FASE II RANDOMIZZATO MOMA
3 TERAPIA DI MANTENIMENTO CON BEVACIZUMAB OPPURE BEVACIZUMAB E
3.7 DISCUSSIONE
Guardando ai risultati dello studio TRIBE, la PFS ha raggiunto un valore mediano di 12.3 mesi (95%Cl 11.0-13.3) nel braccio in trattamento con FOLFOXIRI associato a bevacizumab
versus 9.7 mesi (95%Cl 9.2-10.9) nel braccio in trattamento con FOLFIRI associato
all’antiangiogenico (HR=0.77; 95%Cl 0.65-0.93; p=0.006). Erano stati somministrati fino a 12 cicli di induzione e a seguito il mantenimento con 5FU/LV + bev.
ll guadagno in PFS è stato confermato in tutti i sottogruppi molecolari per il braccio sperimentale ed in più del 50% dei casi si riusciva a garantire un intervallo libero da irinotecan e oxaliplatino di almeno 6 mesi con il mantentenimento di solo 5FU/LV + bevacizumab fino a PD. Questi risultati hanno confermato la centralità e l’importanza della scelta dell’intensità della chemioterapia in prima linea.
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Riguardo all’efficacia e all’importanza della terapia di mantenimento l’unico studio che potrebbe rappresentare un reale termine di confronto rispetto all’analisi MoMa è lo studio AIO 0207145, sebbene con alcune differenze fondamentali.
Si trattava di uno studio di ‘Non Inferiorità’, disegnato per esplorare la non inferiorità appunto, dell’osservazione o mantenimento con solo bevacizumab rispetto al mantenimento con fluoropirimidina e antiangiogenico.
L’altra differenza cruciale sta nel momento della randomizzazione. Nel disegno MoMa è stato scelto di randomizzare tutti i pazienti a monte, prima dei cicli di induzione; nel trial AIO i pazienti arruolati hanno iniziato 24 settimane di induzione, al termine della prima fase solo i pazienti nei quali si era registrata risposta (RP o RC) o stabilità di malattia sono stati randomizzati nei 3 bracci.
Figura 10: Arnold,The Lancet Oncology 2015 16, 1355-1369
AIO 0207
92
Risulta differente anche l’endopint primario dei due studi: PFS per MoMa, TFS per AIO.
I risultati dello studio AIO mostrano che il tempo al fallimento della strategia dalla randomizzazione è risultato 6,5 mesi (95% CI 5∙9–7∙2) per tutti i pazienti; 6,9 mesi (95% CI 6∙1–8∙5) per fluoropirimidina e bevacizumab; 6,1 mesi (5∙3–7∙4) nel gruppo bevacizumab solo e 6,4 mesi (4∙8–7∙6) per il braccio di osservazione.
La PFS mediana calcolata dalla data di arruolamento alla prima progressione risultava di 11,7 mesi (95% CI 10∙8–13∙2) per il braccio fluoropirimidina e bevacizumab, 10,0 mesi (9,4–10∙6) per bevacizumab solo e 9,0 mesi (8∙4–9∙6) per il braccio di osservazione, mentre, come abbiamo già visto, nell’analisi MoMa il confronto tra mantenimento con solo bevacizumab e chemioterapia metronomica + bevacizumab non ha prodotto alcuna sostanziale differenza in termini di PFS ( 9,4 mesi vs 10,4 mesi HR: 0.91 [0.67-1.23] p=0.534).
Dunque, nonostante alcuni evidenti limiti riguardo le possibilità di confronto, i due studi raggiungono conclusioni abbastanza sovrapponibili: il trattamento di mantenimento con una fluoropirimidina più bevacizumab può essere l'opzione preferibile a seguito di un trattamento di induzione con una fluoropirimidina, oxaliplatino e bevacizumab, in quanto consente l’interruzione della terapia di induzione senza compromettere il Disease Control Rate, certamente la non inferiorità è stata dimostrata per il solo bevacizumab rispetto a fluoropirimidina + bevacizumab; non è stato, invece, dimostrato un incremento in termini di PFS per l’aggiunta di chemioterapia metronomica a bevacizumab come terapia di mantenimento perlomeno in questo setting.
CONCLUSIONI
Il trattamento dei pazienti con carcinoma colorettale metastatico, non suscettibili di cure risolutive, dovrebbe mirare ad ottenere il controllo della malattia, ritardare la progressione e migliorare la sopravvivenza. Questi obiettivi dovrebbero essere perseguiti, evitando tossicità e cercando di ottenere il miglioramento della qualità di vita.
Su queste premesse, studi clinici hanno dimostrato l'importanza della terapia di mantenimento nei pazienti metastatici. Tuttavia, alcuni temi chiave restano irrisolti: la durata ottimale della prima linea di trattamento e i farmaci più opportuni da utilizzare nel mantenimento. Sulla base dei risultati disponibili, sembra ragionevole iniziare i pazienti ad un trattamento con la chemioterapia di induzione e agenti mirati per periodi non più
93
lunghi di 6 mesi. In questo panorama, bevacizumab, solo o in combinazione con fluoropirimidine, è l’opzione più frequentemente investigata e consente di prolungare gli effetti positivi del trattamento di prima linea senza modificare il disease control rate. Nonostante una quantità crescente di prove da studi randomizzati che sostengono la sua efficacia in ambito di mantenimento, l'ampio uso di bevacizumab è ancora dibattuto, in particolare poiché l’entità del beneficio in termini di sopravvivenza globale è piuttosto limitato. Inoltre l’analisi di sottogruppo degli studi randomizzati disponibili non permette di identificare quali caratteristiche cliniche permettano di identificare i pazienti che ne possono trarre maggiore beneficio. Sebbene nello studio MOMA l’aggiunta della chemioterapia metronomica con capecitabina e ciclofosfamide non sembri determinare un guadagno considerevole in PFS nella strategia di mantenimento, la combinazione di fluoropirimidina e bevacizumab resta oggi la scelta di mantenimento più opportuna in base alle evidenze disponibili.
Nuovi composti sono attualmente in studio come agenti di mantenimento, al fine di arricchire così le future opzioni disponibili.
I risultati di safety e attività dello studio MOMA confermano d’altra parte l’interesse per FOLFOXIRI+bevacizumab come scelta di trattamento di prima linea per pazienti ben selezionati dal punto di vista clinico in base alle loro condizioni generali ed età. FOLFOXIRI+bevacizumab si conferma infatti come regime fattibile, con tossicità gestibile, in linea con tutti i risultati precedentemente riportati ed estremamente attivo, in grado di garantire controllo di malattia nella stragrande maggioranza dei pazienti.
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