Prostate carcinoma

PROSTATE CARCINOMA ASCO 2006 2508. MDX-010 Ipilimumab (antiCTLA-4)0.5-3 mg/kg d 1 + GMCSF 250 mg/m2/d x 14 d. Prostate cancer: PSA reduction <50% 7/18. Dose response effect with increase in CD4+ and CD8+ T cells. **4560. Prostate ca. Premarin 1.25 mg tid (high dose). 32% PSA response rate after antiandrogen failure. Low dose 1.25 mg qd no effect. 4565. Prostate ca. Addition of somatostatin to LHR + DXMTS prolongs TTP by 3 mo and MDR 3 mo. 4563. Celecoxib anticancer effect in prostate ca. *4573. Prostate cancer. Rising PSA after definitive local therapy in prostatic cancer without metastases (scintigraphy or CT scan). Finasteride 5mg qd + Flutamide 250 mg qd (peripheral androgenic blockade). OR: >50% PSA decrease in 97%. MT to nadir PSA 3.2 mo. M F up 59 mo. 22/101 have had progression. MOS> 5 y; MDFS >5 y. *4613. Prostate cancer. Lu177-PSMA(J591) in androgen refractory prostatic cancer. Doses 65-70 mCi. Tumor targeting excellent. N=14, median age 73 yo. OR: 1 PR + 4 NC (14-23 wks duration).Toxicity grade 3-4 in 50%. *4644. Prostate cancer. Second line Alimta. OR: 19% PSA response and 38% NC. MDR 5-12+ wks. **14500. Prostate cancer. Xel 1 g/m2 qd x 2 wk + Celecoxib (Rofecoxib) 5 mg qd + Pioglitazone 60 mg qd in Study I and adding IFNa 4.5 MU sc tiwk in Study II. OR: None vs 48% (CR 13% + PR 35%). Decrease C Reactive Protein response parallel OR response. MPFS 4.7 mo to 11.5 mo. Control of tumor associated inflammation is important. PROSTATE CARCINOMA- MOLECULAR BIOLOGY T Rebbeck (JNCI 2000;92:76). P450 superfamily: CYP 3A4-V (variant) had increased T6BH testosterone 6 B hydroxylation and confers increased incidence of prostatic cancer. It is more frequent in African, intermediate Caucasian and lowest in Asian. S Signoretti et al (JNCI 2000;92:1918-25). Her-2 neu expression: 17/67 surgical biopsy, 20/34 advanced androgen ablation biopsy, and 14/18 androgen independent tumors. I Osman et al (Clin Ca Res 2001;7:2643-7). Her-2 expression in prostatic cancer (Dako test) defined by >10% cells with complete membrane staining. Her-2 overexpression found in9/45 (20%) untreated, before hormonetherapy, 23/34 (67%) after hormonetherapy, and 16/20 (80%) in metastatic lesions. No correlation with Gleason score, invasion or Ki67 and
related to PSA level and biochemical relapse.
J Chan et al (JNCI 2002;94:1099-109). IGF1 and IGF binding prot 3 in prostate cancer
correlated with advanced disease.
W Nelson et al (NEJM2003;349:366-81). Genetics of prostate cancer:
Normal prostate (susceptibility genes include: RNAse 1q24-25, ELAC2 17p11, MSR1
8p22, AR Xq11-12, CYP17 10q24.3, SRD-5A2 2p23, germline mutation). First event is
proliferative-inflammatory-atrophy (genes participating are GSTP1 CPG
hypermethylation, decrease p27, chromosome 8q gain, chromosome 8p loss). Then occurs
prostatic intraepithelial neoplasia (decrease NKX3.1, loss of 10q, 13q, 16q), followed by
locaslized prostate cancer (gain in 7p, 7q and Xq), then metastatic cancer (AR mutation
or amplification) and androgen independent cancer.
TW Boilean (JCO 2003;21:3328-34) Powder tomato, similarly to lycopene, reduces
prostate cancer risk by 26% in a N methyl N nitrosourea rat model. Implication for diet and
prevention.
A Chakravarti et al (JNCI 2004;96:696-703). Loss of p16 is associated with adverse
outcome (less OS, less DSOS, local progression rate and distant metastasis)
H Li et al (JNCI 2003;95:1578-86). Plasma selenium inverse relation with prostatic cancer
risk (OR 0.4).
J Deber & D Tindall (NEJM 2004;351:1488-90). Mechanisms of androgen refractory
prostate cancer are: 1. Overexpression of androgen receptor (30%) (longer survival); 2.
Mutated androgen receptor gene (small fraction of patients); 3. Alteration in IL6, ILGF1
and other genes that activate AR; 4. Activation of survival pathways that bypass AR as
Neuroendocrine peptide stimulation induced through nearby neuroendocrine resistant cells
(40%) or 5. Disregulation of apoptotic genes (loss of PTEN which allows activation Akt
and block apoptosis via bcl-2 activation).
G Narla et al (Ca Res 2005;65:1213-22). KLF6 tumor supresor gene. A variant
polymorphism (IVS1-27G>A, IVSA allele) produces alternative splicing and inhibition of
KLF6 protein. Present in 15% (sporadic and familial samples) is associated with a >50%
increase in cancer risk.
DJ George et al (Clin Ca Res 2005;11:1815-20). IL6 measurement in CALGB9480
(N=191), median 13.31 pg/mL. Patients below median MOS 19 mo, vs above median MOS
11 mo (HR 1.38).
PROSTATE CARCINOMA- SCREENING
%FREE PSA: Usually PSA complexes with inhibitors (alfa-1 antichymotrypsin and
alfa-2 macroglobulin) but not tumor PSA. Tumors have lower FREE PSA. Cut-off
points are <20-25% to increase PSA sensitivity up to 90% avoiding negative biopsies
(26%) due to poor specificity. With PSA >4 ng/mL positive biopsies only 25%
(sensitivity and specifity falls to 50%). A ratio of Free-PSA/Total PSA <10% increases
probability up tp 50%, specially important in 60 y.o. with a higher incidence of BPH.
*C Stephan et al (Ca Epidem Biomark Prev 2000;9:1130-47). Review PSA determination:
t-PSA >20 ug/l always biopsy, usually metast prostatic cancer
t-PSA 2-20 ug/l, with a >40 mL prostatic volume, low sensitivity (BPH common) and
specifity low (ranges 60%)
t-PSA 2-20 ug/l with <40 mL prostatic volume, always biopsy, both sensitivity and
specificity are higher (ranges 95%).
How to avoid prostatic biopsy in the small t-PSA ranges?.
t-PSA 2-4 ug/l if free PSA < 9% biopsy always due to high specificity but misses are
common: sensitivity 44% and specificity 95%.
t-PSA 4-10 ug/l, if free PSA 9-15%, sensitivity 87% and specificity 78%, biopsy always,
less misses.
t-PSA 2-4.5 ug/l when HK2:fPSA >1, identifies correctly 40% of cancers with only 16% of
the patients having biopsies (HK2: human kalikrein , 78% homology with PSA and initiator
of proteolytic cascade leading to cancer invasion). Unproven needs validation.
**RS Punglia et al (NEJM 2003;349:335-342). PSA verification bias on screening.
Mathematical model suggest that a 4.1 ng/mL cut-off level for biopsy would miss 82% of
cancers in <60 y.o. and also miss 65% of cancers in >60 y.o. It is recommended to lower
PSA= 2.6 ng/mL in < 60 y.o. to double detection rate from 18% to 36% and specificity
would remain high, 0.98-0.94.
S Bagnall (Sem Oncol 2003;30:587-95). Propose wait and defer treatment in patients with
PSA doubling time > 2y, Gleason <7 and PSA <10, because only 20% present with
progressive disease…
***H Lilja et al (JCO 2007;25:431-6). PSA/Kallikrein-2 analysis at age 44-50 y.o. in
Swedish Heart Study, retrospective analysis of prostate cancer and matched control groups
and studied archived serum for both markers. Total PSA (lineal increase) > 1ng/mL
predicted prostate cancer15 to 25 years later (HR 3.69).
PROSTATE CARCINOMA- BENIGN PROSTATIC HYPERTROPHY A Thorpe and D Neal (Lancet 2003; 361:1359-67). BPH >50% of >60 y.o. cause lower urinary tract symptoms and 25% end with prostatectomy due to urinary retention. Acute urinary retention (uncomplicated by renal impairment, large residuum, infection or hematuria) can be treated with alfa-adrenergic blockers (doxazosine, Urolosin 0.4 qd, Omnic 0.4 qd) and have a 40% success rate at medium term finally ending with catheter and surgery. Surgery success relates only to obstruction (flow rates <10 mL/second). Finasteride and Dutasteride (5 alfa reductase inhibitor) reduce BPH at medium term and has 80% success rate. Surgical alternatives: TURP, open resection, laser-holmium (Wavelenght 2140, 0.4 mm depth) or hyperthermia transurethral /transrectal as outpatient (>60% improvement). ED Vaughan (NEJM 2003; 349:2449-51). Finasteride + alfa blocker better than each agent alone. In addition protects of cancer (review study for the high grade incidence of prostatic cancer in Finasteride study). PROSTATE CARCINOMA- CHEMOPREVENTION Peripheral androgen blockade (no decrease in libido/potency) accomplished with Finasteride (5 alfa reductase inhibitor) 5 mg/d in combination with Flutamide 125 mg/ bid-tid or Bicalutamide 50-150 mg/d. Select patients with high grade PIN or early tumor (low risk) under observation management. ****** IM Thompson et al (NEJM 2003; 349:215-24) Prostate cancer prevention trial (PCPT) N=18.882 males >55 yo, negative digital/PSA control, and prior PSA<3, randomized to Finasteride 5 mg qd (PC 803/4368 , 18.4%, Gleason 7-10 N=280) vs Placebo (PC 1147/4692, 24.4%, Gleason 7-10 N=237). Reduction of PC 25% and increased high grade HR 1.27) *****IM Thompson et al (NEJM 2004; 350:2239-46). After 7 y Biopsy found PC in N= 449 (15.2%) and Gleason>7 in N=67 (14.9%). PSA up to 0.5, PC 6.6% (high grade 12.5%) showing lineal increase up tp PSA 3.1-4, PC 26.9% (high grade 25%). ***Y Lotan et al (JCO 2005; 23:1911-20). Reduction of cancer due to Finasteride was 25%. High grade detected earlier and gave a 1.7 mo survival advantage in a 15 y cause specific survival (significative any advantage above 1 mo). Balance cost of treatment, decrease in libido/impotency, less number of patients treated for PC and less patients treated for BPH/urinary symptoms. ***********IM Thompson et al (JNCI 2006; 98:1128-33). PC in placebo group 1111/5112 (with Gleason >7, 240) and PC in Proscar group 695/4579 (with Gleason >7, 264). Differences attributed to a better AUC for PSA and consequently a better accuracy. PSA sensitivity after Finasteride is higher, AND THEREFORE RECOMMEND REPEAT
BIOPSY IN CASE THAT PSA DECREASE IS <50% AFTER 6 MONTHS PROSCAR.
EA Platz et al (JNCI 2006;98:1819-25). Statin reduced advanced PC (RR 0.39).
PROSTATE CARCINOMA- CLINICAL ASPECTS
G Raj et al (Cancer 2002; 94:987-96). 111In-Capromab pendetide (MoAb PSMA,
Prostascint) tested in N= 255 treated with RT only and PSA<4. Prostascint showed 72%
positivity (CT 12% and bone scintigraphy 16% only); divided in one third local, one third
regional and one third distant disease. Not randomized study data… Need validation…
A D´Amico et al (Cancer 2002; 15:2041-3). PSA doubling time after RT or RP correlated
with 5 y OS: PSA DT < 1 y 5 y OS 10%, PSA DT > 1 y, 5 y OS 52%.
M Harisinghani et al MGH (NEJM 2003; 348:2491-9). MRI with lymphotropic
superparamgnetic nanoparticles (2.6 mg iron/kg body weight) in 15-30 min iv (Combidex,
Advanced Magnetics USA and Sinerem, Guerbet, Netherland). MRI was done before and
repeated 24 h later. N=80 patients, Gleason 7, Ly no 334. Sensitivity 100%, specificity
95.7%, accuracy 97.5%, positive predictive value 94.2% and negative predictive value
100%.
A D´Amico et al (JNCI 2003; 95:1376-83). PSA doubling time < 3mo after radical
prostatectomy or RT defines a poor survival group (<6y after PSA failure) as compared
with > 3mo (10 y DSOS) indicating a group which requires early therapy (Hx or others).
A Polack et al (JCO 2003;21:1238-48). DNA ploidy. Diploid 5 y OS 70% vs non diploid 5
y OS 42%. Salvage HT after RT correlates response with ploidy.
A D´Amico et al (NEJM 2004;351:125-35). Annual PSA increment >2ng/mL is associated
with high risk and lower OS.
NCCN Guidelines 2005
Low risk (T1-2a, Gleason 2-6 and PSA <10):
Life expectancy <10 y: 3D-RT, Brachy or observation management
Life expectancy >10 y: 3D-RT, Brachy or prostatectomy s/c pelvic lymphadenectomy or
observation management
Intermediate risk (T2b-2c, Gleason 7 OR PSA 10-20):
Life expectancy <10 y: 3D-RT, c/s Brachy or radical prostatectomy c/s pelvic
lymphadenectomy or observation management
Life expectancy <10 y: 3D-RT, c/s Brachy or radical prostatectomy c/s pelvic
lymphadenectomy
High risk (T3a, Gleason 8-10 OR PSA >20): 3D-RT + Hx 2-3 y (6 mo only one factor), or
radical prostatectomy c/ pelvic lymphadenectomy
Very high risk (T3b-4): 3D-RT + Hx or Hx alone.
S Watcher et al (JCO 2006; 2 4:2513-9). 11C-Acetate PET (active in renal and prostatic
cancer) was used to confirm diagnosis of biochemical recurrence & unknown tumor sites
(fusion CT & MRI imaging), and successfully defined anatomical implant sites in 73% of
foci. After the study management was changed in 14/50 patients.
D Petrylak et al (JNCI 2006; 98:516-21). Surrogate end point of OR: PSA 30% decline at 3
mo (better than 50% decrease) according to SWOG data. Pending validation.
H Ballentine Carter et al (JNCI 2006; 98:1521-7). PSA velocity >0.35 ng/mL/year
predicted for mortality due to PC 10-15 years before the diagnosis was made, and at a time
when disease is curable and early stage.
YJ Choi et al (RG (RSNA) 2007; 27:63-75). MR functional imaging technology:
Conventional T2 loss of high signal indicates PC in peripheral zone. Dynamic contrast
enhanced MRI with fast washout indicate PC in central and peripheral zone but is difficult
to see in transitional zone. Diffusion weighted imaging identified PC with restricted
diffusion (Brownian movement of water) and gives false positives due to post biopsy
hemorrhage up to 6 wks after the procedure. MR spectroscopy showing inversion of peaks
Choline-creatine: Citrate (normal values are citrate high and choline-creatine low) is of
interest in intermediate risk and suspected recurrence after treatment (HX, Surgery or RT)
and in case of discordant clinical or biopsy results.
PROSTATE CARCINOMA- LOCAL THERAPY
*P Anderson et al, G Hanks, Fox Chase PA (Cancer 2000; 89:2565-9). N=163, Gleason >7
score T1-3. PSA<10 <76Gy, 5y Biochemical NED 70% and >76 Gy, 5 y BChNED 100%;
PSA10-19.9 <76Gy, 5y BChNED 42% and >76 Gy, 5 y BChNED 83%; PSA>20 <76Gy,
5y BChNED 21% and >76 Gy, 5 y BChNED 20%; So PSA>20 universally poor OS
requiring multidisciplinary therapy.
A Pollack et al MDACC (JCO 2000; 18:3904-11). N=305, 1-3. Randomized 70 Gy (5yDFS 69%) vs 78Gy (5yDFS 79%), main benefit for PSA>10 and no differences for PSA<10. G Duchesne (Lancer 2001; 2:73). Review advances of RADIOTHERAPY: First conformal RT (3D-CRT) with multileaf reduced 50% normal tissue RT and improvement in anal toxicity from 16% to 8%, GI toxicity from 15% to 5%). Second escalation of the dose (CR defined as PSA 0.2-1.5 ng/mL), >70 Gy benefit poor risk histology (Gleason 8-10) with 10 y OS 27% vs 16%. Third: 3D-CRT dose escalation up to 81 Gy (MSKCC) demonstrated biopsy proven dose-response effect. 81 Gy, 7%; 75 Gy, 48%; 64 Gy, 57%. 3 y NED required >76 Gy (Fox Chase). A randomized trial by MDACC (N>1000) indicated a 4 y RFS (PSA) 67 Gy, 54%; 67-77 Gy, 71%; and >77Gy, 77%. Benefit found for patients with poor risk & PSA>10. Serious side effects with 3D-CRT decrease from 3% to <1%. Fourth: IMRT . N Syed et al (Ca Control 2001; 8:511-21). High dose brachytherapy in poor risk, Gleason 8-10, T3 and PSA >20, with Ir192 implants, 4 sessions of 4 Gy, with associated EBRT 35-50.4 Gy in N=200. Local control with 5 y FU 97%. Rate of severe complications <2% GU & 1.5% GI. Learning curve easier than with permanent implants. Results compared favorably to surgery/EBRT & Brachy with permanent implants. In addition 5 series show similar clinical results… I Abdalla et al (S Hellman) (Ca J 2002; 8:40-6). Metanalysis of radical prostatectomy versus RT published series. Surgery is better but when considering age, health issues and side effects (impotence, incontinence and bowel dysfunction) radiotherapy is best, but differences are small. Ten studies involving N>2600. For Surgery: Age 65.9, 10 y OS 0.67, 10 y DFS 0.83, 10 y MFS 0.76, Incontinence 0.27, Impotence 0.79, Bowel dysfunction 0.12. For Radiotherapy: Age 70.2, 10 y OS 0.49, 10 y DFS 0.76, 10 y MFS 0.70, Incontinence 0.12, Impotence 0.50, Bowel dysfunction 0.12. K Wallner et al (Ca J 2002; 8:67-73). Compared Pd103 & I131 implants. Incontinence higher for I131, small differences. ***M Bolla et al EORTC (Lancet 2002; 360:103-8). N=415, T1-2 G3 and T3-4 N0-1. Randomized RT 50 Gy + Boost 20 Gy /7 wks (5 y DFS 40%, 5 y OS 62% and 5 y Specific DFS 79%) vs RT similar + Goserelin-Cyproterone 150 mg qd x 3 y (5 y DFS 74%, 5 y OS 78% and 5 y Specific DFS 94%). Immediate Hx new standard… L Holmberg et al Scandinavian Prostate Group Study 4 (NEJM 2002; 347:781-9). N=695, T1b-1c-2, M Fup 6.2 y, mage 64 y.o. Randomized Watchful Waiting (deaths 62, PC 8.9%, Other causes 8.9%) vs Radical Prostatectomy (deaths 53, PC 4.6%, Other 10.6%) showing for first time reduction in mortality (distant metastases RH 0.63), and no differences in OS. Same study in term of QOL (G Steineck et al NEJM 2002; 347:790-6) indicated Waiting (erectile dysfunction 45%, urine leak 21% and urine obstruction 44%) better than Radical Prostatectomy (erectile dysfunction 80%, urine leak 49% and urine obstruction 21%) not significant differences. ***A Bill-Axelson et al (NEJM 2005; 352:1977-84). Follow up data showed RP deaths due to PC 50 for watchful waiting and 30 for RP (RR 0.56), in addition to less distant mets (RR 0.6) and local progression rates (RR0.33) favoring RP. Very clear benefit in early tumors (T1b, T1c and T2). P Kupelian et al (JCO 2002;20:3376-85). N=1682, no adjuvant therapy , M F up 51 mo. Randomized RP (8y RFS 72% and T1-2a 51%) vs RP + RT (8y RFS 70% and T1-2a 34%) no impact of RT on outcome, 8 y B-RFS identical. M Roach et al RTOG (JCO 2003;21:1904-11. N=1323, PSA >100, M F up 60 mo, Ly no + 15%. Whole pelvis RT 70.4 Gy + Neoadjuvant Hx x2 mo + Adj Hx x2y improved PFS in high risk patients (4 y PFS 60% vs 44-50% for groups with only NAHT, or Adj HT) S Leibel et al MSKCC (Sem Oncol 2003; 23:6556-60). Dose escalation up to 86-90 Gy is possible with IMRT & 3D-CRT with a constant improvement in cure rate. Also NadjHT improve the results, actually in the range of 10 y OS 95% favorable risk, 90% intermediate risk and 75% unfavorable risk groups. S Freedland et al (Cancer 2004; 100:1646-9). N=1606, T2N0, confined treated with prostatectomy found no differences in 10 y PFS in T2a and T2b (93-95% PFS). A Potosky et al Prostate Cancer Outcomes Study (JNCI 2004; 96:1358-67). Cohort study 1994-1995. Radical prostatectomy (N=901, Sexual function 5 y F up 79%, incontinence 5 y F up 16%, Bowel urgency/hemorrhoids no) and EBR (N286, Sexual function 5 y F up 63%, incontinence 5 y F up 4%, Bowel urgency/hemorrhoids yes) J Sathya et al (JCO 2005; 23:1192-9). N=104, T2-3, M F up 8.2 y. Randomized to Ir implant + EBRT 40 Gy (PSA failure 29%, Bx + 24% and OS 94%) vs EBRT 66 Gy (PSA failure 61%, Bx + 51% and OS 92%), showing better local control. PG Febbo et al (Clin Ca Res 2005; 11:5233-40). Gleason 8-10, T3 or ^SA >20. Neoadjuvant TXT 36 mg/m2 wkly x 6 prior to RP: PSA OR 58%, Maximal MRI OR 25% in 68% and 50% in 21%, no CR. Questionable… SB Hayes and A Pollack (JCO 2005; 23:82004-11) Criteria to use adjuvant RT after RP: Positive margin, PSA doubling time >10 mo, low PSA<1 prior to RT, and Gleason after prostatectomy <7, identify patients with locoregional recurrence in absence of distant metastases. A Stewart et al (JCO 2005; 23:6556-60). In patients with rising PSA after surgery or RT mortality correlated with: post androgen deprivation PSA nadir >0.2 ng/mL and pre androgen deprivation PSA doubling time < 3 mo. AK Lee and A D´Amico (JCO 2005; 23:8192-7). Factors related to local disease progression based on biochemical PSA failure after surgery/RT which indicate possibilities of salvage local treatment are: PSA progression velocity < 2ng/mL/year; interval from initial therapy to PSA failure > 3 y; PSA doubling time post-treatment > 12mo; and Gleason 8-10, no seminal vesicle invasion or lymph node metastases. JA Smith (JCO 2005; 23:8170-5). Da Vinci Robotic assisted laparoscopic prostatectomy improved morbidity and hospital stay, less impotence/incontinence, good margin resection. Requires experience. P Johnstone et al (Cancer 2006; 106:2603-9). SEER Data 1995-2001, N=1093, T4 Ly node +/- and M0. 4 yOS were RP 97%, RT 90%, HT 87%, RT+HT 98%, No Treatment 75%. Ly node negative HR 1 fro RP and 0.81 RT+HT. RP comparable to RT+HT but not single modalities. (Probably RP contained patients with RT/HT…?). G Swanson et al (Cancer 2006; 106:2531-9). In lymph node positive PC retrospective analysis of series: Surgery + HT 5 y OS 70% and 10 y OS 50-60%; while RT + HT (60%, and 60-70%). Single modalities and no therapy worst results (10 y OS 30-40%). J Heymann et al (JCO 2007; 25:77-84). Phase II trial with neoadjuvant androgen deprivation (med 4.7 mo) before RT (less than 6 mo delay) to gain maximal response and then continue with RT and adjuvant HT (total 9 mo): 5 y DFS 63%, 5 y CSS 99%, 5 y OS 89%, most patients recovered potency (65%). EORTC-2296 randomized study compares 2.5 y AD adjuvant with no further AD after NA 3 mo AD/RT+AD concurrence, and complete data is waiting to be published… PROSTATE CARCINOMA- HORMONE THERAPY Prostate Cancer Trialists Group (Lancet 2000; 355:1491-8). 27 randomized trials involving androgen suppression AS (orchidectomy or LHRH analog) alone vs maximal androgenic blockade MAB (flutamide EULEXIN, nilutamide CASODEX, cyproterone acetate ANDROCUR). AS vs MAB gave a 5 y gain of 1.8% (p non-significant); when cyproterone trials are excluded (steroidal toxicity) the gain at 5 y is 2.9% (5 y OS 27.6% vs 24.7%, significant). Cyproterone trials associate with a negative –2.8% survival at 5 y in MAB group. E Small et al (JCO 2000; 18:3595-603). PC-SPES Trial 9 cps/d. N=33 androgen dependent, all >80% PSA decline, MDR 57+ mo, 97% testosterone reduction and N=37 androgen independent (16 with prior ketoconazol), 19 PSA decline >50%, MTT to PSA progression 10 wk. Active in both groups. Orlando M et al (An Oncol 2000; 11:1036-42). Fosfestrol (HONVAN, 100 mg tid) in HT refractory > 2 lines. OR 79%, 21% CR, MDR 3.5 mo, MST 9 mo, MTTP 7 mo. Toxicity: Gynecomastia 38%, edema 32%, GI 19%, DVT 8%, hypertension 5%, hepatotoxicity 2%. G Hanks et al (JCO 2003; 21:3972-8). Long term adjuvant androgen deprivation (R trial)
after RT for T2c-T4 and PSA < 150 ng/mL, provide long term (2 y OS benefit & time to
recurrence) in Gleason 8-10.
A Small et al (JCO 2004; 22:1025-33). Antiandrogen withdrawal response occurs in 15-
30% of patients. Randomized Withdrawal alone (N=132, OR PSA 11%) and Withdrawal
and ketoconazol 400 mg tid + OHCortisone 40 mg qd (N=128, OR PSA 27%), no diff in
OS.
M Smith et al (JCO 2004; 22:2546-53). Randomized Leuprolide 150 mg qd (Bone mineral
density at 12 mo –2.5%, fat mass increase +11%) vs Bicalutamide 150 mg qd (Bone
mineral density +2.5%, fat mass increase +6.4%). Both better than LHRH analogs.
L Bland et al (cancer 2005; 103:717-23). Transdermal estradiol patches 0.1 mg/24 h x 6 qd
in AIPC: OR 3/24 (12.5%), no thromboembolism side effects.
M Bhandari et al (JCO 2005; 23:8212-8). Intermittent androgen deprivation defined as stop
after PSA<4, few bone lesions and during interval until PSA=10. It is useful in side effect
reduction (libido and osteoporosis), and delay androgen independent growth. Good basic
rationale and at least 3 ongoing Phase III trials: EORTC (EC507) IAD vs CAD (cont) fro
PSA relapse after prostatectomy: Preliminary results show no diff PFS. NCIC (PR7)
looking for PSA failure after RT in 1304 patients. INT (0162) Newly diagnosed prostate
cancer in 1512 patients. Trials are due soon…
N Nakabayashi et al (Cancer 2006; 107:975-81). Low dose ketoconazole 200 mg tid, OR
39/138 (PSA >50%, 28.3%) MTTP 3.2 mo, then High Dose ketoconazole 400 mg tid OR
PSA 7/55 (12.7%). Recommend starting with a low dose after progression to initial HT.
M Smith (Clin Ca Res 2007; 13:241-5). LHRH effect less in obese man related to higher
testosterone (x1.8-2.3) as compared with normal BMI man.
W Philip et al N=90 AIPC. Randomized PC SPES (PSA 50 response 40%, MTTP
5.5mo) vs DES (PSA 50 response 24%, MDR 3.8 mo, MTTP 2.9 mo. Detection of DES
identified in PC-SPES and the trial was stopped.
PROSTATE CARCINOMA- CHEMOTHERAPY
R Morant et al SAAK (Ann Oncol 2000; 11:183-8). GEM 1000 mg/m2 2 h iv infusion d 1,
8, & 15 q 4 wk. N=43, Hx refractory. Results: 3/43 PSA response, 1 CR + 3 PR + 7 NC.
MDR 6.6-11 mo. Pain Palliation 32%.
DM Savarese CALGB (JCO 2001; 19:2509-16). N=47. EM 280 mg tid x 14 d + TXT 70 mg/m2 + OH Cortisone 40 mg qd x 14d. N=47. 3 CR + 9 PR/24 evaluable, measurable patients. PSA response 68% (44 patients), PSA75= 57%. Combined PSA/clinical OR 54%. WK Kelly et al MSKCC (JCO 2001; 19:44-53). N=56. TXL 100 mg/m2/wk + EM 10 mg/kg + CBDCA AUC6, repeat q 4 wk. PSA 50 response 67%, clinical OR 6%CR + 39% PR, MTTP 21 wk MOS 19.9 mo. S Cooper et al (Sem Oncol 2001; 28:16-21). TXT 35 mg/m2 wkly x 2 + EM 420 mg po bid x 21 d + DXMTS 4 mg po bid x 3d, repeat q 3 wk. N=30. PSA response 76%, pain response 70%, OR 3CR + 4 PR/12 measurable dx. Mild toxicity. **W Figg et al (Clin Ca Res 2001; 7:1888-93). Thalidomide 200-1200 mg/d . N=63 AIPC. PSA response 18%. Thalidomide increased PSA secretion… C Papandrou et al MDACC (JCO 2002; 20:3072-80). N=38, small cell carcinoma of the prostate. ADM 50 mg/m2 + CDDP 25 mg/m2 x 3 d + VP 120 mg/m2 x 3 d, all q 4 wk. N=38. OR 61% (22 pr), MTTP 5.8 mo, MOS 10.5 mo. Not better than CDDP-VP. D Daliani et al MDACC (Cancer 2003; 97:561-7). N=52 AIPC. CPA 250 mg/d po x 14 d + VCR 1 mg d 1, 8, & 15 + DXMTS 0.75 mg bid x 14 d, repeat q 4 wk. PSA response 29% and clinical OR 25%, MPFS 10 wk, MOS 10.6 mo. D Smith et al (Cancer 2003; 98:269-76). N=20 AIPC. EM 280 mg tid x 7 +VP 50 mg qd x 7 + TXL 135 mg/m2 1 h iv + CBDCA AUC 5 d 1, repeat q 3 wks. OR 58% (7/!2 measurable disease, all PR. PSA response 58% (11/20). MTTP 5.5 mo, MOS 14.2 mo. A Mench et al (Cancer 2003; 98:2192-8). N=40 AIPC. TXL 50 mg/m2 d 1, 8 & 15 + VP 50 mg po bid d 1-10 + EM 280 mg po tid d 1-10, repeat q 4 wks. OR 35%. MST 9.5 mo. AM Glode et al (Cancer 2003; 98:1643-8). Metronomic CPA 50 mg/d am + DXMTS 1 mg/d pm. N=34. PSA 75 response 29% and PSA 50 response 39%. MDR 8 mo. ***B Hellerstedt et al (Cancer 2003; 98:1603-10). N=36. CPA 100 mg qd d 1-20 + PRDNS 10 mg qd continuously + DES 1 mg qd continuously + Warfarin 1 mg/d prophylaxis. OR 42%, MDR 4.5 mo, MOS 16 mo. D Vaughn et al (Cancer 2004; 100:746-50). EM 140 mg tid d-1 to d+1 (3d) + TXL 90 mg /m2 iv 1 hr wkly x 3, repeat q 4 wks. N=63 AIPC. PSA 50 response 42% and OR 15%, MTTP 6.3 mo, MTTP (PSA) 11.4 mo. W Dalnut et al (JCO 2004; 22:2532-9). Randomized TXT 30 mg/m2 wkly x 3 q 4 wk (N=25, PSA 50 response 37%, MPFS 3.7 mo, 18 mo OS 42.9%) vs TXT + Thalidomide 200 mg/qd + low molec weight heparin prophylaxis (N=50, PSA 50 response 53%, MPFS 5.9 mo, 18 mo OS 68.2%) **D Petrylak et al SWOG (NEJM 2004; 351:1513-20). N=770. Randomized: EM 280 mg tid x 5 + TXT 60 mg/m2 d 2 + DXMTS 60 mg divided in three doses before TXT q 3 wk (N=338, MOS 17.5 mo, MTTP 6.3 mo, PSA 50 response 50% and OR 17%) vs MTZ 12 mg/m2 d 1 + PRDNS 5 mg bid qd q 3 wk (N=336, MOS 15.6 mo, MTTP 3.2 mo, PSA 50 response 27%, OR 11%). C Papandreu et al MDACC (JCO 2004; 22:2108-21). Bortezomib Phase I MTD/RD 1.6 mg/m2 wkly x 4-5 wk q 6 wk. Assay demonstrated inhibition of 20SPI. Mild diarrhea. **I Tannock et al (NEJM 2004; 351:1502-12). N=1006 AIPC. Randomized MTZ 12 mg/m2 + PRDN 5 mg qd, repeat q 3 wk (MST 16.5 mo, PSA 50 response 22%), vs TXT 75 mg/m2 + PRDN q 3 wk (Death rate 0.91, MST 18.9 mo, PSA 50 response 35%) vs TXT 30 mg/m2 wkly x 5 q 6 wk + PRDN (Death rate 0.76, MST 17.4 mo, PSA 50 response 31%. *S Oudard et al (JCO 2005; 23:3343-51). N=130 AIPC. Randomized TXT 70 mg/m2 d 2 + PRDN 10 mg qd q 3 wk (PSA 50 response 67%, MTTP PSA 8.8 mo, OS 18.6 mo), vs TXT 35 mg/m2 d 2 q 3 wk + PRDN + EM 280 mg po tid d 1-5 & 8-12 (PSA 50 response 63%, MTTP PSA 9.3 mo, OS 18.4 mo) vs MTZ 12 mg/m2 + PRDN (PSA 50 response 18%, MTTP PSA 1.7 mo, OS 13.4 mo). **A Tolcher et al (Clin Ca Res 2005; 11:3854-61). Oblimersen sodium (antibcl2) civi d 1-8 (7 mg/kg/d) + TXT d 6 75 mg/m2 q 3 wk. PSA 50 response 52%, OR 33% (4/12). MST 19.8 mo. OR was 86% when Css >5 ug/mL & only 25% with Css <5 ug/mL. There was a 50% decrease in Bcl2 in PBMN cells. This would indicate the need for an individual increase in dose. Doses of 2-3 mg/kg/d had given OR in NHL… ***; Galsky et al (JCO 2005; 23:1439-46). N=92. Randomized to Ixabepilone 35 mg/m2 q 3 wk (PSA response 48%, OR 32%, TTP PSA 4.4 mo) vs Ixabepilone + EM 280 mg po tid d 1-5 (PSA response 69%, OR 48%, TTP PSA 5.2 mo). Toxicity neutropenia, fatigue, neuropathy. M Hussain et al (JCO 2005; 23:8724-9). Ixabepilone (Epothilone B, BMS-24-7550) 40 mg/m2 in 3 hr iv q 3 wk. N=48 chemo-naive, KPS 0-1, AIPC. PSA response 33%, MPFS 6 mo, MOS 18 mo. J Ferrero et al (Cancer 2006; 107:738-45). TXL 35 mg/m2/wk x 3 + XEL 625 mg/m2 bid, d5-18 q 4 wk x 4. PSA 50 response 30/44 (68.2%), OS 17.7 mo, Mild toxicity. ***ME Taplin et al (JCO 2006; 24:5408-13). N=62 no mets, PSA PD, after RT/surgery (literature data indicate HT alone < 1y control). TXT 70 mg/m2 q 3 wk + EM 280 mg tid d 1-5 x 4 cycles, and then Goserelin + Bicalutamide x 15 mo. PSA CR after chemotherapy 53%, CR after HT 63%, 1 y after HT 36% remained in CR PSA response. Testosterone >100 dL in 97% after 1 y (M F up 37 mo). No PD after therapy 41%.53% PROSTATE CARCINOMA- RADIONUCLIDE THERAPY Sm Tu et al MDACC (Lancet 2001; 357:336-41). N=103, excluded small cell and predominantly visceral mets, all had bone mets. Induction therapy: DOX 20 mg/m2 wk 1,3 & 5 + Ketoconazole 400 mg tid x 7 d , alternating with EM 140 mg tid x 7 + VBL 4 mg/m2 wks 2,4 & 6 . All with OH Cortisone 30 mg, avoiding omeprazole with ketoconazole and dairy products and calcium with EM. Repeat q 8 wk x 2-3 if OR. Then randomized to DOX wkly x 6 (N=36, MOS 16.8 mo, HR 2.76) vs DOX x 6 wk + Sm89 first wk (2.035 MBq/kg) (N=36, MOS 27.7 mo), then ketoconazole til PD. Mfup til death in 67 patients. Bone targeted consolidation therapy. R O´Donell et al G De Nardo (Clin Ca Res 2001; 7:1561-8). RIT In111-2IT-BAD m170 (M170 mouse MoAb targeting adenocarcinoma) for imaging and Y90-2IT-BAD m170 for therapy (0.185-to 0.740 GBq/m2. MTD 0.740 GBq/m2 (<10% skeletal), 7/13 pain resolution, 7CR, MDR 4.3 wk. W Akerley et al (cancer 2002; 94:1654-60). N=44. EM 600 mg qd wks 1-4 & 7-10 + VBL 4 mg/m2 wkly 1-4 & 7-10 + Sm89 2.2 MBq/kg d 1, repeat q 12 wks. OR 48%, MDR 13 mo, 2 y OS 25%. Only 9 required EBRT. Combination is safe. H Palmedo et al (JCO 2003; 21:2869-75). Rhenium188 (Beta emitter, ½ alfa 17 h, easy generation) one or two doses q 8 wks, required 48 h admisión. N=64. Randomized single 1.1 uCi/kg vs double dose. Pain control 74%. PSA response: single 7 mo OS and double 12.7 mo. M Milowsky et al (JCO 2007; 25:540-7). In111-JS91 (PSMA targeting) actually is directed to neovasculature, not to PSA. Many solid tumors have PSMA. This is a trial of radiotergeted vascular therapy in solid tumors. PROSTATE CARCINOMA- SURAMIN M Hussain et al (JCO 2000; 18:1043-201). Suramin 78 d fixed dose schedule d 1-5 (1100, 400, 300, 250, 200) and then repeat d 8, 11, 15, 19, 22, 29, 36, 43 (275 mg) q 6 mo x 4. N=62 patients. 54% acceptable toxicity, neurotoxicity grade IV 11 patients. 46% had peak levels >300 ug/mL. No CR or PR, 53% NC and 16% PD. Toxicity lead to termination of the study in 33/59 patients (56%). E Small et al (JCO 2000; 18:1440-50). Double blind placebo controlled, prior HT all patients, HRPC. Randomized Suramin 78 d (1 g/m2 d 1, 400 mg/m2 d2, 300 mg/m2 d3, 250 mg/m2 d 4, 200 mg/m2 d 5 and then 250 mg bi wk x 2 & 250 mg/m2/wk x 8 (plasma suramin levels probably 100-300 ug/mL) + OH Cortisone 40 mg/d vs Placebo + OHCortisone and then crossover. Pain reduction 43% vs 28%, MDR 240 d vs 69 d, MTTP RR 1.5, PSA reduction 50% 33% vs 16%. Side effects suramin: rash 57%, asthenia 54%, edema 54%, N&V 44%, fever 33%, anorexia, dyspnea, paresthesia, anemia. E Small et al (JCO 2002; 20:3369-75) N=390. Randomized Suramin low dose 3.192 g/m2 (MST 16, OR 9, PSA OR 24), Intermediate 5.320 g/m2 (MST 14, OR 7, PSA OR 28) and high dose 7.661 g/m2 (MST 13 mo, 15%, PSA OR 34%). No differences in OR nor survival. N Vogelzang et al (Cancer 2004; 100:65-71). Suramin 2.4 g/m2 d1, 1.62 g/m2 d 29, & 1.29 g/m2 d 57 with dexamethasone 0.5 mg bid. N=56. PSA OR 21 (37.5%), Clinical OR 5/27 (1 CR). MOS 15.3 mo. Fatigue 14%. OR after ChX 42%. Active… PROSTATE CARCINOMA- QUALITY OF LIFE F Saad et al (JNCI 2002; 94:1458-68). N=643, PD to HT. Randomized Zoledronate (skeletal events 34%) to placebo (skeletal events 44%). Analgesic, PS, QOL. And time to skeletal event favored Zoledronate. R McDermott et al (Cancer 2004; 101:1639-43). Cranial nerve deficit in 15 pts, all with skull base metastases. 67% death in 3 mo. V Shahinian et al (NEJM 2005; 352:154-64). SEER data on 50.613 pts. Risk of bone fracture with androgen deprivation therapy 19.4% (controls only 12.6%). D Sartor et al (Cancer 2007; 109:637-43). Sm 153, 1 mCi/kg, for bone pain. N=202. Leokothrombopenia median 4 wk, recovering at wk 8 (90%). Multiple doses cumulative incidence. Decreased bone pain 60-80% at wk 4, after each of 1-3 administrations. MD Michaelson et al (JCO 2007; 109). N=40. Administration of LHRH analogs decrease T –2.5% bone density. Randomized trial with Zometa 4 mg x 1 (Lumbar spine +4.0, hip +0.7) vs placebo (lumbar spine –3.1%, hip –1.9%). PROSTATE CARCINOMA- IMMUNETHERAPY P Burch et al (Clin Ca Res 2000; 6:2175-82). N=13. Autologous dendritic cells exposed to a fusion protein (PA2024) consisting in GM-CSF/ human Prostatic acid phosphatase. 0.3-1 mg/injection iv q 1 mo x 2 and then sc q 1 mo x 3. PSA response in 3. Ab against PA2024 & GM-CSF after 2-3 injections (humoral immunity). N Bander et al (Sem Oncol 2003; 30:667-77). J591, MoAb against PSMA. Phase I: In111 tracer 100 mg/m2 and then maintenance 50% dose up to 500 mg/m2 showed good tumor targeting. N=53 treated with Y90-DOTA-J591 trial, MTD 20 mCi/m2. No HAHA, multiple doses allowed. On going… M Milowsky et al (JCO 2004; 22:2522-31) N=29 AIPC. In111-J%)! And 1wk later Y90-J591 5-20 mCi/m2. MTD 17.5 mCi/m2, DLT 20 mCi/m2. No HAHA & HAA. PSA response 2 and NC 6. W Bander et al (JCO 2005; 23:4591-601). Lu177-J591. N=35 up to 3 doses (30 mCi/m2). Myelosuppression at 75 mCi/m2, MTD 70 mCi/m2. PSA 50 response 4 patientsand stabilization x 2 mo 16 patients. B Rini et al (Cancer 2006; 107: 67-74). APC 8015 (autologous presenting cells loaded with PA2024) + BV 10 mg/kg wk 0, 2 & 4. N=22, PSA PD 0.4-6 ng/mL, non metastasic. PSA response 1 and minor response 9 patients. JW Simons et al (Clin Ca Res 2006; 12:3394-401). LNCaP 6x10e7 + PC-3 6x10e7 transfected with GM-CSF, id wkly x 8. N=21: 16 decrease in PSA, 1 response. Biopsies demonstrated dendritic cell infiltrates/macrophages (CD1a/CD68+), oliclonal Ab against cell lines. EJ Small et al (JCO 2006; 24:3089-94). Sipuleucel T (APC 8015) (autologous AP cultured with fusion protein PAP-GMCSF, PA2024) stimulator of T cell immunity to prostatic acid phosphatase. N=227. MTTP 11.7 wk vs 10 wk for placebo, MST 25.9 mo vs 21.4 mo for placebo. E Small et al (Clin Ca Res 2007; 13:1810-5). CTLA4 blockade with Ipilimumab (MDX 010, BMS 734016), 3 mg/kg in N=14: 2 PSA response, autoimmune disease in 1 (skin and pruritus). On going. PROSTATE CARCINOMA- DEVELOPMENTS ***D Deteo-Jones et al (Nature Med 2000; 6:1248-52). L377202 peptide DOX lysed by PSA. Data in mice favorable for PSA secreting tumors. **R DiPaola et al (JCO 2002; 20:1874-9). Phase I with L377202. N=19 AIPC. MRD 225-mg/m2. PSA metabolized peptidic compound to Leu-DOX and DOX. 5 patients were treated at the recommended dose: 2 PR and 1 NC. At levels < 225 mg/m2 no activity was found. D Solit et al (Clin Ca Res 2002; 8:986-93). Ansamycin derivatives (17 AAG block Her2 and AR expression… S Denmeade et al (JNCI 2003; 95:990-1000). Peptide carrier- thapsigargin to be cleared by PSA at tumor sites. Mice study showed that serum prodrug concentration at 7 mg/kg of 15.4 uM and ½ alfa time 2.8 hr. In 24 hr only 0.5% free drug in plasma). Tumor responded with no further growth in case of PSA producing xenografts only… L Lassiter et al (Sem Oncol 2003; 30:678-88). Atrasentan (Endothelin receptor antagonist ET1. Phase I-II, 2.5 mg qd. Toxicity: edema, headache, dyspnea anemia, all mild. Pain response 40%. AJ Pantuck et al (Clin Ca Res 2006; 12:4018-25). Rising PSA after surg/RT >0.2 & <5 ng/mL. Pomegranate juice 570 mg equivalent gallic acid til progression. PSA doubling time improved from 15 mo baseline to 54 mo after therapy. Very active…

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