcomes directly correlate with pathologic stage whereby organ confined
disease and isolated extracapsular extension confer a 5-year progression-free probability
of 77% and 71%, respectively.
• those with seminal vesicle invasion and lymph node involvement have poorer 5-year
outcomes of 28% and 22%, respectively
43

• Patients selected for salvage radical prostatectomy should have
• A biopsy-proved radiorecurrent prostate cancer,
• At least 10 years of life expectancy,
• Lack of identifiable metastasis on imaging, and
• PSA level of less than 10 ng/mL
44

SALVAGE CRYOTHERAPY
• Patients best suited for cryotherapy are those with localized treatment failure after
radiation therapy with biopsy-proved disease, because approximately one third of
patients with biochemical failure will have a positive biopsy result
45

• Considered only for patients with
• low comorbidity,
• life expectancy of at least 10 years,
• an initial organ-confined PCa cT1c to cT2,
• initial ISUP grade < 2/3,
• pre-salvage PSA-DT > 16 months and a pre-salvage PSA < 10 ng/mL.
46

SALVAGE BRACHYTHERAPY
• The evidence for salvage brachytherapy after radiation failure is lacking compared to
salvage prostatectomy and salvage cryotherapy.
• High-dose rate brachytherapy (HDRB) has gained attention because it has the ability to
implant the seminal vesicles and treat extracapsular extension while limiting the dosage
to surrounding organs through a conformal delivery
47

SALVAGE HIGH-INTENSITY FOCUSED ULTRASOUND
• HIFU has been evaluated in the treatment of radiorecurrent prostate cancer with
acceptable cancer control outcomes.
• There is a lack of quality data which prohibits any recommendation regarding the
indications for salvage HIFU
48

ANDROGEN DEPRIVATIONTHERAPY
• In patients
• who refuse local therapy,
• who have too many comorbidities to undergo potentially morbid procedures,or
• Who have decreased life expectancy.
• In reality , 93.5% of men undergoADT as second-line therapy after radiation failure,and
therefore this approach should be clearly defined
49

• Considering the potential morbidity of ADT and the substantial cost, it is reasonable to
start treatment in those patients at highest risk for distant failure.
• The patients with PSA doubling time less than 12 months benefit fromADT, with
freedom from distant metastatic disease of 57% versus 78%.
50

EAU GUIDELINES FOR SECOND LINETHERAPYAFTERTREATMENTWITH CURATIVE INTENT
51

MANAGEMENT OF BIOCHEMICAL RECURRENCE AFTER
DEFINITIVE CRYOTHERAPY IN PROSTATE CANCER
• Neither the AUA Best Practice Statements for PSA testing nor those for cryotherapy
define what is considered a biochemical recurrence after whole-gland cryotherapy of the
prostate
52

• Biochemical recurrence after cryotherapy has been defined as PSA levels greater than 0.5
ng/mL,greater than 1.0 ng/mL,the ASTRO definition (three consecutive rises in PSA), and
the Phoenix definition of nadir + 2 ng/mL
• A unifying definition that consistently predicts for clinical failure is needed.
• Further investigation is warranted to determine these values and definitions
53

• Salvage radiation therapy after failure of cryotherapy has been described in multiple
series.
• IMRT, 72 to 81 Gy
54

• Evidence for salvage radical prostatectomy after cryotherapy failure is lacking
• The best candidates for salvage surgery are those with adequate life expectancy (longer
than 10 years) and absence of metastatic disease
55

MANAGEMENT OF BIOCHEMICAL RECURRENCEAFTER DEFINITIVE
HIGH-INTENSITY FOCUSED ULTRASOUND IN PROSTATE CANCER
• Most groups agree that a positive biopsy result after HIFU is a treatment failure, there
are myriad definitions for biochemical failure,including three consecutive rises of PSA
level and the Phoenix definition of biochemical failure
56

• After a careful review of multiple definitions for biochemical failure determined that
PSA nadir + 1.2 ng/mL,the Stuttgart definition, was the most effective at predicting
for clinical failure and has been proposed as the definition for biochemical failure after
HIFU for prostate cancer.
57

• Salvage radiotherapy - the evidence is lacking
• conformal radiation to a median dose of 72 Gy
• Salvage radical prostatectomy – the evidence is lacking
58

THANK YOU
59

Prostate carcinoma- biochemical recurremce

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