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La terapia focale nel trattamento del carcinoma alla prostata

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Il dott. Comeri presenta la terapia focale, una nuova frontiera nel trattamento del carcinoma alla prostata

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La terapia focale nel trattamento del carcinoma alla prostata

  1. 1. 1° CONVEGNO SIURO LOMBARDIA Il Carcinoma della prostata nel terzo millennio Centro Convegni LE ROBINIE Solbiate Olona (Va) 25 ottobre 2008
  2. 2. CA PROSTATICO E TERAPIE MININVASIVE LA NUOVA FRONTIERA: LA TERAPIA FOCALE <ul><li>GIANCARLO COMERI </li></ul><ul><li>Multimedica Holding - Ospedale di Castellanza (Va) </li></ul>
  3. 3. American Cancer Society , Cancer Facts & Figures 2005 Relative Survival Rates Survival in relation to men who do not have prostate cancer 1995-2005 stage at diagnosis 90% localized 5% distant
  4. 4. LINEE GUIDA INTERNAZIONALI <ul><li>OPZIONI A TUTT’OGGI VALIDATE PER IL TRATTAMENTO DEL CA PROSTATICO LOCALIZZATO </li></ul><ul><li>Chirurgia radicale </li></ul><ul><li>Radioterapia </li></ul><ul><li>Sorveglianza attiva </li></ul>
  5. 5. QUALE NECESSITA’ DI ALTRI TRATTAMENTI? <ul><li>Mentre i risultati di efficacia sono abbastanza sovrapponibili fra Chirurgia e RT, e un recente lavoro conferma una modesta differenza del 5-6% nella sopravvivenza fra chirurgia radicale e sorveglianza attiva, gli effetti sulla qualità della vita sono piuttosto devastanti con le terapie validate. </li></ul><ul><li>La diagnosi di Ca prostatico sulla scorta di screenings opportunistici basati sul PSA avviene sempre più precocemente e porta a scoprire tumori indolenti o poco aggressivi, talora monofocali, con il rischio sempre più frequente di ”overtreatment” </li></ul>
  6. 6. MORBIDITA’ SECONDARIA ALLE PRINCIPALI TERAPIE PER IL CA PROSTATICO <ul><li>INCONTINENZA URINARIA (almeno 1 evento al dì) </li></ul><ul><li>35% Chirurgia </li></ul><ul><li>12% RT </li></ul><ul><li>11% Deprivazione androgenica </li></ul><ul><li>DISFUNZIONE ERETTILE </li></ul><ul><li>58% Chirurgia </li></ul><ul><li>43% RT </li></ul><ul><li>86% Deprivazione androgenica </li></ul><ul><li>TOSSICITA’ INTESTINALE </li></ul><ul><li>1% Chirurgia </li></ul><ul><li>3% RT </li></ul><ul><li>3% Deprivazione androgenica </li></ul><ul><li>Prostate Cancer Outcomes Study, 2007 </li></ul>
  7. 7. MORBIDITA’ DA TERAPIE RADICALI “AGGIORNATE” <ul><li>La prostatectomia radicale laparoscopica e robotica- </li></ul><ul><li>La RT esterna con le sue più recenti migliorie (conformazionale e IMRT)- </li></ul><ul><li>NON HANNO MIGLIORATO SIGNIFICATIVAMENTE LA MORBIDITA’ DEGLI APPROCCI TERAPEUTICI “WHOLE GLAND” </li></ul>
  8. 8. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. 7% 10% 17% 24% 27% 1% 1% 2% 5% 7% 0 5 10 15 20 25 30 ? 0-0.5 0.6-1.0 1.1-2.0 2.1-3.0 3.1-4.0 PSA Level (ng/ml) % of Men with Prostate Cancer and High- Grade Disease Percent with Prostate Cancer Percent with Gleason > 7 Disease Thompson IM, et al. N Engl J Med. 2004 May 27;350(22):2239-46 . (13%) (10%) (12%) (19%) (25%) Relationship of the PSA Level to the Prevalence of Prostate Cancer and High-Grade Disease
  9. 9. EVIDENZE DA PROSTATECTOMIE RADICALI <ul><li>L’incidenza di tumori monofocali nelle casistiche di prostatectomie radicali varia fra il 13 e il 38% </li></ul><ul><li>(Wise et Al, Urology,2006; Simma-Chiang et Al, J Urol, 2006) </li></ul><ul><li>In molti altri casi si reperta una lesione “indice” con foci secondari dalle caratteristiche analoghe a quelle riscontrate incidentalmente nelle autopsie (= tumore biologicamente monofocale) </li></ul><ul><li>(Eggener et Al, J Urol, 2007) </li></ul><ul><li>Il rischio di estensione extracapsulare è proporzionale al volume del tumore principale </li></ul><ul><li>(Ohori et Al , AUA Meeting 2006 abs. 1574) </li></ul>
  10. 10. TUMORE FOCALE SINGOLO LOW-RISK <ul><li>Il riscontro sempre più frequente di un unico focolaio neoplastico low-risk (basso volume, Gl 3+3) al mappaggio bioptico con > 20 frustoli in soggetti giovani pone la difficile scelta fra rischio morbidità da PR o da RT e rischio progressione + ansietà da Sorveglianza Attiva (AS) </li></ul><ul><li>(Emberton et Al, Nature Clin Pract, 2007) </li></ul><ul><li>Il PCA3 potrebbe essere di ulteriore aiuto anche nella definizione di tumore a basso rischio </li></ul><ul><li>(Nakanishi et Al, ASCO 2007) </li></ul>
  11. 11. The PCA3 Score in low volume /low grade PCa is significantly lower than in significant PCa Low volume: tumour volume < 0.5 mL; Low grade: Gleason Score  6 Nakanishi H, et al. ASCO 2007 Prostate Cancer Symposium: abs. 354
  12. 12. GIUSTIFICAZONI ALLA TERAPIA WHOLE-GLAND <ul><li>Multifocalità del carcinoma prostatico (ma nel 13-38% delle </li></ul><ul><li>prostatectomie radicali si riscontra una forma monofocale) </li></ul><ul><li>(Simma Chiang et al, AUA 2006, abs 1163) </li></ul><ul><li>Le modificazioni del microambiente peritumorale ne favoriscono la crescita (ma solo quelle modificazioni adiacenti al focolaio tumorale) ( Chandran et al, BMC Cancer, 2005) </li></ul><ul><li>Il carcinoma prostatico non può essere localizzato con certezza all’interno della ghiandola (ma le evidenze sono già oggi di segno opposto) </li></ul><ul><li>Mancanza di alternative fino a pochi anni or sono ( ma oggi queste alternative ci sono e sono disponibili) </li></ul>
  13. 13. LIMITI DELLA TERAPIA “WHOLE-GLAND” <ul><li>Oggi lo screening con il PSA comporta overdetection di carcinomi “indolenti” </li></ul><ul><li>(Konety et Al, J Urol, 2005) </li></ul><ul><li>Introduce un lead-time bias di almeno 10 anni (Draisma et Al, 2003) </li></ul><ul><li>Con un decorso più favorevole della malattia la mortalità attesa può essere fra il 7 e l’11% a 15 anni per i pazienti in WW e ancora meno per le forme low-risk (oggi mortalità dopo chirurgia = 7% a 15 anni) (Parker et Al, Br J Cancer, 2006) </li></ul><ul><li>Il più moderno regime di Sorveglianza Attiva (SA) ha ridotto la mortalità Ca specifica allo 0-1% a 8 anni (Van As et Al, ASCO 2007, Abs 319) </li></ul>
  14. 14. ARGOMENTI CONTRO LA SORVEGLIANZA ATTIVA (SA) <ul><li>I criteri per la selezione dei soggetti eleggibili per la sorveglianza attiva non sono ben codificati </li></ul><ul><li>Una discreta percentuale di soggetti selezionati per la SA devono passare alla terapia radicale: 19,9% con FU di 22 mesi in una serie UK ( Hardie et al, 2005) e 22% con FU di 64 mesi in una serie Canadese ( Klotz et Al, 2005). Percentuali ancora più alte sono da attendersi dopo 10-15 anni (Johansson et Al, 2004) </li></ul><ul><li>L’intensivo regime di FU previsto dalla SA, con PSA frequenti e biopsie ripetute, finisce per creare problemi a chi partecipa a questo programma: il 10% circa decide di passare al trattamento radicale indipendentemente dalla progressione di malattia (Van As et Al , 2007) </li></ul>
  15. 15. TERAPIA FOCALE <ul><li>Proponibile e di sicuro appeal se: </li></ul><ul><li>Livelli accettabili e provati di efficacia oncologica </li></ul><ul><li>Assenza virtuale di complicanze genito-urinarie e intestinali </li></ul><ul><li>Fruibile in day surgery </li></ul>
  16. 16. TERAPIA FOCALE <ul><li>Può essere vista come la “quadrantectomia della prostata” </li></ul><ul><li>Indispensabile buona localizzazione topografica del focolaio neoplastico nel contesto della ghiandola </li></ul><ul><li>Indicata per le forme monofocali a basso grading </li></ul><ul><li>Alternativa alla sorveglianza attiva, terapia “ponte” </li></ul><ul><li>Aspettative: buona efficacia controllo malattia con rischio minimo-nullo di complicanze </li></ul>
  17. 17. Ahmed HU et al. (2007) Will focal therapy become a standard of care for men with localized prostate cancer? Nat Clin Pract Oncol 4 : 632 –642 doi:10.1038/ncponc0959 Figure 1 Radical prostatectomy step sections.
  18. 18. CRITERI PER LA SELEZIONE DEI PAZIENTI <ul><li>Proposti da: </li></ul><ul><li>International Task Force on Prostate Cancer and the Focal Lesion Paradigm </li></ul><ul><li>CLINICI </li></ul><ul><li>BIOPTICI </li></ul><ul><li>IMAGING </li></ul><ul><li>( Eggener et Al. J Urol, 2007) </li></ul>
  19. 19. CRITERI CLINICI PROPOSTI PER LA SELEZIONE DEI PAZIENTI <ul><li>Stadio clinico T1c o T2a </li></ul><ul><li>PSA < 10 ng/ml </li></ul><ul><li>PSA Density < 0.15 ng/ml/cc </li></ul><ul><li>PSA velocity < 2 ng/ml/y </li></ul><ul><li>(Eggener et Al, J Urol, 2007) </li></ul>
  20. 20. CRITERI BIOPTICI PER LA SELEZIONE DEI PAZIENTI <ul><li>Minimo di 12 prelievi </li></ul><ul><li>No Gleason grado 4 o 5 </li></ul><ul><li>Massima percentuale di Ca in ogni prelievo: 20% </li></ul><ul><li>Massima estensione in ogni prelievo: 7 mm </li></ul><ul><li>Massima percentuale dei prelievi positivi sul totale dei frustoli: 33% </li></ul><ul><li>(Eggener et Al, J Urol, 2007) </li></ul>
  21. 21. CRITERI DI IMAGING PER LA SELEZIONE DEI PAZIENTI <ul><li>Lesione singola con diametro max: mm 12 </li></ul><ul><li>Estensione max contatto capsulare: mm 10 </li></ul><ul><li>Non evidenza di estensione extraprostatica o di invasione vescicolare </li></ul><ul><li>(Eggener et Al, J Urol, 2007) </li></ul>
  22. 22. SELEZIONE DEI PAZIENTI (1) <ul><li>Al momento la metodica più sicura per diagnosticare e localizzare con precisione un singolo focus tumorale (o un “index tumor”) è la biopsia transperineale eseguita ogni 5 mm con lo stesso template utilizzato per la brachiterapia, in anestesia spinale (= 95% di accuratezza) </li></ul><ul><li>(Emberton et Al, 2007) </li></ul><ul><li>Rebiopsiando con eco 3D e template 110 pts con reperto di Ca monofocale alla biopsia transrettale si è avuta conferma della monofocalità nel 55% dei casi ( Onik e Barzell, 2008) </li></ul>
  23. 23. Ahmed HU et al. (2007) Will focal therapy become a standard of care for men with localized prostate cancer? Nat Clin Pract Oncol 4 : 632 –642 doi:10.1038/ncponc0959 Figure 2 Template mapping biopsies demonstrating 4 cores positive for adenocarcinoma out of a total of 30 cores.
  24. 24. SELEZIONE DEI PAZIENTI (2) <ul><li>Nel prossimo futuro la RMN 3 Tesla multisequencing (immagini T2 pesate + spettroscopia + contrasto dinamico + imaging a diffusione) potrebbe essere accoppiata alla mappatura bioptica migliorando ulteriormente l’accuratezza diagnostica </li></ul><ul><li>L’operatore deve assicurarsi che la localizzazione del tumore consenta il risparmio dello sfintere e di almeno 1 dei 2 bundles per minimizzare i rischi di danno funzionale. </li></ul>
  25. 25. SELEZIONE DEI PAZIENTI (3) <ul><li>Studi sono in corso per validare i risultati ottenibili con un nuovo apparecchio diagnostico ad ultrasuoni ( Prostate Histo Scanning ) che utilizza un software specifico per quantificare la disorganizzazione tissutale indotta dal processo neoplastico all’interno della prostata. Iniziali confronti con i reperti istologici da PR per quanto riguarda la topografia dei foci tumorali mostrerebbero una concordanza vicina al 100%. </li></ul><ul><li>( Braeckman et Al, BJUI, 2007) </li></ul>
  26. 26. TECNOLOGIE A DISPOSIZIONE <ul><li>MINI-INVASIVE: </li></ul><ul><li>Brachiterapia </li></ul><ul><li>Crioterapia </li></ul><ul><li>Terapia Fotodinamica (VTP) </li></ul><ul><li>Termoablazione a Radiofrequenza </li></ul><ul><li>NON INVASIVE: </li></ul><ul><li>HIFU </li></ul>
  27. 27. RISULTATI TERAPIA FOCALE: EVIDENZE AD OGGI CON CRIOTERAPIA <ul><li>Crioemiablazione prostatica in 48 uomini, con 4,5 anni di FU medio: </li></ul><ul><li>bDFS =94%, biopsie positive lobo trattato= 0%, positive lobo controlaterale = 10%, DE = 10%, Incontinenza = 0% </li></ul><ul><li>(Onik et Al, Urolol Oncol 2008) </li></ul><ul><li>Crioemiablazione prostatica in 28 uomini con 70 mesi di FU: </li></ul><ul><li>bDFS = 92,8%, biopsie negative = 96%, DE= 11%. </li></ul><ul><li>(Bahn et Al, J Endourol, 2006) </li></ul>
  28. 28. BRACHITERAPIA <ul><li>Le prime esperienze con monoterapia HDR hanno conseguito percentuali accettabili di bDFS ( Grills et Al, 2006) </li></ul><ul><li>In combinazione con imaging adeguato può essere una tecnologia molto promettente per la terapia focale </li></ul>
  29. 29. TERMOABLAZIONE PROSTATICA CON RF
  30. 30. TERMOABLAZIONE PROSTATICA CON RADIOFREQUENZA <ul><li>Produce una distruzione irreversibile del tessuto prostatico per necrosi coagulativa da temperature oscillanti attorno ai 110° </li></ul><ul><li>Trattamento di una lesione in 10’ </li></ul><ul><li>La dimensione di ogni lesione indotta può essere prevista esattamente in base al tipo di ago usato </li></ul><ul><li>Ripetibile </li></ul><ul><li>Complicanze ridotte se adottate opportune precauzioni </li></ul>
  31. 31. RITA dispositivo con infusione di salina
  32. 32. Precauzioni RF prostatica <ul><li>Utilizzo di sonde endorettali biplanari (fondamentale il controllo dell’esatto inserimento dell’ago con la lineare tassativamente per via transperineale) </li></ul><ul><li>Utilizzo del template per condurre l’elettrodo nella posizione desiderata </li></ul><ul><li>Protezione uretra con catetere 3 vie e infuione continua di acqua fredda </li></ul><ul><li>Allontanamento del retto dal piano prostatico </li></ul><ul><li>mediante idrodissezione </li></ul>
  33. 33. TERMOABLAZIONE PROSTATICA CON RADIOFREQUENZA <ul><li>1 Studio pilota con RITA per il trattamento focale del Ca prostatico </li></ul><ul><li>8 pts ricaduti dopo RT, +3 pts non candidabili per terapia radicale ( Gl 7 e 6) </li></ul><ul><li>FU mediano = 20 mesi </li></ul><ul><li>Trattamento ambulatoriale con sedazione endovenosa. </li></ul><ul><li>PSA ridotto >50% in oltre il 90% dei pts </li></ul><ul><li>Rallentamento del PSA DT </li></ul><ul><li>Biopsia con 12 prelievi negativa a 12 mesi nel 67% dei pts. </li></ul><ul><li>Complicanze minime (macroematuria 19%, Spasmi vescicali 9%,) </li></ul><ul><li>Ben tollerata </li></ul><ul><li>Necessità di numeri più grandi </li></ul><ul><li>( Chariat et Al., Prostate, 2005) </li></ul>
  34. 34. Vascular Target Photodynamic Therapy (VTP) <ul><li>Utilizza fotosensibilizzatori derivati dalla Clorofilla, come il WST09 (Tookad), che, somministrati topicamente o per via sistemica, sono in grado di indurre danno vascolare con trombosi e necrosi del tessuto target. </li></ul><ul><li>L’attivazione del fotosensibilizzatore avviene per stimolazione con la luce (inserimentio delle sonde per via transperineale) </li></ul>
  35. 35. Vascular Target Photodynamic Therapy (VTP) <ul><li>Un trial di fase II con WST09 è tuttora in corso: </li></ul><ul><li>28 pts con ca localizzato, ricorrente dopo RT </li></ul><ul><li>In 16 pts con almeno 6 mesi di FU si sono osservate con RMN lesioni ipoperfuse e riduzioni del PSA senza morbidità urinaria, erettile e rettale significativa ( Pinthus et Al., J Urol, 2006) </li></ul><ul><li>Dati maturi sono attesi da questo e da altri trials per definire il ruolo della VTP nel trattamento del Ca prostatico </li></ul>
  36. 36. TERMOABLAZIONE DEL CARCINOMA PROSTATICO CON HIFU
  37. 37. 0 20 40 60 80 100 Radical Prostatectomy Beam RT HIFU Comparison HIFU 5-year biochemical survival with the range published for low-risk prostate cancer since 2000 Biochemical Disease Free Rate (%) 82% 1 94% 4 84% 5 1. Blana et al European Urology, In press, 2007 2. De Meerleer et al Radiother Oncol. 2007;82(2):160-6. 3. Goldner et al Strahlenther Onkol. 2006;182(9):537-42. 4. Stokes et al Int J Radiat Oncol Biol Phys. 2000;47(1):129-36. 5. Ciezki et al Int J Radiat Oncol Biol Phys. 2004;60(5):1347-50. 100% 2 55% 3
  38. 38. 0 20 40 60 80 100 Radical Prostatectomy Beam RT HIFU Comparison HIFU 5-year biochemical survival with the range published for moderate-risk prostate cancer since 2000 Biochemical Disease Free Rate (%) 75% 1 87% 4 72% 5 1. Blana et al European Urology, In press, 2007 2. De Meerleer et al Radiother Oncol. 2007;82(2):160-6. 3. Goldner et al Strahlenther Onkol. 2006;182(9):537-42. 4. Stokes et al Int J Radiat Oncol Biol Phys. 2000;47(1):129-36. 5. Ciezki et al Int J Radiat Oncol Biol Phys. 2004;60(5):1347-50. 94% 2 40% 3
  39. 39. 0 10 20 30 40 50 Radical Prostatectomy ‡ HIFU † Beam RT ‡ 7% 1 2.3% 2 49% 5 5% 6 15% 3 0% 4 Occurrence (%) † excluding grade I, ‡ pad rate. 1. Ficarra et al, BJU Int. 2006 Dec;98(6):1193-8. 2. Chaussy and Thuroff Curr Urol Rep. 2003;4(3):248-52. 3. Zelefsky et al, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1111-6; 4. Brabbins et al, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):400-8. 5. Steineck et al, N Engl J Med. 2002 Sep 12;347(11):790-6; 6. Abou-Elela et al, Eur J Surg Oncol. 2007; 33:96-101 Incontinence (range published in the literature since 2000)
  40. 40. Impotence (range published in the literature since 2000) 0 20 40 60 80 100 Radical Prostatectomy HIFU Beam RT 91% 5 14% 6 63% 3 41% 4 1. Blana et al Urology. 2004 Feb;63(2):297-300. 2. Thuroff et al. J Endourol. 2003 Oct;17(8):673-7. 3. Potosky et al, J Natl Cancer Inst. 2000 Oct 4;92(19):1582-92; 4. Matalinska et al, J Clin Oncol. 2001 Mar 15;19(6):1619-28; 5. Matalinska et al, J Clin Oncol. 2001 Mar 15;19(6):1619-28; 6. Walsh et al, J Urol. 2000 Jun;163(6):1802-7. Occurrence (%) 13% 2 53% 1
  41. 41. Rectal Injury (range published in the literature since 2000) 1. Gelet et al J Endourol. 2000 Aug;14(6):519-28; 7. Poissonnier et al Prog Urol. 2003;13(1):60-72; 3. Chrouser et al J Urol. 2005 Jun;173(6):1953-7. 4. Gillitzer et al J Urol. 2004 Jul;172(1):124-8. 5. Shrader-Bogen et al. Cancer. 1997 May 15;79(10):1977-86. 6. Lim et al J Urol. 1995 Oct;154(4):1420-5. 0 1 2 3 4 5 Radical Prostatectomy HIFU (pre 2003) Beam RT Occurrence (%) ≤ 1.0 % 1 0 10 20 30 40 50 Radical Prostatectomy HIFU Beam RT 19% 6 0% 43% 5 0% Occurrence (%) NONE REPORTED Severe (fistula – requiring intervention) Moderate (bleeding, urgency, diarrhea) ≤ 0.6 % 3 ≤ 1.1 % 4 0% ≤ 0.5 % 2 HIFU (post 2003)
  42. 42. HIFU RISULTATI TERAPIA FOCALE: EVIDENZE AD OGGI <ul><li>Emiablazione prostatica con HIFU Sonablate 500 </li></ul><ul><li>25 pts, FU medio:34 mesi. bDFS a 2 anni = 83,3%; biopsie neg. a 1 anno = 82% </li></ul><ul><li>(Muto et Al, Jpn J Clin Oncol,2007) </li></ul>
  43. 43. HIFU FOCALE E COSTI A CONFRONTO <ul><li>Costo medio P.R.R. * € 6.500 </li></ul><ul><li>Costo medio RT esterna € 5.500 </li></ul><ul><li>Costo medio brachiterapia € > 10.000 </li></ul><ul><li>Costo medio HIFU focale ** € 3.000 </li></ul><ul><li>* Rimborso DRG reg. Lombardia € 4.000 </li></ul><ul><li>** “ “ “ 2.800 </li></ul>
  44. 44. FOLLOW-UP DOPO TERAPIA FOCALE <ul><li>Deve necessariamente prevedere determinazioni seriate del PSA almeno ogni 6 mesi </li></ul><ul><li>Biopsia di controllo a 1e 3 anni e in caso di incremento del PSA > 0.4 ng/ml/anno </li></ul><ul><li>Impiego eventuale nomogrammi per PSADT previsti per pazienti in Sorveglianza Attiva </li></ul>
  45. 45. TERAPIA FOCALE: CONCLUSIONI <ul><li>Il razionale per il ricorso alla terapia focale è solido e condiviso dalla maggior parte delle Istituzioni Internazionali </li></ul><ul><li>I risultati preliminari dischiudono scenari molto interessanti per molti pazienti con malattia biologicamente monofocale a basso rischio di progressione </li></ul><ul><li>Occorrono trials clinici prospettici controllati per stabilire l’efficacia del controllo oncologico e la sicurezza di questo approccio nonché per stabilire quale delle metodiche oggi disponibili abbiano realmente i requisiti per divenire nel prossimo futuro uno standard terapeutico per pazienti selezionati </li></ul>

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