Optimizing Hormonal Control in Prostate Cancer
Done by Abdullah AL-Sinan
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Cell Biology & Morphology of The Normal Prostate
Epithelial compartments:
1.
2.
3.
Basal epithelial cell. Glandular (secretory) cells (secrets PSA, PAP & prostaglandins into the glandular lumen). These cells androgen dependant. Neuro-endocrine cells, nonepithelial fixed macrophages & intra-acinar lymphocytes.
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Cell Biology & Morphology of The Normal Prostate
Although there is a separation by the basement memb., soluble growth factors such as basic fibroblast GF (bFGF), keratinocyte GF (KGF), epidermal GF (EGF), insulin-like GF (IGF) & transforming GF-beta (TGF-beta) are responsible for crosstalk between the epithelial & stromal compartments. Paracrine stimulation & inhibition of epithelial growth.
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Cell Biology & Morphology of The Normal Prostate
The stromal comp. is composed of the extracellular matrix with fibroblast, smooth muscle cells, endothelial cells, nerves & infiltrating cells.
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Effect of Androgens on Epithelial Cells Development
Androgen regulation:
Testosterone is converted via 5alpha-reductase isoenzymes into 5alpha-dihydrotestosterone (DHT). DHT has much higher affinity for the androgen receptor than testosterone. Direct effect on epithelial cells induces differentiation. Indirect effect on transient proliferation is mediated by GF. Direct stimulation of production of vascular endothelial GF.
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Hierarchical Stem Cell Model
Postulated by Isaacs & Coffey, 1989. Stem cells give rise to a larger number of progenitor cells. These cells differentiate into androgen independent but androgen sensitive intermediate stem cells or amplifying cells. These amplifying cells differentiate & translocate towards the epithelial compartment & gain either neuro-endocrine or exocrine CCC.
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Hierarchical Stem Cell Model
The prostate stem cell is responsible for the steady-state , self renewing maintenance condition of the prostate.
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The Cancer Stem Cell Hypothesis
Neoplastic transformation of TP/A intermediate stem cells would explain why some cancer show exocrine & another neuroendocrine CCC. TP/A intermediate stem cells are highly enriched in proliferative inflammatory atrophy (PIA) lesion, which represent a pre-neoplastic process. (so, these cells may serve as preferred target in prostate cancer treatment).
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Optimizing Hormone Therapy in Localized & Early Disease
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Introduction
For most patient diagnosed with early disease, radical therapy (prostatectomy or radiation) is the standard treatment. The addition of the hormone therapy in the neoadjuvant &/or adjuvant setting to radical therapy is common. However, the question remains, who should receive hormone treatment, when & for how long.
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Active Surveillance Versus Radical Treatment
Good risk prostate cancer:
1. 2. 3.
Can be defined as patient diagnosed with: T1c-T2a PCa. A low Gleason score (<=6). Low PSA levels (<=10-15 ng/ml). According to the Kattan nomogram:
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Active Surveillance Versus Radical Treatment
PSA level (ng/ml) 5 years biochemical DFS 5 91%
10
15
87%
81%
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Active Surveillance Versus Radical Treatment
As consequence, these patients should be monitored closely. Following a patient on active surveillance to monitor the PSA doubling time is warranted. Patients who have been frequently biopsied, the incidence of PCa detection increase 6 times.
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Active Surveillance Versus Radical Treatment
PSA doubling time:
Is one means to differentiate which Pt. have a slowly progressing disease & can be spared from the side effect of surgery, & which Pt. have more progressive disease & will benefit from radical prostatectomy. Distributions of PSA DT in 231 Pt. on active surveillance after a median follow-up of 55 m., the median PSA DT was 7 years.
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Active Surveillance Versus Radical Treatment
21% had a PSA DT of <3 years. 42% had a PSA DT of >10 years. 24% underwent radical prostectomy for having PSA DT of <2 years. A short PSA DT is associated with more aggressive PCa. This suggest that the appropriate cut point for radical treatment is a PSA DT of less than 3 y.
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Active Surveillance Versus Radical Treatment
Low serum testosterone:
Low serum free & total testosterone levels were defined as 1.5 ng/dl or less & 300 ng/dl. Patients who had Low free serum testosterone levels had more extensive disease & a higher Gleason score (>=8) at biopsy.
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Active Surveillance Versus Radical Treatment
Selecting Pt. for active surveillance:
Pt. with good risk prostatic cancer & PSA levels of <=10 ng/ml are eligible for active surveillance with periodic PSA level determination & re-biopsies.
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Intermediate to High Risk Localized Prostate Cancer
Neoadjuvant hormonal therapy prior to radical prostatectomy:
Several trials show a 50% reduction in the rate of positive margins, after NHT prior to surgery. But none show a difference in PSA recurrence.
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Investigator
Labrie 1995 Soloway 1995
No.
PCa stage
Type of NHT
change + MR In PSA NHT vs.
RP (%)
161 T2/T3 303 T2b
3M L+A NA 3M L+A 14.3 to
0.5 14 to 1
8 vs 34
PSA re NHT vs. RP (y) 18 vs 7 (4)
18 vs 48 22 vs 21 (3)
Van Poppel 1995
Klotz 1999 Fair 1997 Witjes 1997
130 T2b/T3 6W EP
213 T1/T2 148 T1/T2 354 T2/T3
3M A
20 vs 46 14 vs 18 (3)
13 to 1.1 28 vs 65 36 vs 39 (6)
3M L+A 0.9 to
0.5
18 vs 37 16 vs 11 (2)
3M L+A 20 to 0.8 27 vs 46 NA
1.5
Hugosson 1996
111 T1/T3a 3M L+A 15.5 to WWW.SMSO.NET
23 vs 41 NA
Intermediate to High Risk Localized Prostate Cancer
Overall, this data suggest that there is limited benefit for NHT in patient with low to intermediate risk localized PCa. However, there may be a benefit for NHT to radical prostatectomy for patient at high risk (PSA >20ng/ml, Gleason 8-10).
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Intermediate to High Risk Localized Prostate Cancer
Adjuvant hormonal therapy after radical prostatectomy:
The Eastern Cooperative Oncology Group (ECOG) trial provides information on the role of immediate HT to RP in patients who had undergone RP & bilateral pelvic lymphadenectomy for clinically localized disease.
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After a median Patients receiving Patients receiving follow up of 7.1 y immediate HT deferred TTT Patients had died Due to PCa 15% 43% 35% 89%
Recurrent disease 33%
Overall survival (10 years) 72.4%
82%
49%
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Intermediate to High Risk Localized Prostate Cancer
In conclusion, the combination of RP & adjuvant HT resulted in a significant improvement of both overall & cause specific survival in node positive patients.
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Intermediate to High Risk Localized Prostate Cancer
Neoadjuvant HT prior to radiation therapy:
The Radiation Therapy Oncology Group (RTOG) randomized 471 patients with T2b-T4 PCa into radiotherapy alone or the combination of radiotherapy & HT (LHRH agonist + antiandrogen) 2months before & 2months during the therapy.
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After 8y follow up Radiotherapy (230) Local failure Distant metastases Disease-free survival Biochemical D-F survival (PSA <1.5 ng/ml) Cause specific failure 42% 45% 21% 3%
Combination therapy (226) 30% 34% 33% 16%
31%
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23%
Intermediate to High Risk Localized Prostate Cancer
Adjuvant HT to radiation therapy:
The European Organization for Research and treatment of Cancer (EORTC) compared radiotherapy alone with combination of radiotherapy & immediate LHRH agonist therapy.
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Combination therapy Disease-free rate Disease progression 85% 20 (9.7%)
Radiotherapy alone 48% 78 (37.5%) 43%
5-years failure-free 81% rate after biologic response
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Intermediate to High Risk Localized Prostate Cancer
Long term follow up of 66 months in412 patients confirmed these results. Immediate androgen suppression with LHRH agonist given during radiotherapy & 3 years after radiotherapy, improved disease-free & over all survival.
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Intermediate to High Risk Localized Prostate Cancer
Rising PSA after radical treatment:
The US Department of Defense Center for Prostate Disease Research examined 1,352 database patients who suffered from PSA-only recurrence after previous surgery (PSA >0.2 ng/ml). All patients received HT, either immediate (355 Pts) or delayed when clinical metastases appeared (997 Pts).
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Intermediate to High Risk Localized Prostate Cancer
If the patient had a Gleason score >7 &/or a PSA DT of <=1 year, early HT was associated with delayed clinical metastases. Stratification by PSA also indicated that for patients with a Gleason score of 7 or more, or a PSA DT of <= 1 year, the benefit of early HT is similar whether PSA DT initiated at PSA <5 or <10 ng/ml.
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Intermediate to High Risk Localized Prostate Cancer
This data, suggest that high risk patients with a high Gleason score (8-10) &/or a rapaid PSA DT (<=1 year) should be treated with a PSA between 5 & 10ng/ml.
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Conclusions
Patients diagnosed with favorable PCa can, in many cases, be spared of SE of RT. Active surveillance with periodic re-biopsies & measurement of their PSA DT enables selective delayed therapy for the minority with more aggressive disease.
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Conclusions
Pts. Diagnosed with intermediate to high risk disease, need immediate curative therapy, either RP or radiotherapy. Although several studies investigate the benefit of combining HT with RT, more studies are needed to ultimately define with whom, when & for how long HT is indicated.
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Conclusions
Limited data support neoadjuvant HT prior to RP in high risk patients. A more prolonged course of therapy (8months) may be of benefit. There is no convincing evidence for neoadjuvant therapy prior to surgery in patients with low to intermediate risk. Patients diagnosed with positive nodes benefit from adjuvant HT following surgery.
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Conclusions
Neoadjuvant HT before radiation therapy is appropriate for patients with intermediate to high risk disease. The optimal duration, however, is not clear. Adjuvant HT after radiation therapy for patients diagnosed with intermediate to high risk disease is also strongly supported by evidence from randomized trials.
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Conclusions
For patients with PSA recurrence after surgery, who either are very likely to have systemic recurrence or have failed salvage radiation, hormonal therapy is appropriate.
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Optimizing Hormone Therapy in Advanced Diseases
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Introduction
Defined as patients having a tumor extended beyond the prostatic capsule without evidence of distant metastatic spread. (T3b-T4, N0, M0 or T1-T4, N+, M0 or pT3, N0, M0). & patients with a PSA relapse after RT. The treatment objectives are delaying progression, improving survival, preserving quality of life & ultimately palliation.
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Patients with a PSA Relapse
Rising PSA levels are the earliest predictor of future clinical metastasis &/or death from PCa. A critical way to identify who should be treated is the patient PSA DT.
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Patients with a PSA Relapse
Who should be treated:
D Amico recently described a cohort of 8,669 Pts. With localized or locally advanced PCa who already underwent surgery or radiation therapy.
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Patients with a PSA Relapse
HT should be initiated immediately when the patient has a PSA DT of <3 months. Overall, PSA DT is an independent predictor of biochemical & clinical disease recurrence following radical therapy. As a consequences, Pts with PSA relapse & a long PSA DT could remain on active surveillance. If the biochemical relapse thought to be metasteic, HT will be the first line treatment.
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Patients with a PSA Relapse
Type of HT:
LHRH agonist. Antiandrogen (NSAA & SAA) 2 studies showed LHRH agonist to be more efficacious in delaying time to progression (346 days) (225 days in AA). Also treatment withdrawals due to adverse events occurred less frequently in Pts receiving LHRH agonist (4%) (4-10% in NSAA).
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Patients with a PSA Relapse
Currently, the available evidence suggests that the standard of care in these Pts should be LHRH agonist. Short term AA can be added to prevent the flare response.
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Patients with a PSA Relapse
Timing of HT:
In the absence of prospective randomized comparative trials, the value of IHT remain subject of debate as current study results are inconclusive.
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Patients with Advanced PCa
Treatment objective:
Treatment objectives are related to the delay of PCa progression. Qol should be improved or at least maintained.
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Patients with Advanced PCa
Type of HT:
Androgen suppression, either achieved surgically with bilateral orchiectomy or chemically with LHRH agonist. Antiandrogen monotherapy may not be considered as standard of care for patients with advanced disease.
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Patients with Advanced PCa
Combined androgen blockade:
First, to inhibit production of testosterone (by LHRH agonist or orchiectomy). & second, by blocking the androgen receptor to inhibit the effects of adrenal & locally produced androgen (by an antiandrogen). CAB has only a modest benefit over LHRH agonist monotherapy for increasing survival.
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Patients with Advanced PCa
The disadvantages of CAB such as increased side effects & increased costs, suggest that CAB may only be benefit in a small proportion of patients with advanced disease.
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Patients with Advanced PCa
Optimal timing of HT:
The final answer on the timing of HT remains inconclusive.
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Conclusions
PSA DT has become most important instrument for deciding who to treat. LHRH agonists are the preferred form of HT & monotherapy with androgens is no longer advised. Psychological distress & irreversibility of surgical castration, has led to replacement of orchiectomy by LHRH agonists in the majority of the patients.
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Conclusions
CAB seems to have only modest benefit over LHRH agonist monotherapy & this at the expense of increased SE & cost. The timing of initiation of LHRH agonist therapy remains subject of debate although some data point in the direction of early treatment. The occurrence of risks of long term androgen deprivation should be carefully monitored.
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THE END
Thank You
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