Prostate Cancer

Response of PSA post-RT

  • PSA half-life following EBRT —> 3 months
  • Lowest PSA —> ~ 24 to 36 months after RT
    • Continued to decline ( even till 4-5yrs )

Post brachytherapy:

  • Median nadir tends to be lower and to occur later

All about lymph nodes in prostate cancer.

  • The bottom-line is that there is no consensus on indication of LN dissection or LN sampling.
  • In low risk usually it is not done.
  • In moderate to high risk it is justifiable
    • If LN comes back + then hormone will be indicated ( change in management )
  • In very high risk can be spared.
    • Hormone and LN RT will be given anyway.
  • Even if LN+, a subgroup of patients might live long ( more than 10years )

The standard lymph node dissection:

  • From the bifurcation of the common iliac vessels medially to the pelvic floor and to the inferior border of the prostate, and then superiorly along the hypogastric vessels back to the bifurcation of the common iliac vessels.
  • LN neg is considered neg. Skip metastasis is rare
  • Correlation between the side of palpable tumor and the side on which metastatic nodes
  • Sensistivity —> 65%
  • MRI can be used to check LN status. ( high sensitivity )
  • MR spectroscopy ( high specificity )

To treat or not to treat lymph nodes.

Let's imagine different situations!

Radical Prostatectomy —> LN+

  • Hormones yes or no?! :)
    • We have Messing/ECOG trial
      • Prospective
      • No RT
      • Improved OS and reduced risk of death.
    • Also there os a RTOG subset analysis.
    • HT+RT vs RT alone in LN+ as adjuvant therapy
    • HT+RT group had better Biochemical Control, Metastasis, DSF, Absolute survival
  • So maybe HT is enough alone. Why RT?
    • We have two retrospective studies.
    • LN+ —> HT+RT vs HT alone
    • HT+RT better

Adjuvant RT for LN+

Volumes?

Radical RT treatment for a radiologically LN+

  • Hormones based on same justifications

RT Lymph nodes

  • Evidences/volumes
  • Higher dose to LN+ (?)

Radical RT treatment for intermediate to high risk; LN unknown

Evidence(?)

Adjuvant RT

For High-Risk Patients After Radical Prostatectomy

Retrospective Nonrandomized Studies

  • Retrospective studies → adjuvant RT following RP for poor prognostic ⇒ improves biochemical-free survival & reduces the risk of local recurrence
  • No impact on systemic relapse or overall survival
  • This is expected → It is a local treatment only

Four possible clinical scenarios in the postprostatectomy setting

  1. No residual disease ⇒ adjuvant irradiation is not necessary
  2. Persistent disease is present in the prostatic fossa only ⇒ adjuvant XRT may provide long-term cure
  3. Presence of residual local disease + microscopic disseminated disease ⇒ adjuvant ERBT may eradicate the disease locally but no impact on the systemic component
  4. Only systemic ⇒ adjuvant local irradiation is unnecessary

Adjuvant irradiation is only beneficial in the second scenario

  • Results of several series of adjuvant versus salvage EBRT
    • 5-year biochemical disease-free survival after adjuvant treatment are better→ likely because:
      • Smaller tumor burden in the adjuvant setting
      • Timely eradication of clonogens
      • Those patients subjected to adjuvant RT may never had required treatment →Improved outcomes therefore may be biased in favor of patients receiving adjuvant treatment.

Randomized Studies

Two large randomized trials

  • EORTC
    • 1,005 patients
    • Positive surgical margins
    • pT3 (ECE and SVI)
    • Arms
      • Adjuvant EBRT (50 Gy to the prostatic fossa and periprostatic tissue + 10-14Gy boost to the prostatic fossa only)
      • No immediate treatment
    • 5-year biochemical PFS
      • Adjuvant irradiation→ 74%
      • No treatment → 52.6%
    • Clinical progression-free survival
      • Adjuvant XRT → 85%
      • No treatment →78%
    • Loco-regional failure
      • Adjuvant XRT → lower
      • No treatment→ worse
    • 5-year metastasis-free survival
    • Cause-specific survival
    • Overall survival
      • NO DIFFERENCE
  • South Western Oncology Group (SWOG) trial
    • 425 patients
    • High-risk localized disease(T3N0)
    • Arms
      • 60-64 Gy to the prostatic fossa(Adjuvant RT)
      • Observation
    • Median PSA relapse-free survival
      • Adjuvant XRT → 10.3 years
      • No treatment → 3.1 years
    • Median recurrence-free survival
      • Adjuvant XRT → 13.8 years
      • No treatment → 9.9 years
    • Metastasis-free & Overall survival
      • IMPROVED ( recently updates. )

Role of Androgen Deprivation Therapy in Combination with Adjuvant RT

Limited information on the role of hormones in combination with adjuvant RT in the post-prostatectomy setting

RTOG 8531 - subset analysis

  • Post-prostatectomy
  • If used LHRH analogue → better bNED ( biochemichal non-evidence of diseae )
    • But no impact on survival
  • If salavage ⇒ Hormone ⇒ reduced the risk of biochemical failure
  • If adjuvant ⇒ no advantage

A retrospective study

  • 2 groups after prostatectomy + adjuvant RT
    • With transient AA prior to adjuvant RT
    • Without transient AA prior to adjuvant RT
    • 5-year bNED
      • Significantly better in patients treated with transient AA
      • Mean duration of 6 months

Optimal Radiation Dose

  • Low doses in the range of 45-50 Gy
  • Beneficial in terms of local control & DFS
  • EORTC → 60 Gy over 6 weeks
  • ASTRO recommendations → 64 Gy
    • improved biochemical outcomes using higher radiation doses/ well tolerated

Management of the Rising PSA after Definitive Local Therapy

  • Failing Surgery
    • Salvage Radiation
  • Failing radiation
    • Salvage radical prostatectomies
    • Salvage cryotherapy
    • Brachytherapy
    • If not candidates for definitive salvage therapies
      • Surveillance
      • ADT
  • Prognosis

Rising PSA post-RP

Definition of PSA failure after surgery:

Basically PSA should be non-detectable post prostatectomy.

  • Anything > 0.03 vs non-detectable PSA:
    • 1 year biochemical recurrence-free survival
      • 68% vs 95%& 36%
    • 5 year biochemical recurrence-free survival
      • 36% vs 72%
  • Overall Survival
    • 63% vs 80%

** Most commonly used:**

  • > 0.2 ng/ml

Multiple definitions:

  • PSA greater than 0.5 ng/ml
  • > 0.4 ng/ml
    • Doesn't sound logical <— Many normal men(with prostate) have PSA around 0.4
  • > 0.3 ng/ml

Higher relative risk of failure post salvage treatment.

  • Johns Hopkins Hospital
    • ADT was avoided unless metastatic disease or symptoms intervened
    • Median time to metastatic disease → 8 years
    • Median survival → 13 years
    • Most important factor linked to survival : PSADT ( PSA doubling time )
      • PSADTs > 15 months → rarely associated with prostate-cancer specific mortality
      • PSADTs < 3 months → almost invariably associated with death from prostate cancer
        • Median survival of 5 to 6 years
      • Using PSADT as a stratification variable
        • Majority of deaths from prostate cancer → associated with PSADTs < 9 months
  • Gleason score: Prognostic factor
  • Time of recurrence: Prognostic factor
  • For PSADT other factors need to be considered
    • Prior/current treatments
    • Absolute PSA level
    • Number of PSA determinations
    • Timing of the PSA determinations
    • In nonsurgically treated patients: noncancerous factors capable of influencing PSA
      • Radiation therapies, particularly brachytherapy→ PSA “bounces” that do not represent cancerous relapse
      • PSAs are influenced by testosterone levels
        • Circulating testosterone measurement
        • PSADTs are not reliable unless stable testosterones
        • No drugs that influence the androgen axis
          • 5-alpha reductases
          • Antiandrogens
        • Also if PSA < 0.2 ng/mL→ PSADT not very reliable
        • A minimum of three PSA determinations and more than 3 months
  • PSADT calculators:

http://www.mskcc.org/mskcc/applications/nomograms/PSADoublingTime.aspx.

PSA < 10ng/mL

  • Mosly negative bone scan
  • Probability of a positive bone scan → < 5% : until PSA increased to 40 to 45 ng/mL
  • Factors which predicts bone scan positivity during this disease state.
    • PSA velocity
    • PSA slope
    • PSA value at the time of the scan

Treatment

Salvage Radiotherapy after Radical Prostatectomy

  • Factors related to subsequent biochemical failure and disease progression after salvage XRT
    • Surgical Gleason score
    • SVI
    • Absolute pre-RT PSA level
    • pre-RT PSADT
    • Choice of salvage therapy
      • Local only
      • Local and systemic
      • Systemic only
      • Better results with salvage RT
    • Preradiotherapy PSA < 1.0 ng/mL

Predictors of subsequent PSA failure after salvage RT

  • Negative margins
  • Absence of ECE
  • Presence of SVI
  • Positive margins & no poor prognostic features→77% achieved PSA control after salvage

Total 4-year progression-free survival → 46%

Retrospective analysis of salvage irradiation

  • 5yr PFS 50%
  • Favorable risk features
    • Positive surgical margins
    • Gleason < 8
    • PSADTs < 10 months ( ? )
  • PSA relapse-free survival → 70% to 80% at 5 years.

Rising PSA post-RT

Definitions of PSA failure:

ASTRO

Three consecutive rises in the PSA
ASTRO still can be used if no ADT treatment. But requires adequate F/U

Problems with ASTRO definition:

  • Does not specify how much of a rise was significant
  • Three consecutive rises may occur by chance alone
  • PSA tends to increase normally with age ==> very small increases separated over a long period might not represent progression. * Not clear what is the NADIR?
    • Lowest value ever achieved?
    • Lowest value prior to rising?
    • How tied values (e.g., 0.1, 0.2, 0.3, 0.3, 0.7, and 0.9 ng/ml) should be dealt with
    • After brachytherapy was particularly problematic
      • PSA bounce in 20%
  • PSA control in patients treated with short-term ADT
    • Rise of PSA in response to the recovery of testosterone with no true failure
  • Importance of the duration of follow-up
    • Requires long term F/U
      • Median follow-up should be > estimated date of biochemical control at 2 years before estimates of control stabilize.
      • If the median follow-up is 5 years, only estimates at 3 years or less are likely to be accurate.
  • Backdating
Phoenix

Better sensitivity and specificity than ASTRO.

  • Rise of PSA by 2 ng/ml or more above the nadir PSA after the completion of EBRT with or without HT
  • Date of failure be determined at time of detection of failure. (not backdated)

Treatment

Salvage Surgery after Radiotherapy Failure

  • Salvage RP is technically challenging
  • Short-term and long-term complication rates > standard RP

Appropriate patient selection and surgical expertise Options

  • Salvage surgery
  • Brachytherapy (open or ultrasound-guided)
    • Rectal injuries occurred in 12% but are now rare.
    • Long-term complications remain high
    • Bladder neck contractures
    • 20% → anastomotic stricture
    • Urinary incontinence
  • 15-year non-progression rate → 29%
  • 15-year cancer-specific survival → 64%
  • 5-year actuarial non-progression
    • → 86% for patients with organ-confined cancer (pT2N0)
    • → 61% for those with ECE
    • → 48% for those with SVI

Salvage Brachytherapy

Patients undergoing salvage brachytherapy should have

  • Histologically confirmed local recurrence
  • No clinical or radiologic evidence of distant disease
  • Adequate urinary function
  • Overall 5- to 10-year life expectancy
  • Prolonged disease-free interval (more than 2 years) from primary RT
  • Long PSADT (> 6-9 months)

Salvage brachytherapy should be avoided

  • Evidence of SVI recurrence
  • Extracapsular disease
  • 3-year & 5-year biochemical recurrence-free survival of 48% and 34%
  • PSA nadir of 0.5 ng/mL or less was found to be a significant predictor of BCR-free survival
  • Overall survival rate of 93%.
  • Complications with brachy re-irradiation
    • Urinary retention (14%)
    • Hematuria (4%)
    • Dysuria (6%)
    • Rectal ulcers (4%)
    • Rectal bleeding (2%)
    • Incontinence (24%) ]
    • Grade 3 or 4 GU complications (47%)
    • Grade 3 sexual dysfunction (10%)
    • Grade 3/4 GI toxicities NONE

Cryotherapy
Ideally, prostate volumes for salvage cryotherapy should be 20 to 30 g

  • If > 60 g
  • history of TURP
    • ⇒ Increased risk for urethral sloughing & urinary retention
  • Biochemical disease-free survival rates : 34%-98%
  • High primary setting complication → 70%
  • Erectile dysfunction (77% to 100%)
  • Rectal pain (10% to 40%)
  • Urinary incontinence (4% to 20%)
  • Urinary retention (0% to 7%)
  • Urethral sloughing (0% to 5%)

High-Intensity Focused Ultrasound
A local ablative technology that causes tissue damage through focused ultrasound generating intense heat in targeted areas.

Originally designed to treat BPH

  • Report in 71 patients
  • Radiorecurrent disease
  • F/U 15 months
  • 30-month actuarial survival (negative biopsy and absence of BCR) → 38%
  • 30-month actuarial positive prostate biopsy rate after salvage HIFU → 27%

Complications

  • Prolonged urinary retention secondary to edema and urethral sloughing → the most common complications
  • Recto-urethral fistulas
  • One serie→ Long-term complications
  • recto-urethral fistulas (6%)
  • incontinence (35%)
  • rectal or perineal pain (3%)
  • bladder neck contractures or urethral strictures (17%)

ADT for PSA Relapse post-RT

Median time to development of metastases was 12.4 years after starting ADT

  • Poor prognostic factors associated with death from prostate Ca
    • PSADT < 3 months
    • PSA nadir of 0.2 ng/mL or more
    • PSA prior to initiation of ADT

After Surgery

  • PSADT < 12 months
  • Gleason > 7
  • Less likely to develop bone metastatic disease if initially treated with ADT while PSA < 5

Adverse prognostic findings and a rising PSA after definitive therapy

  • Chemotherapy + ADT
  • Intermittent, as opposed to continuous, hormonal therapy may be a way to diminish morbidity of ADT

The Veterans Administration Research Service Cooperative Urological Research Group (VACURG) randomized
* Immediate vs Deferred therapy
* Asymptomatic patients
* 1,900 patients w Locally advanced or metastatic disease
* Arms
* Placebo
* Placebo + orchiectomy
* DES(5 mg/day)
* Orchiectomy + DES
RESULTS:

  • Estrogen-treated ⇒ cardiovascular complications
  • For patients with metastatic disease→no differences in overall survival

In another trial offering T2-T4(Tumour stage(?))
ARMS:

  • Orchiectomy
  • Radiation
  • Combination of both

TESULTS:

  • Orchiectomy alone and orchiectomy plus radiation arms were superior to the radiation alone arm with respect to metastases-free survival
  • No differences in either local disease control or overall survival

SAKK 08/88 trial
Immediate vs deferred ADT

  • 197 patients
  • No differences in overall survival or the overall pain-free interval
  • Time to new metastases, time to ureteric obstruction, and/or time to first pain favored those receiving immediate treatment.
  • Prostate cancer-specific survival was not significantly different

The MRC PR03 trial
immediate versus deferred treatment

  • Patients with either locally advanced or M1 prostate cancer

RESULTS:

  • No overall survival differences between the groups
  • Time to death from prostate cancer was improved with immediate treatments

*Benefits of immediate ADT:
* Less-frequent TURPs
* Fewer cases of:
* Ureteral obstruction
* Pathologic fracture
* Spinal cord compression
* Each of these complications was roughly twice as common in the deferred treatment arm

A recent large trial(early versus deferred ADT)

  • 985 patients
  • M0
  • Median F/U: 7.8yrs
  • 541 patients had died, mostly from prostate cancer (n = 193) or cardiovascular disease (n = 185).
  • Surprisingly, there was an overall survival benefit from immediate treatment
  • Prostate-cancer specific mortality was not different
  • Non–prostate cancer deaths were fewer
  • Unexpected findings

An important international trial (MRC PR07)

  • ADT plus or minus radiation in patients with T3-T4N0M0 disease at diagnosis
  • Better OS with addition of XRT to ADT

All about Hormone Therapy

Types and dosage available

Generally, two classes of anti-androgens:

  • Steroidal
    • Cyproterone Acetate
    • Mifepristone

Might have partial agonist activity…

  • Non-Steroidal
    • Flutamide
    • Bicalutamide
    • Nilutamide

Indications and Use

Side Effects

Generally side effects can be categorized into three groups:

  • Subjective ( patient complaint )
    • Loss of libido
    • Erectile dysfunction
    • Hot flashes
    • Decrease in testicular and penile volume
    • Hair changes
    • Fatigue
    • Depression
    • Aches and pain
    • Muscle weakness
    • Cognitive changes
  • Objective
    • Loss of bone density
    • Loss of muscle mass
    • Gynecomastia
    • Changes in serum lipids
    • Exacerbation of DM and HTN
    • Anemia
      • Normocystic, normochromic

Treatment and interventions

  1. Depression needs treatment
    1. anti-depressant and sometime stimulant
  2. Nutritionist consult can be helpful in prevention of weight gain
    1. Healthy food
    2. Exercise —> should be emphasized
      1. Consider age and baseline of the patient ==> consult with physiotherapist as well as a personal trainer
  3. Calcium(1200-1600mg/day) and Vit-D(600-800IU/day)
  4. Preventive RT for gynecomastia is not standard
  5. Baseline mineral bone density should be checked —> + F/U BMD
    1. If osteoporosis ==> begin biphosphonate
      1. Alendronate
      2. Zoledronic Acid 4mg q3m
    2. Repeat BMD q12-24m
  6. Advise stop smoking, limit caffeine and alcohol intake —> for bone maintenance as well as mood/anxiety

Castrate Resistant Prostate Cancer

Prostate Brachytherapy