Presentazione sul tema: "Teresa Gamucci Sora-Frosinone"— Transcript della presentazione:
1 Teresa Gamucci Sora-Frosinone Highlights in the Management of Urogenital CancerImproving the standard of care for patients with hormone resistant prostate cancerTeresa GamucciSora-FrosinoneRoma 9 Maggio 2008
2 Tumore della prostata ormonorefrattario Circa l’80% dei paziente affetti da Ca della prostata metastatico che ricevono un blocco androgenico andrà in progressione entro 24 mesiSopravvivenza mediana 12 mesi dalla progressioneSopravvivenza in relazione alla tipologia di presentazione:18 mesi in caso di sola progressione biochimica12 mesi in caso di progressione clinica asintomatica6 mesi in caso di progressione clinica sintomatica
3 Tumore della prostata ormonorefrattario Prima del 1991 :HRPC 26 studi di fase II con agenti singoliRR 8.7 % Median Survival mesiTumore della prostata : neoplasia non chemioresponsivaYagoda, Cancer 2003
4 Tumore della prostata ormonorefrattario Tannok I: J Clin Oncol, 1996Kantoff P: J Clin Oncol, 1999Due studi randomizzati dimostrano un vantaggio in QoL ed in “pain relief “ utilizzando Mitoxantrone e Corticosteroidi vs solo Corticosteroidi(non vantaggio in sopravvivenza)
8 Tumore della prostata ormonorefrattario Tannok I: N Engl J Med, 2004Petrylak D: N Engl J Med, 2004Due grandi studi di fase tre con Docetaxel dimostrano un vantaggio in sopravvivenza per i pazienti trattati rispetto a quelli trattati con Mitoxantrone e Corticosteroidi
10 At a median follow-up of 32 months, 64% (217/338) of the patients randomized to docetaxel and 70% (235/336) ofthe patients randomized to mitoxantrone had died. Both overallsurvival and disease-free survival were significantly longerwith docetaxel plus estramustine than with mitoxantroneplus prednisone (Table 2). The relative risk for death was
11 SWOG 9916 : N Engl J Med 2004 Docetaxel 3-weekly plus Estramustine Ph significantly improves :OS 17.5vs 15.6m p = 0.02HR (95% CI )PSA response vs 27 % p=Objective response vs 11 % p= 0.15Median time to prog vs 3.2 m p= 0.001
12 Toxicities were significantly higher in the docetaxel– estramustine group. Sixteen percent of patients in thedocetaxel–estramustine group and 10% in the mitoxantrone–prednisone group discontinued treatment as a resultof adverse events. Rates of grade 3–4 neutropenia did not
13 Toxicities were significantly higher in the docetaxel– estramustine group. Sixteen percent of patients in thedocetaxel–estramustine group and 10% in the mitoxantrone–prednisone group discontinued treatment as a resultof adverse events. Rates of grade 3–4 neutropenia did notdiffer between groups, but the incidence of severe and lifethreateningfebrile neutropenia was higher with docetaxelplus estramustine (5% vs. 2%; p =.01). Gastrointestinal,neurologic, metabolic, and cardiovascular events were alsosignificantly more common with docetaxel plus estramustine.The protocol was amended about halfway through itsaccrual to include prophylactic use of warfarin and aspirin;however, this did not appear to reduce the initial incidenceof severe thromboembolic complications.
16 TAX 327 : OVERALL SURVIVAL D3P vs MP + 2.9 months P =.004 HR =0.79 survival analysis was performed in August 2003 when 557deaths had occurred. By March 2007, 310 additional deaths wererecorded, resulting in a total of 867 deaths; 111 patients have been lostto follow-up, and 28 patients were alive with a last follow-up datewithin the previous year. Updated survival curves are shown in Figure1, and details are listed inDR Berthold JCO 2008
17 TAX 327: JCO 2008 Docetaxel 3-weekly significantly improves : OS vs 16.3 m p =.0009HR (95% CI )PSA response vs 32 % p=Objective response vs 7 % p= 0.11Pain response vs 22 % p= .01QoL (FACT.P) vs 13 % p= .009
18 When compared with the previous analysis, the difference in median survival between the D3P and MP arms hasincreased slightly to 2.9 months, the hazard ratio (HR) has changedminimally, and the P value is slightly stronger (P.004). The differencein survival between the D1P and MP arms remains nonsignifi-cant (P .09). The percentages of patients who survived for morethan 3 years in the D3P, D1P, and MP arms were 18.6%, 16.8%, and13.5%, respectively (Table 1).Subgroup AnalysesMedian survival times and 95% CIs for the defined subgroups as
19 Similar trends in survival between treatment arms were seen for patients greater than and less than the median age of 68 years. The HRsfor younger and older patients were 0.81 and 0.77, respectively, forD3P compared with MP. Similar results were found when using amore extreme age cutoff of 75 years (HR0.80 for older patients).(20% del totale)
20 In the TAX 327 study, the median serum PSA at baseline was 115ng/mL In the TAX 327 study, the median serum PSA at baseline was 115ng/mL. Among patients with lower and higher PSA levels at baseline, theHRs were 0.83 and 0.73, respectively, indicating similar benefits of D3Pcompared withMPfor patients with a greater or lesser burden of disease.The presence of visceral involvement is a known adverse prognostic factor for men with metastatic prostate cancer when compared with patients with only bone and/or nodal disease. In the present study, the 22% of patients with visceral disease died on average 6 months earlier than those without visceral metastases. The HR was0.87 for the subgroup of men with visceral metastases when comparing D3P with MPcompared withMPfor patients with a greater or lesser burden of disease.The presence of visceral involvement is a known adverse prognosticfactor for men with metastatic prostate cancer when comparedwith patients with only bone and/or nodal disease. In the present
21 There were 456 patients with substantial pain at baseline (defined by PPI2 and/or AS10), and survival time was shorter for thosewith pain. The HRs for patients without and with pain were 0.73 and0.85, respectively, for D3P compared with MP.
22 Patients with a KPS 90% lived approximately 8 months longer than patients with aKPS80%; however, theHRsfor these groups weresimilar at 0.75 and 0.82, respectively, for D3P compared with MP.
23 Men with better or worse QOL, as indicated by their FACT-P score at baseline, had HRs of 0.92 and 0.66, respectively, when treatedwith D3P compared with MP. For minimally symptomatic patients
24 For minimally symptomatic patients (FACT-P score128, PPI2, and AS10), the trend for survivalbenefit was maintained for D3P compared with MP.
25 Therefore, the earliermentioned factors are indicators of poor prognosis but not predictorsof response
27 HRCP: confronto fra gli studi SWOG 99-16TAX 327Soprav. Docet18 mesi19.2 mesiSoprav. Mitox16 mesi16.3 mesiMiglioramento OS2 mesi2.5 mesiHR0.800.79RR PSA Docetax50 %45.4 %RR PSA Mitox27 %32 %
28 Tumore della prostata ormonorefrattario The HRs for death similar in the TAX327 and SWOG 9916The secondary endpoints (PSA response, pain response, and QoL response)The docetaxel–prednisone regimen appeared to be better toleratedDocetaxel plus prednisone is the appropriatechoice for the first-line treatment of HRPCThe regimen approved for use in HRPC in the U.S. and EuropOudard and colleagues  conducted a meta-analysisusing the data from all three trials to determine if theschedule of docetaxel treatment affected survival. Theyassessed overall survival at 12, 18, 24, 30, and 36 monthsand evaluated the impact of weekly and Q3W therapy onoverall survival. Using combined data from 1,807 patients,they found that overall survival was significantly greaterwith docetaxel at all time points evaluated. The relative riskfor death ranged from 8%–21% lower. As in TAX327, thedifference in survival was significant for the comparisonof Q3W docetaxel with MP but not for weekly docetaxelcompared with MP. Second, the utility of estramustineand its associated toxicity is another important consideration.Because the HRs for death and the secondary endpoints (PSA response, pain response, and QoL response)were similar in the TAX327 and SWOG 9916 trials, yet thedocetaxel–prednisone regimen appeared to be better tolerated,it is reasonable to conclude at this time that treatmentwith docetaxel plus prednisone alone is the appropriatechoice for the first-line treatment of HRPC. The regimenapproved for use in HRPC in the U.S. and Europ
29 Tumore della prostata ormonorefrattario : quando trattare In contrast to the earlier Canadian study1 that evaluated mitoxantrone,the TAX 327 trial has included patients with and withoutsymptoms. In general, the chances of prolonging survival with D3Pseemed similar among patients with higher and lower disease burdenas indicated by level of serum PSA, the presence or absence of substantialpain, and the QOL or performance score. This analysis does notaddress whether docetaxel should be used in patients with minimalsymptoms or whether it is appropriate to defer treatment until moresymptoms occur. However, considering the similar benefit amongsubgroups and the potential for QOL to deteriorate as a result ofdisease progression, it seems reasonable to offer treatment to patientswith symptoms and to those who are likely to develop symptoms inthe near future, based on the burden of disease and the PSA doublingSternberg CN, ASCO Education ,June 2006
30 Tumore della prostata ormonorefrattario : quando trattare TAX 327 ha incluso pazienti con e senza sintomiLa probabilità di prolungare la sopravvivenza sembra uguale nei pazienti con alto o basso “disease burden”Ragionevole offrire il trattamento ai pazienti sintomatici e a quelli che svilupperanno sintomi nel prossimo futuro basandosi sulla clinica e sul “PSA doubling “In contrast to the earlier Canadian study1 that evaluated mitoxantrone, the TAX 327 trial has included patients with and withoutsymptoms. In general, the chances of prolonging survival with D3P seemed similar among patients with higher and lower disease burden as indicated by level of serum PSA, the presence or absence of substantialpain, and the QOL or performance score. This analysis does not address whether docetaxel should be used in patients with minimal symptoms or whether it is appropriate to defer treatment until more symptoms occur. However, considering the similar benefit amongsubgroups and the potential for QOL to deteriorate as a result ofdisease progression, it seems reasonable to offer treatment to patientswith symptoms and to those who are likely to develop symptoms inthe near future, based on the burden of disease and the PSA doubling
32 HRPC : Trattare tutti nello stesso modo ? Il TAX327, ha dimostrato che la somministrazione settimanale di Docetaxel è attiva anche se non dimostra un vantaggio significativo in sopravvivenza verso il MitoxantroneHR median survivals 17.8 mPSA % (p )QoL % (p 0.005)Trattamento indicato per l’anziano frail
34 Tumore della prostata ormonorefrattario Dal 2004 il trattamento chemioterapico standard dell’HRPC è il DocetaxelSWOG 9916 e TAX 327Complessivamante 1600 pazienti trattatiSWOG 9916: Docetaxel + Estramustina vs Mitoxantrone + Prednisone ↑ 2 mesi in OSTAX 326: Docetaxel q21 + Prednisone vs Mitoxantrone + Prednisone ↑ 2.5 mesi in OS