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Advanced Prostate Cancer

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					Advanced Prostate Cancer AUA 2002

Can we define parameters important in prostate cancer progression?
Abstract 696 (Kuefer et al)
– 21 patients with high grade or locally advanced PCa on androgen suppresion after RP – Follow up of > 2 years – 12 progressed, 9 stable – Conventional retrospective analysis (Gleason score, stage , pretreatment PSA, node burden) did not discriminate between successes and failures of androgen suppression – EZH-2 cDNA overexpression with immunohistochemical corroboration did

Abstract 695 (Xin et al),
– Characterize the expression of genes in the prostates of 15 patients died from hormone resistant PCa harvested in warm autopsies – cDNA expression analysis and immunohistochemistry in tissue microarrays – Annexins 1, 2, 4, 7, 11 downregulated

Abstract 1189 (A Chinnaiyan et al)
• 10k cDNA expression analysis and immunohistochemistry in tissue microarrays (IHC) performed on 60 prostate samples (benign to HRPC). • EZH-2 overexpressed in HR metastatic PCA and localized Pca compared to benign prostate tissue 1.63 and 1.20 median fold increase. By IHC positive EZH-2 35% in localized CaP and 100% in HR PCa.Associated with higher Gleason score and extraprostatic extension. Regression analysis suggests a trend to early PSA recurrence (Hazard ratio 2.0)

Expression of EZH-2 may be a marker for aggressive CaP vs indolent CaP.

Abstract 1191 (Kondo et al)
• 77 patients with metastatic CaP were assessed for alterations in 8q24 and 8p22 and correlated with cancer specific survival. • Metastatic CaP had higher incidence of 8q24 than localized CaP. No difference in 8p22. Patients with both alterations had 4.4 times increased risk of rapid death from CaP. Alterations in 8p22 and 8q24 carry poor prognosis. Chromosome 8 has role in advanced CaP.

Abstract 1198 (Roehl et al) What are the prognostic factors associated with recurrence and SVI after RP?
• 235 pts with seminal vesicle invasion treated with radical retropubic prostatectomy from 1983 – 2001 followed for recurrence and survival. • Recurrence and survival were compared in the pre PSA (1983 –1991, n = 77) and PSA (1992 –2001, n = 158) era. • PFS 5 year pPSA 29% • ACS 5 year 81% PSA 45% 86 p=0.03 0.04

Progression free and all cause survival were significantly better in the PSA era. PSA level at diagnosis, positive margins, Gleason grade were predictors of recurrence.

Abstract 1202 (Crawford et al)
What factors are associated with prolonged survival with metastatic CaP?
• 1286 men with metastatic prostate cancer treated with orchiectomy +/flutamide in SWOG 8894. The characteristics of 10 year survival were identified. • 620 men followed > 10 years. – 77% lived < 5 years – 17% lived 5-10 years – 6% lived > 10years Factors associated with prolonged survival are: minimal disease severity, better performance status, lower Gleason score, and lower serum PSA.

Abstract 1200 (Kattan et al)
• A survival nomogram for castrated men with progressive HR prostate cancer was constructed using routinely available parameters. Gives probability of 1, 2 year survival and median life expectancy. • 409 men used to construct nomogram. Assessed internally and validated externally with 458 pts (concordance 0.67). The nomogram is useful to assess prognosis, guide treatment, and design clinical trials.

Can we image sites of local recurrence after failure of local therapy? Abstract 698 (N Mohideen et al)
• Prostascint in 49 patients undergoing RT to prostatic bed after RP • Assessed in: prostatic bed, nodes, outside bed compared to 3 yr bNED • Positive predictive value = 12% • Negative predictive value = 71% • PSA < 2 ng/ml 84% 3 year bNED • Gleason < 6 91% 3 year bNED

Scan status had no impact on biochemical control.

Abstract 697 (N Oyama et al),
• C-11 acetate PET (AC-PET) compared to 18F-fluorodeoxyglucose PET (FDG-PET) and CT (697). • 18 patients post RP and 12 post RT with rising PSA. AC-PET > FDG-PET C-11 acetate PET scanning may be a useful adjunct in staging these patients.

Abstract 2001 (Waldert et al)
• 45 asymptomatic men with rising or elevated PSA after RP or XRT assessed with C-11 acetate PET scanning. – 12/45 (24%) false negative – 7/45 non expected or non conventionally detected lesions found. C-11 acetate PET scanning may be a useful adjunct in staging these patients.

• Define the prognostic characteristics and outcome of patients on intermittent androgen ablation (IAA) Abstract 700 (A De La Taille et al),
• 72 patients with localized or advanced CaP and 74 with PSA recurrence after local treatment. Treated for 6 months or nadir and then off treatment until PSA rose to 4ng/ml (RP) or 10 ng/ml • Mean follow up 45.6 months Cox multivariate analysis = Younger men (70), Gleason >7, short duration of initial response (<12 mo), advanced disease = poor prognostic characteristic

Abstract 701 ( Waltregny et al)
• 68 patients offered either IAA (35) or continuous AA (38) in non randomized but balanced study • Mean follow up 30.4 mo • 3 year progression rate was 6.7% in IAA and 37.5% in CAA • No difference between groups in patients with bone metastases Androgen independence may be delayed by IAA in patients with locally advanced disease

Treatment Estrogens
Abstract 702 (J Ockrim et al)
• 20 patients with locally advanced (10) or metastatic (10) CaP (treated with transdermal estradiol patches • Median follow up 10 months • Endocrine suppression of LH, FSH, and testosterone PSA mean suppression of 95.1% No cardiovascular side effects, BMD maintained, no hot flushes, 70% gynecomastia • Cost 10% of GnRH agonists Estradiol patches may be an effective and less costly treatment for hormonal therapy of CaP

Abstract 1204 (Oefelein)
• 20 patients requiring HT were treated with GnRH agonist based on monthly serum testosterone levels. GnRH was re-administered when testosterone approached the castrate level. PSA, QOL and satisfaction were followed. • PSA remained supressed • QOL and satisfaction were improved with testosterone triggered dosing. • Cost was significantly reduced ($7315 vs $3972).

Intermittent GnRH administration based on testosterone suppression yield improved satisfaction, decreased costs, with no loss of clinical efficacy.

Abstract 699 (J Moul et al) and 1194 (L Sun et al)
• Define the risk of PSA recurrence in men treated with hormone therapy (HT) or observation after PSA recurrence following RP • 5019 RP, 3790 no neoadjuvant or adjuvant therapy • 783 PSA only recurrence (>0.2 ng/ml) = 20.7% • 187 hormone therapy (23.9%), worse c-stage, t-stage, grade, margin positivity, seminal vesicle involvement. • DFS(%) 8 yr yr at 50% DFS • 0.2> PSA< =1 53.2 10.7 • 1>PSA<2 59.0 10.7 • >2PSA< 3 60.5 11.2 • Prolonged bNED • 79.7% 8 year objective DFS on HT • 91.1% 8 year objective DFS on WW Prolonged disease free survival in both treatment arms. Eight year disease free survival is similar in patients with poor prognostic factor on early hormone therapy and patients with good prognostic factors on WW. Hormone therapy may alter the course of PSA only recurrence after RP

Abstract 1197 (Studer et al)
• 188 patients with CaP not amenable to curative therapy randomized to immediate or deferred orchiectomy (O) on symptomatic progression. • 67% T3-4, 20% N+ • Median time to disease progression 2.8 years longer in immediate O group. • Overall pain free interval, maximum pain and performance status same in both groups • Cancer specific survival longer in immediate O group. • No difference in overall survival. • Deferred O in only 60% of patients (40% never required O)
Asymptomatic pts not undergoing curative therapy treated with immediate O had no survival or quality of life advantage over deferred O. 40% may never require any HT and may incur unnecessary side effects. Immediate HT in selected pts is not beneficial and may be detrimental.

Effect of bisphosphonates on CaP Abstract 1190 (G Oades et al)
• Cell growth and viability were measured in three CaP cell lines : DU 145, PC3,and LNCaP incubated with the bisphosphonates pamidronate or zoledranate. • Bisphosphonates inhibited growth and viability of cell lines via increased apoptosis. Increased caspase activity suggested a bisphosphonate mediated induction of apoptosis initiated by inhibition of mevalonate pathway resulting in impaired protein prenylation. • Clinical effects of bisphosphonates may be the result of the same mechanisms.

Abstract 703 (F Saad et al)
• 643 with hormone resistant CaP with bony metastases • Double blind randomized phase 3 trial • Zoledronic acid 4 mg or 8 mg or placebo via 15 min infusion every 3 weeks • 15 month mean follow up Zoledronic acid reduced by 25% SRE (33 vs 44%), path fracture (13 vs 22%). It significantly delayed the time to SRE and path fracture.

Abstract 704 (D Yao et al)
• • • Phase 1 dose escalation trial of 90Y J591 (humanized MAB to PSMA ext) 29 evaluable patients with metastatic progressive HR CaP At 15 mCi/m2 3 of 4 patients reduced PSA by >25%, at 20 mCi/m2 4 of 4 patients had an average PSA reduction of 42%. Suggesting a dose related tumor effect No HAMA, toxicity largely reversible thrombocytopenia

•

Abstract 705 (C Schulman et al)
• Phase 2 randomized blinded trial of Atrasentan (Endothelin A receptor antagonist) 288 with hormone resistant CaP Randomized to 2.5 mg/day, 10 mg/day, placebo Previously active agent reported to delay time to PSA progression, objective progression, decrease bone turnover, and increase survival (3months) 244 patients evaluable PSA analyzed as median time to progression, median time to 100% increase, and median PSA doubling time No differences in groups on PSA progression

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Abstract 706 (E Goluboff et al)
• Open label 12 month extension trial of Exisulind (cGMP PDE inhibitor) of 12 month DBPC study of rising PSA after RP • 60 patients (PE 33, EE 27) • 400-500 mg/day • PSA DT significantly increased from 5.6 mo pretreatment to 12.6 mo at 24 months in high risk EE group (p = 0.041). There were trends towards significance in the intermediate risk EE group (13.3 mo to 19.6 mo, p = 0.067), and overall PE group (14.7 mo to 26.9 mo, p = 0.094). • Side effects were asthenia, abdominal pain, diarrhea, and increase in transaminases. Eight patients withdrew. Exisulind increased PSADT in selected men with rising PSA after RP.

Abstract 1199 (Pruthi et al)
• 13 pts with biochemical failure after RP or XRT were treated with the COX-2 inhibitor celecoxib (200 mg bid). PSA followed at 3 monthly intervals. PSA assessed for changes in doubling time (PSADT) and slope of the line of logPSA vs time. Serum testosterone was assessed. • COX-2 inhibition slowed the PSADT and decreased the slope of the logPSA line. COX-2 inhibition may have a role to play in delaying progression.

Abstract 2008 (Konety et al) Feasibility of Chemohormonal therapy and RP in high risk localized CaP.
• 36 pts with high risk but presumably localized CaP treated with neoadjuvant chemo-hormonal therapy followed by RP. Treatment included goserelin and 4 cycles of paclitaxel and estramustine and carboplatin. – Clinical Stage – 39% decreased, 25% unchanged, 36% increased – No serious adverse events – Positive margin rate 22% – 83% continent, 15% potent – At 17.8 months of follow up 51.5% are bNED

RP is feasible after chemo-hormonal therapy. Clinical benefit is uncertain at this time.

Abstract 1195 (Salzmann et al)
• 64 pts with symptomatic HR Pca treated with 5-FU and folinic acid.
– Group 1 - 24 treated with bolus infusion – Group 2 - 28 treated with protracted infusion (via port over 5 days) – Group 3 - 12 received oral 5-FU

• Group 1) PSA response of 30%, pain response 70%, 54% sig toxicity • Group 2) PSA response of 28%, pain response 60%, 25% sig toxicity • Group 3) PSA response of 20%, pain response 20%, 8% sig toxicity
• Protracted infusion of 5- FU and folinic acid offers equivalent efficacy with less toxicity

Abstract 1203 (Small), 1207 (Elgamal)
• Autologous dendritic cells pulsed with pap or psma in pts with HR CaP. Enhanced immune response but no objective clinical responses at this time.

Abstract 1205 (Satoh)
Results of 3 trials of in situ gene therapy (HSV-tk) as neoadjuvant or adjuvant therapy.
Enhanced immune response but no objective clinical responses at this time.

Abstract 1193 (Wilhelm et al)
• Orchiectomized mice carrying C4-2B intraosseous prostate cancer xenografts treated with 1) placebo, 2)antisense oligonucleotide to mRNA template of telemerase 3) dummy adenovirus plus taxol, 4)adenovirus plus taxol, 5) adenovirus plus taxol plus antisense oligonucleotide to mRNA template of telemerase. Mice in group 5 were “cured” of their cancer. This combination therapy including antitelomerase therapy may warrant further investigation.

Abstract 1192 (Pfitzenmaier et al) What factors are associated with Cachexia of CaP?
• Levels of PSA, TNFalpha, IL-1, IL-6, IL-8 were assessed in normal pts, pts with localized CaP, pts with advanced CaP without cachexia, and pts with advanced CaP and cachexia. • Levels of TNFalpha, IL-6, IL-8 were elevated in cachexia group. TNFalpha, IL-1, IL-6, IL-8 cytokines may play a role in cachexia of CaP.

Abstract 1196 (Engelhardt et al) How do we assess BMD change?
• 47 pts assessed for BMD using standard T and Z scores for osteoporosis and osteopenia (derived from women) and absolute bone mineral density (BMD). – Group 1 - 31 treated with hormone therapy – Group 2 - 16 treated with matched healthy controls without • Group 1) 61% osteoporotic, 26% osteopenic, BMD = 69.9 g/cm2 • Group 2) 50% osteoporotic, 31% osteopenic, BMD = 97.9g/cm2 • No significant differences in standard measures of osteoporosis or osteopenia but significant differences in BMD. Gender specific definitions needed for osteoporosis and osteopenia.


				
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