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Terapia del cancro colorettale: gestione oncologica - Gastrolearning®

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Gastrolearning II modulo/1a lezione
Terapia del cancro colorettale - Gestione oncologica
Prof. C. Barone - Università Cattolica Sacro Cuore (Roma).

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  • Come dimostra questa metanalisi del gruppo del MD Anderson di Houston la sopravvivenza sia mediana sia a 5 anni dei pazienti è progressivamente aumentata nel corso degli anni e questo può essere spiegato principalmente da 2 fattori: il maggior numero di farmaci attivi disponibili (e quindi un maggior utilizzo ed efficacia delle terapie mediche) e, di conseguenza, un maggior ricorso alla resezione chirurgica delle metastasi epatiche in pazienti che si presentano con malattia inizialmente non resecabile <br />
  • Come dimostra questa metanalisi del gruppo del MD Anderson di Houston la sopravvivenza sia mediana sia a 5 anni dei pazienti è progressivamente aumentata nel corso degli anni e questo può essere spiegato principalmente da 2 fattori: il maggior numero di farmaci attivi disponibili (e quindi un maggior utilizzo ed efficacia delle terapie mediche) e, di conseguenza, un maggior ricorso alla resezione chirurgica delle metastasi epatiche in pazienti che si presentano con malattia inizialmente non resecabile <br />
  • Come dimostra questa metanalisi del gruppo del MD Anderson di Houston la sopravvivenza sia mediana sia a 5 anni dei pazienti è progressivamente aumentata nel corso degli anni e questo può essere spiegato principalmente da 2 fattori: il maggior numero di farmaci attivi disponibili (e quindi un maggior utilizzo ed efficacia delle terapie mediche) e, di conseguenza, un maggior ricorso alla resezione chirurgica delle metastasi epatiche in pazienti che si presentano con malattia inizialmente non resecabile <br />
  • Questa analisi effettuata sui pazienti con metastasi epatiche resecate radicalmente dal gruppo del Memorial Sloan Kattering Cancer Center di New York, dimostra che dopo un follow up minimo di 10 anni si può vedere chiaramente che vi è una quota di pazienti che può essere definita guarita definitivamente dalla malattia grazie alla resezione delle metastasi epatiche, ma è evidente anche come si tratti di una quota piuttosto piccola di pazienti (17%) e perciò vi è necessità di integrare la chirurgia con la terapia medica al fine di incrementare i risultati a lungo termine della strategia terapeutica <br />
  • Figure 1. Overall Survival among Patients with Metastatic Colorectal Cancer Who Were Treated with Hepatic Arterial Infusion plus Systemic Chemotherapy (Combined Therapy) or with Systemic Chemotherapy Alone (Monotherapy). <br />
  • 20% of the total liver volume is considered the minimum safe volume that can remain after extended resection in patients with normal underlying liver. The presence of extrahepatic disease is not considered as an absolute contraindication to hepatic resection as it once was, only if the patient is carefully screened, and a total resection of intra and extrahepatic disease is attainable. <br />
  • 20% of the total liver volume is considered the minimum safe volume that can remain after extended resection in patients with normal underlying liver. The presence of extrahepatic disease is not considered as an absolute contraindication to hepatic resection as it once was, only if the patient is carefully screened, and a total resection of intra and extrahepatic disease is attainable. <br />
  • 20% of the total liver volume is considered the minimum safe volume that can remain after extended resection in patients with normal underlying liver. The presence of extrahepatic disease is not considered as an absolute contraindication to hepatic resection as it once was, only if the patient is carefully screened, and a total resection of intra and extrahepatic disease is attainable. <br />
  • 20% of the total liver volume is considered the minimum safe volume that can remain after extended resection in patients with normal underlying liver. The presence of extrahepatic disease is not considered as an absolute contraindication to hepatic resection as it once was, only if the patient is carefully screened, and a total resection of intra and extrahepatic disease is attainable. <br />
  • Una successiva pubblicazione sempre del gruppo dell’Hopital Paul Brousse di Parigi ha dimostrato inoltre che la prognosi dei pazienti inizialmente non resecabili che sono stati resi resecabili e di fatto resecati dopo una terapia medica è sovrapponibile a quella dei pazienti resecabili ab inizio e soprattutto nettamente migliore rispetto alla prognosi dei pazienti in cui non si riesce ad ottenere la resecabilità delle metastasi. Questa curva fa riferimento ad una pooled analysis in cui sono stati inseriti pazienti trattati con vari regimi di chemioterapia prima della introduzione in clinica dei farmaci a bersaglio molecolare (principalmente FOLFOX e in misura minore FOLFIRI e FOLFOXIRI). <br />
  • FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. <br />   <br /> A meta-analysis was performed combining the clinical results of both the CRYSTAL study and the OPUS study, which compared FOLFOX alone vs FOLFOX plus cetuximab. By stratifying patients according to KRAS genotype status, results showed highly statistically significant improvements in both progression-free and overall survival with the addition of cetuximab, but only in patients with wild-type KRAS. <br />
  • L’altro studio, presentato di recente, in cui è stato possibilie valutare l’impatto della mutazione di N-RAS, è il FIRE-3. Non entro nei dettagli dello studio… <br />
  • Pur se i dati su mutazioni di altri esoni non sono disponibili, è emerso che i pazienti K-RAS WT che presentavo una mutazione RAS avevavo un PFS peggiore, con una differenza statisticamente significativa, rispetto ai RAS WT, p 0.004 e HR 0,54. <br />
  • Analoghi dati sono emersi per quanto riguarda la sopravvivenza, con una p 0.011 e HR 0.57. <br />
  • I dati sulla sopravvivenza sono netti, anche se non era l’obiettivo dello studio. Questi sono i primi dati su una possibile sequenza di anti EGFR e antiangiogenetici, ma necessitano di ulteriori conferme. <br />
  • Considerando solo la mutazione di KRAS, il PFS era aumentato, con una p di 0.02 e HR 0.80, considerando invece anche RAS WT e gli esoni 3 e 4 , il beneficio a carico del PFS è più marcato, con una p 0.004 e HR 0.72 <br />
  • La sopravvivenza, che non era significativa nella valutazione primaria limitata al solo KRAS, diviene statisticamente significativa quando l’analisi viene estesa a NRAS e agli esone 3 e 4 di KRAS. <br />
  • La stessa analisi è stata condotta in maniera prospettica anche sullo studio PEAK e sono state riscontrate le setsse percentuali di mutazioni di RAS e di esoni 3 e 4 di KRAS. <br />
  • Questo può essere spiegato dalla diversa frequenza di mutazioni a carico di alcuni geni nei diversi distretti del colon, con maggiore numero di mutazioni nel colon destro. <br />

Terapia del cancro colorettale: gestione oncologica - Gastrolearning® Terapia del cancro colorettale: gestione oncologica - Gastrolearning® Presentation Transcript

  • Terapia del cancro colorettale Carlo Barone Oncologia Medica Università Cattolica del S. Cuore Ce nc oO ntr ic log o o
  • Argomenti • Terapia adiuvante del cancro del colon • Terapia del cancro del retto • Terapia della malattia metastatica – Metastasi epatiche (± polmonari) – Metastasi multiple
  • Trials with Oxa: Adjuvant Setting Trial Pts Treatment Data MOSAIC 224 6 FOLFOX-4 x 6 mos 5-FULV2 x 6 mos 5-y DFS 6-y OS Safety FLOX x 6 mos Bolus 5-FULV w x 6 mos 5-y DFS Safety XELOX x 6 mos Bolus 5-FULV w/q4w x 6 mos 5-y-DFS Safety (NEJM 2004, ASCO 2005, ASCO 2007) NSABP C-07 2407 (JCO 2007) ASCO 2008 ROCHE NO16968 (JCO 2007) 1886
  • MOSAIC: 5-yrs DFS Updated 3.8 7.5 André T, et al. JCO 2009
  • MOSAIC Updated: OS – 6 years 2.5 André T, et al. JCO 2009
  • MOSAIC OS Updated: 6 yrs, by stage p=0.996 0.1% p=0.029 4.4% André T, et al. JCO 2009
  • X-ACT updated: 5-Year DFS and OS Xeloda 5-FU/LV 0.8 0.6 Absolute difference at 5 years: 4.1% 4 0 1 2 3 4 5 Years HR = 0.86 (95% CI 0.74-1.01) p = 0.0600 0.8 0.6 Absolute difference at 5 years: 3.1% 4 6 7 5-year OS (%) 71.4 68.4 1.0 HR = 0.88 (95% CI 0.77-1.01) p = 0.0682 OS estimate DFS estimate 1.0 5-year DFS (%) 60.8 56.7 (n = 1,004) (n = 983) 8 0 Twelves C, et al. ASCO GI 2008. Abstract 274. 1 2 3 4 5 Years 6 7 8
  • NO16968 XELOXA Trial Primary endpoint: DFS XELOX 5-FU/LV 1.0 0.8 0.6 0.4 HR=0.80 (95% CI: 0.69–0.93) p=0.0045 0.2 0.0 0 1 2 3 Years ITT population 4 5 6
  • 3-year DFS: benefit with XELOX maintained over time 3-year DFS XELOX 5-FU/LV 1.0 70.9% 66.5% 0.8 Δ at 3 years: 4.5% 0.6 0.4 0.2 0.0 0 1 2 3 Years ITT population 4 5 6
  • 4-year DFS: benefit with XELOX maintained over time 3-year DFS 70.9% 66.5% XELOX 5-FU/LV 1.0 4-year DFS 68.4% 62.3% 0.8 Δ at 3 years: 4.5% 0.6 Δ at 4 years: 6.1% 0.4 0.2 0.0 0 1 2 3 Years ITT population 4 5 6
  • 5-year DFS: benefit with XELOX maintained over time 3-year DFS 1.0 5-year DFS 70.9% 66.5% XELOX 5-FU/LV 4-year DFS 68.4% 62.3% 66.1% 59.8% 0.8 Δ at 3 years: 4.5% 0.6 Δ at 4 years: 6.1% 0.4 Δ at 5 years: 6.3% 0.2 0.0 0 1 2 3 Years ITT population 4 5 6
  • NO16968 (XELOXA) and MOSAIC: DFS in stage III disease FOLFOX4 DFS (%) (%) 3-yr 1 NO16968 LV5FU2 72.2 65.3 XELOX 70.9 3-yr3 5-yr 66.4 2 XELOX NO16968 5-yr3 66.1 1. ITT population 5-FU/LV 66.5 58.9 HR (95% CI) 0.76 (0.62–0.92) 0.80 (0.69–0.93) p=0.0045 0.78 (0.65–0.93) p=0.005 5-FU/LV 59.8 André et al. NEJM 2004; 2. André et al. 2009; 3. Haller et al. ESMO 2009
  • NO16968 (XELOXA) and MOSAIC: DFS in stage III disease Estimated probability 1.0 NO16968 (XELOXA)1* XELOX MOSAIC2,3** FOLFOX4 3-yr DFS 5-yr DFS (n=944) 70.9% 66.1% (n=672) 72.2% 66.4% 0.8 0.6 0.4 0 1 *Median observation time: 57.0 months **Median follow-up: 71.3 months Cross-trial comparison ITT population 2 3 Years 4 5 6 1. Haller et al. ESMO 2009 2. André et al. NEJM 2004 3. André et al. JCO 2009
  • Oxaliplatin with Fluoropyrimidine Conclusion • • • Significantly improved DFS Neurologic toxicity is an issue Previous analyses have demonstrated surrogacy of 3yr DFS for 5yr OS • Long term survival benefit now demonstrated in stage III • Both FOLFOX and XELOX are acceptable
  • Should patients with stage II colon cancer receive adjuvant therapy? Meta-analyses Direct evidence from randomized trials Identification of “high risk” patients
  • To B or Not To B?
  • QUASAR: Study design Colon or rectal cancer • Stage I-III • Complete resection with no evidence of residual disease 2x2 randomization to 5-FU with low- or high-dose LV and Lev or placebo Clear indication for chemotherapy (n = 4320) No clear indication for chemotherapy (n = 3239) * Prior to 10/1997 chemotherapy patients were randomized as in clear indication arm; after 10/1997 patients received 5-FU/low-dose LV. R A N D O M I Z E Observation (n = 1617) Chemotherapy (n = 1622)* Gray et al. ASCO 2004. Abstract 3501. At: http://www.asco.org/ac/1,1003,_12-002511-00_18-0026-00_19-0010698,00.asp. Accessed November 2004.
  • The QUASAR Trial 100 Observation (n=1622) Chemotherapy (n=1617) % of Patients 80 60 40 P = .02 5-year OS, Obs = 77.4% vs CT = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97) 20 0 0 1 2 3 4 5 Years QUASAR group Lancet 2007 6 7 8 9 10
  • DFS: High-Risk Stage II Patients only 1.0 0.9 0.8 FOLFOX-4 n = 286 Probability 0.7 LV5FU2 5.0 n = 290 0.6 0.5 3-year 5-year 0.4 FOLFOX-4 85.4% 82.1% 0.3 LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52-1.06] 0.2 7.2 0.1 High-risk stage II – defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, <10 lymph nodes examined Data cut-off: June 2006 0 0 6 12 18 24 30 36 42 48 54 Disease-Free Survival (months) 60 66 72
  • MOSAIC OS Updated: 6 yrs, by stage p=0.996 0.1% p=0.029 4.4% André T, et al. J Clin Oncol 2009;27:3109-16.
  • OXA in stage II Pooled data from recent NSABP colon trials Estimates by Risk Group Endpoint 5-FU/Lv 5-FU/Lv + Oxa Increase with Oxa 86.7 90.2 + 3.5 89.2 91.7 + 2.5 DFS - HiRisk 76.3 80.7 + 4.4 - LoRisk 80.6 83.6 + 3.0 - HiRisk 84.0 89.2 + 5.2 - LoRisk 89.0 91.6 + 2.9 - Risk Group OS - HiRis - Lo Risk TTR
  • CONCLUSION The best estimate of the magnitude of survival benefit from AC, if it exists, is an absolute improvement of 2-4% in 5-year survival
  • Should Stage II Pts Receive Adj Therapy? A Statistical Perspective Number of patients needed to detect a realistic treatment benefit assuming a true relative risk reduction of 18% with a power of 90% (two sided) Survival ARR No. of patients At 3 years 85% 2.5% 8000 At 4 years 80% 3.3% 5800 At 5 years 75% 4.0% 4700 Buyse M, Piedbois P. Semin Oncol 2001;28(1 Suppl 1):20-4.
  • Stage II: Conclusions The observed HR & KM estimates suggest a trend for benefit from Oxa in stage II Benefit of monotherapy • 2-3% in 5 yr DFS/OS • Clinically meaningful? • Prior 12 LN era – still relevant? Additional benefit of Oxaliplatin • No benefit overall • ≈ 3 % in high risk stage IIs • Needed number to treat: ≈ 33 Should be considered stage II, but … • Biomarker?
  • Shift of the Paradigm Shift of the Paradigm The role of adjuvant chemotherapy The role of adjuvant chemotherapy 1975 Simpler strategies 1990 More complex strategies 2005 Surgery RT/CT + CT RT Surgery CT Surgery CT + RT/CT + CT RT+CT Surgery CT The role of adjuvant CT is The role of adjuvant CT is not easily recognizable easily recognizable
  • Two paradigms of RT: Two paradigms of RT: Different outcomes, different role for adjuvant CT Different outcomes, different role for adjuvant CT Radioterapia post-operatoria Radioterapia post-operatoria Obiettivi: Obiettivi: Sopravvivenza Sopravvivenza DFS DFS Controllo locale Controllo locale Radioterapia preoperatoria Radioterapia preoperatoria Obiettivi: Obiettivi: DFS DFS Ruolo della chirurgia: Primario Ruolo della chirurgia: Primario Ruolo della CT adiuvante: Chiaro e Ruolo della CT adiuvante: Chiaro e significativo. Tutti gli obiettivi significativo. Tutti gli obiettivi USA: L’evidenza del NCI USA: L’evidenza del NCI Consensus del 1990 ha Consensus del 1990 ha dominato la scena sino ai primi aa. dominato la scena sino ai primi aa. 2000 2000 Controllo locale Controllo locale Retrostadiazione Retrostadiazione Chir. Conservativa Chir. Conservativa Sopravvivenza, Sopravvivenza, Ruolo della chirurgia: Comprimario Ruolo della chirurgia: Comprimario Ruolo della CT adiuvante: Difficile Ruolo della CT adiuvante: Difficile da definire. Quali obiettivi? da definire. Quali obiettivi? Europa: Sopravvivenza con RT Europa: Sopravvivenza con RT preoperatoria non inferiore a RCT preoperatoria non inferiore a RCT post-operatoria post-operatoria
  • Randomized trials with post-operative CRT Randomized trials with post-operative CRT  La CRT adiuvante migliora la Sopravvivenza rispetto  La CRT adiuvante migliora la Sopravvivenza rispetto alla Chirurgia da sola, alla RT da sola o alla CT da sola alla Chirurgia da sola, alla RT da sola o alla CT da sola ● GITSG 7175 (NEJM 1985) ● GITSG 7175 (NEJM 1985) ● NCCTG 79-47-51 (NEJM 1991) ● NCCTG 79-47-51 (NEJM 1991)  Impatto meno chiaro sulla sopravvivenza  Impatto meno chiaro sulla sopravvivenza ● NSABP R-01 (JNCI 1988) ● NSABP R-01 (JNCI 1988) ● NSABP R-02 (JNCI 2000) ● NSABP R-02 (JNCI 2000)
  • Neoadjuvant Chemoradiotherapy: Neoadjuvant Chemoradiotherapy: The Shift of Paradigm The Shift of Paradigm 1975 1975-1990 1990 1990-2000 2004 2000-Oggi 1990 2005 USA CRT Post-op; Europa RT Pre-op NCI Consensus: CRT adiuvante Pre-op CRT Trial Tedesco (Pre-op Standard) Nuove combinazioni terapeutiche in Pre-op Ruolo della terapia adiuvante Nuove strategie
  • CAO/ARO/AIO-94 Study: The Shift CAO/ARO/AIO-94 Study: The Shift Adjuvant versus neoadjuvant RChT Adjuvant versus neoadjuvant RChT OP 5-FU (120h) 1000mg/m2 Rest 4-6 weeks Bolus 5-FU 500mg/m2 Radiotherapy 50,4 + 5,4 Gy Weeks 1 25 5-FU (120h) 1000mg/m2 5 9 ARM A 13 17 ARM B OP 4-6 weeks rest period Radiotherapy 50,4 Gy Sauer R, NEJM 351: 2004 21
  • CAO/ARO/AIO-94 Study: Local Failure CAO/ARO/AIO-94 Study: Local Failure Sauer R, NEJM 351: 2004
  • CAO/ARO/AIO-94: Distant Metastases CAO/ARO/AIO-94: Distant Metastases Sauer R, NEJM 351: 2004
  • CAO/ARO/AIO-94: Overall Survival CAO/ARO/AIO-94: Overall Survival 76% CRT post 74% CRT pre Post-operative CRT Pre-operative CRT Sauer R, NEJM 351: 2004 P= 0.80
  • FFCD-9203 FFCD-9203 Pre-operative radiotherapy vs radiochemotherapy Pre-operative radiotherapy vs radiochemotherapy Randomisation 762 pts PreOp-RT Resection Regimen PreOp-RT = 45 Gy in 5 weeks Week 1 and 5: 5 days FU/FA: 350/20 mg/m² 4 x FU/FA Gerard JP, ICO 2006 PreOp-RT+ 2 x FU/FA Resection 4 x FU/FA
  • FFCD-9203 FFCD-9203 Pre-operative radiotherapy vs radiochemotherapy Pre-operative radiotherapy vs radiochemotherapy Randomisation 762 pts PreOp-RT Resection Regimen PreOp-RT = 45 Gy in 5 weeks Week 1 and 5: 5 days FU/FA: 350/20 mg/m² 4 x FU/FA Gerard JP, ICO 2006 PreOp-RT+ 2 x FU/FA Resection 4 x FU/FA
  • FFCD-9203 FFCD-9203 Pre-operative radiotherapy vs radiochemotherapy Pre-operative radiotherapy vs radiochemotherapy Randomisation 762 pts PreOp-RT Resection 16.5% Local Failure 8.0% Regimen PreOp-RT = 45 Gy in 5 weeks Week 1 and 5: 5 days FU/FA: 350/20 mg/m² 4 x FU/FA Gerard JP, ICO 2006 PreOp-RT+ 2 x FU/FA Resection 4 x FU/FA
  • FFCD-9203 FFCD-9203 Is there a role for adjuvant chemotherapy? Is there a role for adjuvant chemotherapy? Randomisation 762 pts PreOp-RT Resection 4 x FU/FA Regimen PreOp-RT = 45 Gy in 5 weeks Week 1 and 5: 5 days FU/FA: 350/20 mg/m² Does it increase OS or DFS ? Does it increase only toxicity? Gerard JP, ICO 2006 PreOp-RT+ 2 x FU/FA Resection 4 x FU/FA
  • FFCD-9203 FFCD-9203 Pre-operative radiotherapy vs radiochemotherapy Pre-operative radiotherapy vs radiochemotherapy RT CT+RT Gerard JP, JCO 2006
  • EORTC-study 22921 EORTC-study 22921 Randomisation 252 pts 253 pts 253 pts 253 pts PreOp-RT PreOp-RT+ 2 x FU/FA PreOp-RT PreOp-RT+ 2 x FU/FA Resection Resection Resection Resection 4 x FU/FA 4 x FU/FA Regimen PreOp-RT = 45 Gy in 5 weeks 180 pts Week 1 and 5: 5 days FU/FA: 350/20 mg/m² Bosset JF, NEJM 2006 189 pts
  • Pre-operative treatment: CT vs CRT Pre-operative treatment: CT vs CRT 65.8% 64.8% Bosset JF, NEJM 2006
  • Adjuvant CT: Yes or Not Adjuvant CT: Yes or Not Bosset JF, NEJM 2006
  • Post-operative treatment: Yes or not Post-operative treatment: Yes or not Progression free Survival Bosset JF, NEJM 2006
  • Local recurrence as first event Local recurrence as first event Bosset JF, NEJM 2006
  • Ca. Retto: Modalità di trattamento - 1 cT3 (MRF-) N0-2 M0
  • Ca. Retto: Modalità di trattamento - 2 cT3 (MRF+) N0-2 M0 o cT4 ogni N M0
  • Ca. Retto: Modalità di trattamento in corso di valutazione
  • Ca retto localmente avanzato: RAPIDO trial Rt Short Rt +Chemo Chemo Restaging Restaging Surgery Surgery Chemo
  • Timing della CT: CRT o CT prima?
  • Timing della CT: CRT o CT prima? 3 years DFS RT-CHEMO SURGERY CHEMO 68% CHEMO RT-CHEMO SURGERY 70% Fernandez-Martos C et Al - ASCO - 2011
  • Potenzialmente resecabile dopo CT? No Il pz può tollerare una CT intensiva? Si No Il pz può tollerare una CH maggiore? No B Sintomi presenti o imminenti? Comportamento aggressivo del tumore? No C Si Si Malattia molto avanzata o “bulky” No Si Il pz può tollerare una CT intensiva? No Si Gruppo 2: intermedio Gruppo 3: non intensivo/”sequenziale Si Gruppo1:intensivo A
  • Gruppi Clinici per la stratificazione del trattamento di I linea (induzione) • Gruppo 0 – Metastasi epatiche e/o polmonari chiaramente resecabili R0 • Gruppo 1 – Solo metastasi epatiche e/o polmonari non resecabili R0, che: • Potrebbero divenire resecabili dopo CT di induzione • Possono essere associate a metastasi limitate/localizzate in altre sedi (es.: lfn) • Si riferiscono a pazienti in grado di affrontare un intervento chirurgico maggiore e terapia medica intensiva
  • Gruppi Clinici per la stratificazione del trattamento di I linea (induzione) • Gruppo 2 – Metastasi (o siti metastatici) multiple, con: • Rapida progressione e/o • Sintomi correlati al tumore e/o rischio di rapido deterioramento • Co-morbidità che richiede trattamento intensivo • Gruppo 3 – Metastasi (o siti metastatici) multiple, con: • Nessuna opzione per resezione chirurgica • e/o assenza di sintomi maggiori o rischio di rapido deterioramento • e/o comorbidità serie (che escludono possibilità chirurgiche e/o trattamento intensivo)
  • Obiettivi e Intensità del trattamento Obiettiivo Intensità del trattamento Gruppo 0 Guarigione Riduzione del rischio di recidiva Nessuna o Moderata (FOLFOX) Gruppo 1 Massima riduzione del tumore Regime più attivo Gruppo 2 Rapida riduzione tumorale cliicamente rilevante Controllo della progressione di malattia Combinazione attiva: almeno doppietta Gruppo 3 Prevenzione di ulteriore progressione Riduzione tumorale meno rilevante Bassa tossicità più rilevante • “Watchful waiting” (eccezionalmente) • Approccio sequenziale (inizio con agente singolo o doppietta con bassa tox) • Eccezionalmente triplette
  • Survival by year of diagnosis Retrospective review of 2470 pts with MCRC who received their primay treatment between 1990 and 2006 at M.D. Anderson and Mayo Clinic 2004-2006 2001-2003 1990-2000 Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83
  • Improved use of medical treatments *Compared with irinotecan use in 1998 and normalized by yearly patient volume Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83
  • Increased percentage of resected pts Kopetz S et al, J Clin Oncol. 2009 Aug 1;27(22):3677-83
  • Hepatic surgery increases survival • 2470 pts with mCRC undergone CHT (Mayo Clinic 1990-2006); 231 liver resections • Landmark analysis of survival of pts alive 12 months after diagnosis (70% of initial population) mOS (monthsi) 5 yrs Surv Resected patients 65,3 55% Not resected 26,7 19,5% HR 0,35 70% della popolazione inclusa Error bars represent 95% CLs Sensible increase of long-term survival: Actual possibility of cure Kopetz S et al. J.Clin.Onc. 2009;27:3677-3683
  • LiveMetSurvey: OS 14,744 pts Resected vs operated but not resected Initially resectable vs non resectable http://www.livermetsurvey.org, June 2011.
  • Resection of CRC liver metastases • Accepted standard practice despite lack of randomized trial • Due to substantial cure rate reported in initial series1, 2 • Survival directly related to liver metastases resectability – 5-y OS = 40-58% following successful resection3 – As high as 71.5% following solitary resection4 • It follows that we accept resection as a realistic standard of cure From: 1. Kopetz S et al J Clin Oncol 27: 3677-83; Adam R et al Ann Surg 2010; 3. Vauthey JN, et al. Semin Oncol 2005;32:S118-22; 4. Aloia TA, et al. Arch Surg 2006;141:460-6; .
  • Liver Resection - New Perspective OLD Required limited number of metastases Resectability determined by “what comes out” NEW No. of mts no longer a decision factor Anticipated negative margins ≥30% liver mass and two continuous segments preserved Associated with a near zero operative mortality rate Resectability determined by “what stays in”
  • Actual 10-y Survival after Resection of CLM 612 pts resected from 1985 to 1994 at MSKCC with 10-year follow up THE MAJORITY OF PATIENTS are NOT CURED! 10-y Survival: 17% Tomlinson J, JCO’07
  • How reach a consensus on resectability of CRC liver metastases in MDT 1.Appropriate Rx margins 2.Up to 4 mts 3. No negative prognostic factors 1. Rx margins not appropriate 2. Negative prognostic factors 3. Surgery possible only after relevant tumour shrinkage Heterogenous group: • Unresectable extrahepatic metastases • Comorbidities • Other … 15% 35% 50% Easy resectable Marginally or Potentially resectable Unresectable and never likely to be resectable Modified from Masi G et al, Future Oncol 2011 and from Nordlinger et al, Ann Oncol 2009
  • Multimodality Management of CRC Liver Metastases – Neoadjuvant/Perioperative chemotherapy • Resectable liver metastases: – Facilitate surgery – Obtain predictive and prognostic information – Early systemic therapy for poor-prognosis pts – Conversion chemotherapy • Unresectable liver metastases: – Allow R0 resection via downsizing – Postoperative (adjuvant) chemotherapy • Hepatic arterial infusion (HAI) • Systemic treatment
  • Bittoni, Giampieri et al, CROH 2012
  • EPOC study: Trial Design and Objectives FOLFOX4 x 6 cycles R 364 pts Surgery Surgery FOLFOX4 x 6 cycles • Potentially resectable (1-4) liver metastases • Primary endpoint: to demonstrate a 40% increase in mPFS (HR=0.71) with 80% power and 2-sided significance level 5% Nordlinger et al, Lancet 2008
  • Primary Endpoint N pts N pts CT Surg % absolute difference in 3-year PFS Hazard Ratio (CI) P-value All Patients 182 182 +7.2% (28.1% to 35.4%) 0.79 (0.62-1.02) 0.058 All eligible Patients 171 171 +8.1% (28.1% to 36.2%) 0.77 (0.60-1.00) 0.041 All resected Patients 151 152 +9.2% (33.2% to 42.4%) 0.73 (0.55-0.97) 0.025 MOSAIC: 3-yr DFS for stage III: +7.2%
  • EPOC trial PFS in eligible patients 100 90 HR= 0.77; CI: 0.60-1.00, p=0.041 80 70 60 50 +8.1% at 3 years 36.2% 40 30 20 28.1% 10 0 (years) 0 O N 134 182 126 182 1 2 3 4 Number of patients at risk : 86 62 47 34 118 78 59 47 Nordlinger et al, ASCO 2007, Lancet 2008 5 21 28 6 9 13 7 8 4 4 Treatment Surgery Pre&Postop CT
  • EPOC trial OS update 2012 HR= 0.87; CI: 0.66 -1.14, p=0.303 100 90 80 Periop CT 52.4.% (55.0 months) 70 +8.7 months in median OS +4.1 % at 5 years 60 50 40 Surgery only 48.3% (63.7 months) 30 20 10 0 (years) 0 O 2 N Number of patients at risk : Nordlinger et al, ASCO 2012 4 6 8 10 12 Treatment
  • Resectable liver metastases “New EPOC” phase III study Previously untreated patients with resectable mCRC R Planned: n=340 ERBITUX + oxaliplatin + fluoropyrimidine for 12 weeks Oxaliplatin + fluoropyrimidine for 12 weeks Protocol amendment Patients with KRAS mutant tumors excluded Available at clinicaltrials.gov NCT00482222 R E S E C T I O N Adjuvant therapy for 12 weeks (same schedule as pre-operatively) Started February 2007 PFS
  • Results: Overview • Planned vs enrolled pts: 340 vs 271 • Planned vs enrolled events: 212 vs 96 • Amendments: – 2008, recruitment restricted to KRAS wt – 2010, CAPOX proscribed – 2010, FOLFIRI allowed for all pts PFS (m) CR+PR (%) RR (%) OS (m) FP+Oxa+Cet 14.1 58.4 90 39.1 FP+Oxa 20.5 43.7 87 n.r. HR 1.5 p <.048
  • Concerns • Inclusion of capecitabine • Analysis with less than 50% of planned events (96 vs 212) • Most patients characteristics in favour of the B arm (PS 2, G3, synchronous, CEA >30, size, extrahepatic disease, not resected primary, prior adj oxa) • Unknown percentage of randomized patients actually completing Cetuximab • … waiting for definitive publication …
  • Bevacizumab+CT: only phase II studies 56 pts 39 pts
  • Suggestions from approximate comparison do not make sense Trial Resp. R (%) Res. R (%) mPFS (m) mOS (m) - 84 ≈ 12 48.3 43 83 ≈ 18 55 58.4 90 14 39.1 CT 43.7 87 20.5 n. reach. Gruenberger ’08 73.2 92.8 n. rep. n. rep. Nasti ‘13 66.7 84.6 14 38 EPOC Surg CT New EPOC Surg
  • Adjuvant Chemotherapy May reduce the risk of recurrence • Focus on completed and current trials – Hepatic artery infusion (HAI) – Systemic chemotherapy
  • HAI plus Systemic Chemotherapy (Combined Therapy) vs with Systemic Monotherapy Alone Median: 68.4 months 2 Only 6% ad pt s h of ha ore t m n f 0% o 5 th a AI pl eH Median: 55.2 months Kemeny, N. E. et al., NEJM 341:2039, 1999 NEJM 352:734, 2005 74 pts o ed d nn se 82 pts
  • HAI adj CT for pts having resection or ablation of liver CRC mts Lygidakis excluded Cochrane Database Syst Rev 2006
  • HAI adj CT for pts having resection or ablation of liver CRC mts Cochrane Database Syst Rev 2006
  • HAI +/- adj sys CT vs +/- adj sys CT after resection of liver metastases Study Pts Surgery HAI Sys CT 4 yrs DFS 4 yrs OS ECOG Kemeny 2002 75 + + FUDR 5FU 25 vs 46% p 0,04 52,7 vs 61,5% p NS Lorenz 1998 226 + + 5FU/AF - 13,7 vs 4,2 mesi p NS 40,8 vs 34,5 mesi p NS MSKCC 156 Vauthey 2006; Aloia 2006 + + FUDR 5FU/AF 5FU/AF 33 vs 48% p 0,045 27 vs 41%* p NS Lygidakis 2001 + + Im/ ito/5FU 5FU/Mito/Im 33 vs 58%§ Mito/5FU p 0,002 64 vs 78%§ p NS 122 * 10 years OS; §Estrapolated from Kaplan-Meier curve
  • Adj HAI + Sys CT +/- Bevacizumab L I V E R S U R G E R Y HAI HAI +  Kemeny et al, J Clin Oncol 2011 Sys CT + Bevacizumab Sys CT alone
  • Adj HAI + Sys CT +/- Bevacizumab HAI + Sys CT + Bev (n. 38) HAI + Sys CT (N. 35) p 4 yrs RFS 37% 46% 0,4 4 yrs OS 81% 85% 0,5 Bilirubin >3 mg/dl 38% 0 0,02 Biliary stent 11,4% 0 0,05 Kemeny et al, J Clin Oncol 2011
  • Adjuvant Systemic Treatment after Liver Resection Power and Kemeny, JCO 2010
  • Mitry E, JCO 2008
  • Mitry et al, J Clin Oncol 2008
  • § Median DFS (A) in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. § No significant differences were found in OS (72% vs 73%) (B) § A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17) Ychou M et al. Ann Oncol 2009;20:1964-1970
  • Adjuvant CT after resection of metastases Study n. Treatment Result Lorenz et al ‘98 226 HAI 5FU/FA 6 months vs Surgery alone Kemeny N et al ‘99 and ‘05 156 Sys 5FU+ HAI Flox + Dex vs Systemic 5FU Improved DFS Kemeny M et al ‘02 75 Sys 5-FU + HAI Flox vs Surgery alone Improved RFS Langer et al ‘02 107 Systemic 5-FU/FA 6 courses vs Surgery alone Trend for improved DFS and OS Portier et al ‘06 173 Systemic 5-FU/FA 6 courses vs Surgery alone Improved DFS Mitry et al ‘08 278 Systemic 5-FU/FA 6 months vs Surgery alone Trend for improved DFS and OS Ychou et al ‘09 306 Systemic 5-FU/FA 6 months vs FOLFIRI 6 months No difference in DFS or OS No improved DFS or OS.
  • Post-operative, not pre-operative, CT impacts survival in single metachronous liver mts • Retrospective analysis of 1.471 pts from MetSurg International Registry Surgery vs pre-operative CT 5 yrs OS: 60% vs 60%, p =.57 Adam et al, Ann Surg 2010 Surgery vs post-operative CT 5 yrs OS: 36% vs 58%, p =.04
  • Perioperative or Adjuvant Therapy for Resectable Liver Mts - Conclusions • Despite improvement of 3-yrs survival, EPOC randomized phase III study failed to show a definite longterm OS advantage for neoadjuvant therapy • Studies continue to draw attention to adjuvant therapy • Value of HAI-based therapy to be assessed • Conclusion: – In patients with resectable liver metastases neoadjuvant CT might be considered before surgery, but the possibility of adjuvant CT only after surgery might be of value • NCCN Guidelines – “Patients who have completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy… observation or a shortened course of chemotherapy is considered for patients who have completed neoadjuvant chemotherapy.”
  • Treatment of CRC liver metastases A sensible strategy for MDT If a biological concern…. may be it is better to try to improve DFS and OS may be pCR could affect survival If a techical concern….. may be it is better to improve RR to surgery
  • Strategies in resectable liver metastases
  • Conversion to Resection of CRC Metastasis: an Optimal Treatment Goal COLORECTAL CANCER ~50% will develop metastases (synchronous or metachronous) 30-35% liver only metastases 10-25% candidate for surgery Convert? AIM: R0 RESECTION Cure rate: 20-30% 5 yrs survival: 40-60% 75-90% non candidates for surgery PALLIATIVE THERAPY 70-80% relapse within 2 years Leonard JCO 2005; Chua Clin Colorectal Cancer 2006; Kemeny Oncologist 2007; Leichman Surg Oncol Clin N Am 2007; Van Cutsem Eur J Cancer 2007; Kemeny et al. NEJM 1999
  • What Do We Expect from Ideal Conversion Chemotherapy? • High (anatomical) response rate – RR = aim of therapy in stage IV CRC only for • Conversion therapy • Patients with significant tumor-related symptoms • Good toxicity profile – No hepatotoxicity – No interference with surgery – No interference with liver regeneration
  • Survival after Liver Resection of CRC Mts Paul Brousse Hospital (Apr. 88 - Jul. 99) 91% 100 Survival (%) 80 Resectable : 335 Initially non resectable : 138 66% P= 0.01 60 48% 30% 52% 40 33% 20 23% No Surgery 0 1 2 3 4 5 6 Years 7 8 9 10 Adam R et al. Ann Surg 2004
  • Adam R, J Clin Oncol 27. 2009
  • Conversion therapy: prospective phase II studies in non-resectable liver mts* Schedule Author Selected Patients N°. of Patients RR (%) Resezioni R0 (%) FOLFOX4 Alberts Yes 42 52 30 FFL4-10 crono Giacchetti Yes 151 59 32 FOLFOX4 + Cetuximab GOIM2402 No 53 60 21 FOLFOX4 + Cetuximab André No 43 72 23 FOLFIRI Barone Yes 40 48 33 Folprecht No 19 68 21 FOLFOXIRI Masi No 74 71 26 FOLFOXIRI de la Camara Yes 212 64 43 FOLFOXIRI Quenet Yes 26 73 35 POCHER Garufi Yes 26 83 60 AIO+CPT-11 + Cetuximab * No extrahepatic metastases
  • Phase III studies in non-selected pts with PCT Treatment N. RR (%) Mts resection (%) Author IFL FOLFOX IROX 264 267 265 31 45 35 1 4 4 Goldberg, 2004 5FU/AF (AIO) 5FU/AF (AIO) + IRI 216 214 34 64 1 3 Köhne, 2005 FOLFIRI FOLFOX 109 111 56 54 9 15 Tournigand, 2004 FOLFIRI FOLFOX 178 182 34 36 5,1 4,4 Colucci, 2005 XELOX FUOX 171 171 37 46 10 12,9 Diaz-Rubio, 2007 FOLFIRI FOLFOXIRI 147 138 34 43 4 10 Souglakos, 2006 FOLFIRI FOLFOXIRI 122 122 41 66 6 (12 liver only) 15 (36 liver only) Falcone, 2007
  • Conversion therapy Studies N RR Resection (R0) 20–40 50–70% 29–43% 20–40 40–70% ~20% 200–500 30–60% 8–24% Phase II Selected Phase II Non-selected Phase III Non-selected Folprecht et al Ann Oncol 2005
  • Conversion Therapy: Resectability Correlates With Response Rate Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) 0.6 Resection rate 0.5 0.4 Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) 0.3 0.2 0.1 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate Folprecht G, et al. Ann Oncol 2005;16:1311–1319 Phase III studies including nonselected patients with mCRC (dashed line) (r=0.67; p=0.024)
  • Cetuximab increases pts candidates to hepatic resection 60 * KRAS WT ** ITT LLD=liver limited disease
  • CRYSTAL e OPUS: Cetuximab increases patients with ETS CRYSTAL Cetuximab + FOLFIRI 38% 62% ≥20%* (n=184) <20%* (n=115) n=299 OPUS Cetuximab + FOLFOX4 31% 69% ≥20%* (n=54) <20%* (n=24) n=78 *Radiologic evaluation reported by the investigator and reviewed by an IRC FOLFIRI 51% 49% ≥20%* (n=163) <20%* (n=169) n=332 FOLFOX4 54% 46% ≥20%* (n=41) <20%* (n=49) n=90 Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • Response rate with CT doublet plus cet, pan or bev RR(%) FOLFIRI/ Cet FOLFOX/ Cet OxMdG/ XELOX/ Cet FOLFOX/ Pan IFL/ Beva FOLFOX/ XELOX/ Beva XELOX/ Beva>XELOX/ Beva XELO/ Beva>Beva Cape/ Beva Cape/ MitoC/ Beva 0 10 20 30 40 50 60 70 Van Cutsem et al, NEJM 2009, JCO 2011; Bokemeyer et al, JCO 2009; Maughan et al, ASCO 2010; Douillard et al, ECCO-ESMO 2009, JCO 2010, ASCO 2011; Hurwitz et al, NEJM 2004; Saltz et al, JCO2008; Tabernero et al, 2010; Tebbutt et al, JCO 2010
  • Phase III studies in non-selected pts with PCT+biologics Pts RR Res R0 FOLFIRI (KRASwt) FOLFIRI+Cet (KRASwt) 599 599 43 59 2.5 6.0 1.5 (4.5*) 4.8 (9.8*) XELOX/FOLFOX XELOX/FOLFOX+Bev 701 699 38 38 11.6 12.3 - FOLFOX (KRAS wt) 331 FOLFOX+Pan (KRAS wt) 325 48 57 18 28 - * Liver limited disease Falcone, JCO 2007; Van Cutsem, JCO 2009, Saltz, JCO 2008; Douillard, ASCO 2011
  • Summary of randomized trials with EGFR mAbs plus CT in KRAS wt CRC Grothey A et al, JCO 2012
  • RR allows to standardize resectability The CELIM phase II study Folprecht G et al, Lancet Oncol 2009
  • The CELIM study Standardizing resectability FOLFOX + Cet N = 53 FOLFIRI + Cet N = 53 K-RAS WT N = 67 RESPONSE RR 68% (n = 36) 57% (n = 30) 70% (n = 47) 95% CI 54-80% 42-70% 58-81% RESECTION RATE All resections 49% (n = 26) 43% (n = 23) 46% (n = 31) R0 resections 38% (n = 20) 30% (n = 16) 34% (n = 23) Folprecht G et al, Lancet Oncol 2009
  • Resectability after CT + cetuximab (Studio CELIM) 5/7 Non resecabile Resecabile Voto dei revisori (%) Basale (A) Voto dei revisori (%) Resecabile Non resecabile Dopo trattamento (B) Non resecabile Scelta chemioterapia Bordeline per resecabilità all'esplorazione Resecabile Pazienti Folprecht et al, Lancet Oncol 2010 104
  • CT+ Cet Surgery 20 pts 70 pts R Median No. of CT cycle: 6 68 pts CT Ye LC, JCO 2013 Surgery 9 pts
  • Results Arm A Arm B P Response rate (%) 25.7 7.4 <.01 R0 resection rate (%) 57.1 29.4 <.01 41 18 .013 Median survival (m) 30.9 21.0 .013 Median survival in resected 46.4 25.7 <.01 3-yrs survival (%)
  • cCR vs pCR of liver mts following CT Author Pts N. liver mts with cCR Liver mts with confirmed pCR Benoist et al J Clin Oncol 2006 38 66 17% Tanaka et al Ann Surg 2009 23 72 69% Auer et al Cancer 2010 39 118 66% van Vledder et al J Gastrointest Surg 2010 40 112 45% Ferrero et al J Gastrointest Surg 2012 33 67 39 %
  • pCR is associated with better long-term outcome 767 undergone CT and hepatectomy (1985-2006) Factors predicting a pCR p RR Age ≤60 yrs 0,03 4,1 Diameter ≤3 cm 0,05 3,1 CEA ≤30 ng/ml 0,03 5,6 cRC/RP after CHT 0,04 3,9
  • Clinical and biological risk factors in pts with liver mts – pTN • Timing • • Synchronous Mts Metachronous Mts – Characteristics of Mts • • Number/diameter Site/anatomic relationships – CEA • Basal/Absolute value – Free Interval – Resection • • • – Extra-hepatic disease From T resection From M resection From end of adj CT • R0, R1, R2
  • R0 vs R1 in liver resection +/- pre-operative CT R0 R1 No pre-operative CT (N. 172) DFS (m) 17 8 p<0,001 OS (m) 53 30 p<0,001 Pre-operative CT (n. 92) DFS (m) Ayez et al, Ann Surg Oncol 2011 18 9 p=0,303 OS (m) 65 nr p=0,645
  • Unfavourable prognostic factors for OS Author Timing CEA Mts Ø mts Margin Fong, 1999 <12 m >60 >1 ≥5 cm Pos Iwatsuki, ’99 ≤30 m >2 >8 cm Scheele, ’01 pT G3 Nagashima, ’04 pN N+ Syn ≥5 cm N+ Rees, 2008 >3 N2 G3 Yes >1 Pawlik, 2005 Minagawa, ’07 ≥50 N+ >60 >1 ≥5 cm >1 Vigano, ’08 Syn Konopke, ’09 Syn Reissfelder, ‘09 N+ Settmacher, ‘11 N2 Extra-liv LFN ≥5 cm Pos Yes >3 >200 ≥4 >200 ≥2 Yes
  • Predictors of Recurrence after Liver Resection N+ in the primary DFI < 12 months > 1 extrahepatic mts ∅ > 5 cm CEA > 200 ng/ml The Fong’s Clinical Score 80% 70% 60% 5 yrs Survival      50% 40% 30% 20% 10% 0% 0 1 2 Score Fong Y, Ann Surg 1999 3 4 5
  • Survival in liver mts is related to prognostic factors 1.613 consecutive pts with CRC liver mts (2000-2010) Negative prognostic factors • Undiffer. primary tumour • Metastases ≥4 • Size ≥5 cm • No liver surgery 5 yrs OS Low risk 47% <0,001 High risk Dexiang et al, Ann Surg Oncol 2012 p 7%
  • No dangerous halo Focal dangerous halo a Diffuse spiculated dangerous halo CT st Po ol h at p ict ed pr al viv ur ss b y gDiffuse polylobated dangerous halo o Rubbia-Brandt et al 2007; Mentha et al 2009; Maru et al 2010 c d
  • Patterns di danno epatico da chemioterapia Pattern Farmaco Impatto clinico Evidenza Steatosi 5Fluorouracile Aumento morbilità (complicanze infettive) Analisi multivariata in studio caso-controllo Sindrome da ostruzione sinusoidale Oxaliplatino Aumento morbilità ed emotrafusioni Studio caso-controllo e analisi retrospettiva Steatoepatite Irinotecan Aumento morbilità e mortalità a 90 giorni Analisi multivariata in studio caso-controllo Sclerosi biliare extra-epatica Floxouridina i.a. Danno biliare a lungo termine (permanente) Studio caso-controllo e analisi retrospettiva Vauthey et al, J Clin Oncol 2006; Khan et al, J Hepatobiliary Pancreat Surg 2009
  • Timing of Conversion Therapy • Evaluation for conversion therapy • CT firstly (2-4 months): less exposure-less tox (importance of ETS) – Except symptomatic patients • Surgery of primary tumour firstly • Surgery – Metastases and primary tumour • In two stage hepatectomy resection of primary tumour better during first intervention • Post-operative CT – Overall 12 cycles (6 months) on CT, including preand post-surgery
  • Strategies in potentially resectable liver metastases
  • Synchronous resectable CRC liver metastases • • • UK hospitals: retrospective analysis 112 consecutive patients (200-2012) 36 simultaneous resections and 76 sequential resections Slesser AAP et al, Eur J Surg Oncol 2013 3 yrs OS: 75% vs 64% p = 0.379 3 yrs DFS: 33% vs 32% p = 0.837 Simultaneous resection results in similar short-term and long-term outcome as pts receiving sequential resection with comparable metastatic disease
  • Combined first-stage hepatectomy and CRC resection in a two stage hepatectomy strategy • 33 pts from two institutions (2000-2008) Karoui M et al., Brit J Surg 2010 Survival for completing procedure 3 yrs 5 yrs OS 80% 48% DFS 44% 22% In pts with bilobar synchronous CRC liver mts candidate for two-stage hepatectomy, combined resection of the primary and first-stage hepatectomy optimizes procedures and CT
  • First-liver approach for synchronous liver mts A systematic review of four cohort studies 121 patients: 90 pts (74%) completed the planned treatment 23 pts (19%) progressed during treatment protocol Preferred algorithm: CT → liver res → CT/CT-RT → Primary res → CT?
  • First-liver approach for synchronous liver mts A systematic review of four cohort studies Brouquet’s study (156 pts) Combined Classic Reverse Pts 43 72 27 N. mts 1 3 4 3yr OS 65 58 79 5yr OS 55 48 39 Combined = primary+liver resection Classic = primary resection first Reverse = liver resection first Conclusion: a) Similar outcomes b) Reverse for asympt primary Jegatheeswaran S et al, JAMA Surg 2013 De RosaA et al, Hepatobil Pancr Sci 2013 Comparison among studies 5 yrs OS: 31-41%
  • Patients based analysis comparing liver-first and combined approach Survival No differences regarding the approach (p =0.94) 5 yrs Overall Survival Mayo SC et al, J Am Coll Surg 2012
  • Some arguments to be considered in MDT Combined Surgery • Preferred with limited disease • Removes all macroscopic cancer, but might leave occult metastases • Prevents delay of adjuvant tehrapy • May avoid post-operative immunodeficiency Staged Surgery • Preferred in high risk patients • Majority of metastatic disease is not suitable for resection • Allows more aggressive surgery and optimizes chances of R0 and CT • Early control of systemic disease • First stage: easy side of liver
  • Trattamento di I linea (induzione) Fattori correlati al paziente Presentazione clinica Finalità del trattamento Fattori correlati al tipo di trattamento Manifestazioni cliniche della biologia neoplastica Fattori correlati ai farmaci
  • Aspetti clinici Paziente - Localizzazione - Dinamica di crescita - Sintomi - Impossibilità di trattamento in caso di fallimento - Biomarcatori progn. -Età biologica - Comorbidità - Performance Status -Capacità di tollerare trattamenti intensi - Capacità psicologica/ volontà di affrontare trattamenti intensi Attività/tossicità - Potenzialità di indurre una riduzione max delle mts - Potenzialità di prolungare PFS o OS - Profilo di tossicità - Farmacosensibilità Fattori che influenzano la scelta Farmaci - Disponibilità - Rimborsabilità - Sostenibilità
  • Opzioni terapeutiche • Categorie di farmaci – Citotossici, Biologici • Numero di farmaci – Monoterapia, Doppiette, Triplette – ….. • Strategie – – – – – – Trattamento sino a progressione Sequenze di linee “Stop and go” Mantenimento/Depotenziamento “Watchful waiting” “Rechallenge”
  • Possibili Scenari  Malattia metastatica resecabile  Malattia metastatica potenzialmente resecabile Malattia non resecabile  Malattia asintomatica non voluminosa  Malattia “bulky” ma asintomatica  Paziente “unfit”  Sintomi cancro-correlati Sopravvivenza Continuum Sintomi of care QoL P
  • Continuum terapeutico e Obiettivo sopravvivenza I Fase - Induzione Scelta dominante Bilancio P RP/SD Scelta II Fase – Rescue non cross-resistente Interruzione Mantenimento Prosecuzione Recidiva II Fase P Rechallenge
  • 1a linea: IFL + bevacizumab vs IFL Median progression-free survival 6.2 vs 10.6 months HR=0.54 p<0.0001 0.8 0.8 IFL + bevacizumab IFL + placebo 0.6 0.4 0.2 IFL + bevacizumab IFL + placebo 0.6 0.4 0.2 6.2m 0 Median survival 15.6 vs 20.3 months HR=0.66 p<0.001 1.0 Probability of survival Probability of being progression free 1.0 0 15.6m 10.6m 10 Time (months) 20 30 0 0 10 20.3m 20 30 40 Time (months) Hurwitz et al. NEJM 2004
  • PFS in NO16966: General and On-Treatment Populations 1.0 FOLFOX or XELOX + placebo PFS estimate FOLFOX or XELOX + bevacizumab 0.8 HR=0,83 (IC 97,5%): 0,72 - 0,95) p=0,0023 0.6 HR=0,63 (IC 97,5%): 0,52 - 0,75) p<0,0001 0.4 0.2 0 8.0 0 5 9.4 10 10.4 15 20 Months Bev-containing arm: Separation after ≈6 months occurs between the PFS for General vs. On-treatment populations Saltz LB, ASCO 2007
  • Rassegna dei principali studi di fase III con Bevacizumab associato a politerapia AVF 21072 NO169661 XELOX or FOLFOX ± Bev XELOX ± Bev IFL ± Bev E32003 FOLFOX4 ± Bev FOLFOX ± Bev Bev Control (n = 286) (n = 291) Bev (n=699) OR (%) Median PFS (mos) (95% CI) Control (n=701) Bev (n=350) Control (n=350) Bev (n=349) Control (n=351) Bev (n=402) Control (n=411) 38 38 NA NA NA NA 45 35 22.7 8.6 9.4 8.0 9.3 7.4 9.4 8.6 10.6 6.2 7.3 4.7 ∆ Median PFS 1.4 1.9 Hazard Ratio 0.83 0.77 (mos) (95% CI) Median OS (mos) (95% CI) ∆ Median OS (mos) Hazard Ratio (95% CI) # (0.72, 0.95) p = 0.0023 # 21.3 19.9 1.4 0.89 (0.76, 1.03) p = 0.077 0.8 (0.63, 0.94) 21.4 2.2 (0.68, 1.04) (0.73, 1.08) 21.2 # 20.3 0.9 0.94 (0.75, 1.16) 2.6 0.54 0.89 # 19.2 0.84 4.4 0.61 p < 0.001 20.3 15.6 4.7 0.66 p < 0.001 97.5% CI Saltz LB, et al. J Clin Oncol 2008; 26:2013-9; 2Hurwitz H, et al. N Engl J Med 2004; 350:2335-42; 3Giantonio 2007. 1 p < 0.0001 12.9 10.8 2.1 0.75 p = 0.0011
  • CRYSTAL study: OS in unselected patients All mCRC patients CRYSTAL Erbitux + FOLFIRI (n=599) FOLFIRI (n=599) 1.0 OS estimate 0.8 0.6 19.9 HR=0.878 p=0.0419 18.6 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 Time (months) Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019 54
  • Analysis by KRAS optimizes clinical outcome KRAS analyzed population CRYSTAL Erbitux + FOLFIRI (n=316) FOLFIRI (n=350) 1.0 OS estimate 0.8 0.6 23.5 HR=0.796 p=0.0093 20.0 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 Time (months) Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019 54
  • CRYSTAL KRAS WT mCRC (n=666): PFS Advantage statistically and clinically meaningful 1.0 FOLFIRI (n=350) Cetuximab + FOLFIRI (n=316) PFS estimate 0.8 HR=0.70; p=0.0012 0.6 1-year PFS rate 25% vs 43% 0.4 0.2 0 8.4 0 4 9.9 8 12 Time (months) 16 20 Van Cutsem, et al. ASCO 2010; Van Cutsem, et al. JCO 2011
  • CRYSTAL: efficacy according to KRAS FOLFIRI FOLFIRI + cetuximab n 350 316 RR (%) 39.7 57.3 < 0.0001 mPFS (mos) 8.4 9.9 0.0012 mOS (mos) 20 23.5 0.0094 FOLFIRI FOLFIRI + cetuximab P value n 183 214 RR (%) 36.1 31.3 0.34 mPFS (mos) 7.7 7.4 0.26 mOS (mos) 16.7 16.2 0.75 KRAS wild-type KRAS mutated Δ 1.5 Δ 3.5 P value Interaction test: PFS p = 0.03; OS p = 0.046; ORR p = 0.0005 Van Cutsem et al, ASCO GI 2010
  • PRIME: OS and PFS in KRAS wt patients Panitumumab + FOLFOX4: ~2 Years Median OS in Patients with KRAS WT Tumours Douillard JY, et al. J Clin Oncol 2010; 28:4697-705. Panitumumab + FOLFOX 4: Median PFS of 9.6 Months in Patients with KRAS WT Tumours
  • KRAS Status in Response to Cetuximab  CRYSTAL and OPUS meta-analysis[1] – Pooled efficacy analysis of two randomized phase III trials – CRYSTAL: FOLFIRI + cetuximab vs FOLFIRI alone[2] – OPUS: FOLFOX + cetuximab vs FOLFOX alone[3] – After 90% of samples were subjected to KRAS genotype testing, HRs for benefit of addition of cetuximab shown to be highly statistically significant in patients with wild-type KRAS – PFS—HR: 0.66 (P < .0001) – OS—HR: 0.81 (P = .0062) 1. Bokemeyer C, et al. ASCO 2010. Abstract 3506. 2. Van Cutsem E, et al. N Engl J Med. 2009;360:1408-1417. 3. Bokemeyer C, et al. J Clin Oncol. 2009;27:663-671.
  • Combinazione a 3 farmaci Studio GONO FOLFIRI N=122 FOLFOXIRI N=122 P-value RR* (%) 34 60 <0.0001 CR+PR+SD* (%) 68 81 R0 resection (%) (all patients) 6 15 0.033 R0 resection (%) (liver limited) 12 36 0.017 PFS (mos) 6.9 9.8 0.0006 OS (mos) 16.7† 22.6 0.032 * externally reviewed; †67% 2nd line FOLFOX Falcone et al, JCO 138 2007
  • Stato dell’arte al 2011 • Gli anti-EGFR hanno un ruolo definito nei paz KRAS wt in prima linea • L’efficacia del Bev in prima linea è limitata al PFS, quando combinato con uno schema comprendente una FP infusionale • Il FOLFOXIRI è una alternativa valida in prima linea • Il Bev è efficace in seconda linea in combinazione con FOLFOX • Gli anti-EGFR (Pan) in seconda linea in combinazione con FOLFIRI migliorano la PFS, ma non la OS • La monoterapia può essere una opzione nei pazienti fragili o nella malattia torpida
  • MACRO: Bev di Mantenimento vs Bev + XELOX continuativo Patients with previously untreated mCRC (N = 480) Induction Therapy XELOX + Bevacizumab 6 cycles XELOX + Bevacizumab (n = 239) Bevacizumab (n = 241) Disease progression, severe toxicity, or consent withdrawal Maintenance cycles administered q3w: Oxaliplatin 130 mg/m2 IV on Day 1 Capecitabine 1000 mg/m2 BID PO on Days 1-14 Bevacizumab 7.5 mg/kg IV on Day 1 Tabernero et al, ASCO 2010
  • MACRO: Durata paragonabile della PFS  No significant difference between treatment arms in any efficacy outcome  Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed – The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32 Bevacizumab (n = 241) XELOX/ Bevacizumab (n = 239) HR (95% CI) OR (95% CI) Median PFS,* mos 9.7 10.4 1.11 (0.89-1.37) -- Median OS,* mos 21.7 23.4 1.04 (0.81-1.32) -- 49 46 -- 0.89 (0.62-1.27) Outcome Confirmed objective response, % *Median follow-up: 20.4-21.1 mos. Tabernero et al, ASCO 2010
  • Studio ML18147 (fase III) BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n=820) Standard second-line CT (oxaliplatin or irinotecanbased) until PD PD Randomise 1:1 CT switch: Oxaliplatin → Irinotecan Irinotecan → Oxaliplatin Primary endpoint Secondary endpoints included Stratification factors BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecanbased) until PD • Overall survival (OS) from randomisation •Progression-free survival (PFS) •Best overall response rate •Safety • First-line CT (oxaliplatin-based, irinotecan-based) • First-line PFS (≤9 months, >9 months) • Time from last BEV dose (≤42 days, >42 days) • ECOG PS at baseline (0/1, 2) Study conducted in 220 centres in Europe and Saudi Arabia
  • OS: popolazione ITT CT (n=410) BEV + CT (n=409) 1.0 OS estimate 0.8 0.6 Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) 0.4 Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) p=0.0211 (log-rank test) 0.2 9.8 mo 0 0 6 11.2 mo 12 18 24 30 36 42 48 Time (months) No. at risk CT 410 293 162 51 24 7 3 2 0 BEV + CT 409 328 188 64 29 13 4 1 0 Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0) a Primary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
  • PFS: popolazione ITT CT (n=410) BEV + CT (n=409) 1.0 PFS estimate 0.8 0.6 Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test) 0.4 Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) p<0.0001 (log-rank test) 0.2 0 4.1 mo 0 No. at risk CT 410 BEV+CT 409 5.7 mo 6 12 18 24 30 36 42 Time (months) 119 189 20 45 6 12 4 5 0 2 0 2 0 0 a Primary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
  • Velour: studio di fase III 600 pts Aflibercept 4 mg/kg IV + FOLFIRI q 2 weeks Patients with metastatic colorectal cancer after failure of an oxaliplatinbased regimen R DISEASE PROGRESSION 1:1 DEATH 600 pts STRATIFICATION FACTORS: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) FIRST PATIENT IN: November 2007 ENROLLMENT COMPLETED: 1226 randomized, 1216 treated Final analysis at 863 OS events Placebo + FOLFIRI q 2 weeks PRIMARY ENDPOINT: OS SECONDARY ENDPOINTS: ORR, PFS, safety, PK Clinicaltrials.gov. NCT00561470. Van Cutsem, et al. Ann Oncol. 2011;22(suppl 5). Abstract O-0024 and presentation at: ESMO 13th WCGIC. June 22-25, 2011; Barcelona, Spain. 145
  • Velour: overall survival ITT population Censor Placebo/FOLFIRI: median = 12.06 months Aflibercept/FOLFIRI: median = 13.50 months 1.0 0.9 0.8 Stratified HR = 0.817 [95.34% CI, 0.713–0.937] Log-rank P = 0.0032 KAPLAN-MEIER ESTIMATE 0.7 0.6 0.5 0.4 0.3 0.2 Cut-off date: February 7, 2011 Median follow-up: 22.28 months TIME (months) 0.1 0.0 NUMBER AT RISK SURVIVAL PROBABILITY 0 3 614 612 573 566 6 9 485 401 498 416 79.1% 81.9% 12 15 286 193 311 216 50.3% 56.1% 18 21 131 87 148 104 30.9% 38.5% 24 27 51 31 75 49 18.7% 28.0% 30 14 33 12.0% 22.3% 33 36 39
  • Velour: PFS ITT population Censor Placebo/FOLFIRI: median = 4.67 months Aflibercept/FOLFIRI: median = 6.9 months 1.0 0.9 0.8 Stratified HR = 0.758 [99.99% CI, 0.578–0.995] Log-rank P = 0.00007 KAPLAN-MEIER ESTIMATE 0.7 0.6 0.5 0.4 0.3 0.2 TIME (months) 0.1 NUMBER AT RISK Cut-off date: May 6, 2011 0.0 0 3 6 9 12 15 18 614 612 355 420 171 247 94 99 46 43 24 17 9 7 21 24 27 30
  • CORRECT study 2:1 Evaluation with CT scan of abdomen and chest every 8 weeks • Multicenter, randomized, double-blind, placebo-controlled, phase III – Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region • Global trial: 16 countries, 114 centers • Recruitment: May 2010 to March 2011
  • Sopravvivenza globale Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)
  • Sopravvivenza libera da malattia Regorafenib significantly improves PFS compared to placebo
  • Modellizzazione del Tumor Shrinkage utilizzando la misurazione del diametro maggiore LDi(t) • La somma delle misurazioni dei diametri maggiori delle lesioni “target” che quantifica le dimensioni del tumore viene elaborata informaticamente per il tempo di valutazione t e il paziente i:1 1. Mansmann U, et al. ASCO GI 2012 (Abstract No. 580); 2. Eisenhauer EA, et al. Eur J Cancer 2009;45:228–247
  • Ruolo della risposta nella 1° linea Analisi dello studio Crystal CRYSTAL (KRAS wt) • Quantitativa Response rate (%) 60 50 p<0.001 57 40 30 40 20 10 0 • Qualitativa Change in lesion (%) n=72 n=68 100 80 60 40 20 0 -20 -40 -60 -80 -100 ERBITUX + FOLFIRI (n=316) FOLFIRI (n=350) FOLFIRI (n=276) • Early tumor shrinkage 55% <20% ≥20% 45% ERBITUX + FOLFIRI (n=251) 36% 64% <20% ≥20% Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Van Cutsem E, et al. ASCO 2010 (Abstract No. 3570); Piessevaux H, et al. ESMO 2010 (Abstract No. 596P)
  • CRYSTAL e OPUS: Cetuximab increases patients with ETS CRYSTAL Cetuximab + FOLFIRI 38% 62% ≥20%* (n=184) <20%* (n=115) n=299 OPUS Cetuximab + FOLFOX4 31% 69% ≥20%* (n=54) <20%* (n=24) n=78 *Radiologic evaluation reported by the investigator and reviewed by an IRC FOLFIRI 51% 49% ≥20%* (n=163) <20%* (n=169) n=332 FOLFOX4 54% 46% ≥20%* (n=41) <20%* (n=49) n=90 Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • ETS is related to better PFS in Cetuximab-treated patients Cetuximab + FOLFIRI FOLFIRI 1.0 0.8 mPFS 14.1 mo 0.6 HR 0.32 p<0.001 0.2 mPFS 7.3 mo 0 5 10 15 20 mPFS 9.7 mo 0.6 0.0 mPFS 7.4 mo 0 5 10 15 20 25 (mesi) FOLFOX4 ≥20%* (n=54) <20%* (n=24) 1.0 HR 0.58 p<0.001 0.2 25 (mesi) Cetuximab + FOLFOX4 ≥20%* (n=41) <20%* (n=49) 1.0 0.8 mPFS 11.9 mo 0.4 0.6 OPUS 0.8 0.6 mPFS 7.2 mo 0.4 HR 0.22 p<0.001 0.2 0.0 0.8 0.4 0.4 0.0 ≥20%* (n=163) <20%* (n=169) mPFS 5.7 mo 0 5 CRYSTAL ≥20%* (n=184) <20%* (n=115) 1.0 10 15 20 (mesi) *Radiologic evaluation reported by the investigator and reviewed by an IRC HR 0.89 p=NS 0.2 0.0 mPFS 7.2 mo 0 5 10 15 20 (mesi) Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • Ruolo della risposta nella 1° linea Analisi dello studio Crystal CRYSTAL (KRAS wt) • Quantitativa Response rate (%) 60 50 p<0.001 57 40 30 40 20 10 0 • Qualitativa Change in lesion (%) n=72 n=68 100 80 60 40 20 0 -20 -40 -60 -80 -100 ERBITUX + FOLFIRI (n=316) FOLFIRI (n=350) FOLFIRI (n=276) • Early tumor shrinkage 55% <20% ≥20% 45% ERBITUX + FOLFIRI (n=251) 36% 64% <20% ≥20% Köhne C-H, et al. ASCO 2011 (Abstract No. 3576); Van Cutsem E, et al. ASCO 2010 (Abstract No. 3570); Piessevaux H, et al. ESMO 2010 (Abstract No. 596P)
  • CRYSTAL e OPUS: Cetuximab increases patients with ETS CRYSTAL Cetuximab + FOLFIRI 38% 62% ≥20%* (n=184) <20%* (n=115) n=299 OPUS Cetuximab + FOLFOX4 31% 69% ≥20%* (n=54) <20%* (n=24) n=78 *Radiologic evaluation reported by the investigator and reviewed by an IRC FOLFIRI 51% 49% ≥20%* (n=163) <20%* (n=169) n=332 FOLFOX4 54% 46% ≥20%* (n=41) <20%* (n=49) n=90 Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • ETS is related to better PFS in Cetuximab-treated patients Cetuximab + FOLFIRI FOLFIRI 1.0 0.8 mPFS 14.1 mo 0.6 HR 0.32 p<0.001 0.2 mPFS 7.3 mo 0 5 10 15 20 mPFS 9.7 mo 0.6 0.0 mPFS 7.4 mo 0 5 10 15 20 25 (mesi) FOLFOX4 ≥20%* (n=54) <20%* (n=24) 1.0 HR 0.58 p<0.001 0.2 25 (mesi) Cetuximab + FOLFOX4 ≥20%* (n=41) <20%* (n=49) 1.0 0.8 mPFS 11.9 mo 0.4 0.6 OPUS 0.8 0.6 mPFS 7.2 mo 0.4 HR 0.22 p<0.001 0.2 0.0 0.8 0.4 0.4 0.0 ≥20%* (n=163) <20%* (n=169) mPFS 5.7 mo 0 5 CRYSTAL ≥20%* (n=184) <20%* (n=115) 1.0 10 15 20 (mesi) *Radiologic evaluation reported by the investigator and reviewed by an IRC HR 0.89 p=NS 0.2 0.0 mPFS 7.2 mo 0 5 10 15 20 (mesi) Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • ETS is related to prolonged OS in Cetuximab-treated patients Cetuximab + FOLFIRI FOLFIRI ≥20%* (n=163) <20%* (n=169) 1.0 0.8 0.8 mOS 30.0 mo 0.6 mOS 24.1 mo 0.6 HR 0.71 p=0.006 0.4 0.4 0.2 HR 0.53 p<0.001 mOS 18.6 mo 0.0 0 10 20 30 40 50 60 (mesi) Cetuximab + FOLFOX4 ≥20%* (n=54) <20%* (n=24) 1.0 0.4 HR 0.43 p=0.006 mOS 15.7 mo 0.0 0 10 FOLFOX4 20 30 40 50 0.8 mOS 21.6 mo 0.6 0.4 0.2 0.0 HR 0.89 p=NS mOS 17.8 mo 0.2 0.0 60 (mesi) ≥20%* (n=41) <20%* (n=49) 1.0 mOS 26.0 mo 0.6 mOS 18.6 mo OPUS 0.8 0.2 CRYSTAL ≥20%* (n=184) <20%* (n=115) 1.0 0 10 20 30 40 (mesi) *Radiologic evaluation reported by the investigator and reviewed by an IRC 0 10 20 30 40 (mesi) Piessevaux H, et al. JSMO 2012 (Abstract No. IS9-3)
  • TRIBE Study Design FOLFIRI+bev 508 mCRC pts 1st line unresectable stratified by  center  PS 0/1-2  adjuvant CT (up to 12 cycles) 5-FU/LV +Bev R PD FOLFOXIRI+bev (up to 12 cycles) INDUCTION 5-FU/LV +Bev MAINTENANCE
  • Primary endpoint: PFS (updated) – ITT population FOLFIRI + bev Progression-free survival probability FOLFOXIRI + bev Median follow up: 32.3 mos FOLFIRI + bev: N = 256 / Progressed = 226 FOLFOXIRI + bev: N = 252 / Progressed = 213 FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos Unstratified HR: 0.77 [0.64-0.93] p=0.006 Stratified HR: 0.75 [0.62-0.90] p=0.003 F-up time (months) FOLFIRI/bev 256 203 94 46 26 14 7 3 0 0 FOLFOXIRI/bev 252 208 125 74 35 21 11 5 2 1
  • Secondary endpoint: Response rate (updated) - ITT population FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 Complete Response 3% 5% Partial Response 50% 60% Response Rate 53% 65% Stable Disease 32% 25% Progressive Disease 11% 6% Not Assessed 4% 4% p Best Response, % 0.006
  • Secondary endpoint: OS (preliminary) – ITT population FOLFIRI + bev FOLFOXIRI + bev Median follow up: 32.3 mos Overall survival probability FOLFIRI + bev: N = 256 / Died = 155 FOLFOXIRI + bev: N = 252 / Died = 131 FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 31.0 mos Unstratified HR: 0.83 [0.66-1.05] p=0.125 Stratified HR: 0.79 [0.63-1.00] p=0.054 F-up time (months) FOLFIRI/bev 256 233 216 172 109 69 36 15 5 0 FOLFOXIRI/bev 252 234 205 175 119 70 35 15 4 0
  • PRIME study RAS analysis PFS (primary analysis) WT KRAS exon 21 WT RAS2 100 100 HR = 0.80 (95% CI, 0.66–0.97) P = 0.02 80 70 60 50 40 30 20 90 Proportion event-free (%) Proportion event-free (%) 90 HR = 0.72 (95% CI, 0.58–0.90) P = 0.004 80 70 60 50 40 30 20 10 10 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Events n (%) 199 (61) 9.6 (9.2–11.1) FOLFOX4 (n = 331) 215 (65) 8.0 (7.5–9.3) 2 4 6 8 10 12 14 16 18 20 22 24 Months Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 156 (60) 10.1 (9.3–12.0) FOLFOX4 (n = 253) 170 (67) 7.9 (7.2–9.3) Median (95% CI) months Panitumumab + FOLFOX4 (n = 325) 0 1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705; 2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34. WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)
  • PRIME study RAS analysis OS (primary analysis) WT RAS2 WT KRAS exon 21 100 100 HR = 0.83 (95% CI, 0.67–1.02) P = 0.072 80 70 60 50 40 30 20 90 Proportion alive (%) Proportion alive (%) 90 HR = 0.78 (95% CI, 0.62–0.99) P = 0.043 80 70 60 50 40 30 20 10 10 0 0 0 4 8 12 16 20 Months 24 28 32 36 Events n (%) 165 (51) 23.9 (20.3–28.3) FOLFOX4 (n = 331) 190 (57) 19.7 (17.6–22.6) 4 8 12 1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705; 2. Douillard JY, et al. N Engl J Med 2013; 369:1023-34. 16 20 Months 24 28 32 36 Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 (21.7–30.4) FOLFOX4 (n = 253) 148 (58) 20.2 (17.7–23.1) Median (95% CI) months Panitumumab + FOLFOX4 (n = 325) 0 WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)
  • PEAK study WT KRAS exon 2 mCRC Metastatic CRC WT KRAS exon 2 (n = 285) o f (Q2W) t r e a t m e n t R 1:1 S a f e E n d mFOLFOX6 (Q2W) + panitumumab 6 mg/kg mFOLFOX6 (Q2W) + bevacizumab 5 mg/kg (Q2W) Tumour Assessment Q8W (±7 days); Treatment administered until disease progression, death, or withdrawal from study t y 30 days (+ 3 days) f o l l o w u p P o s t t r e a t m e n t f o l l o w E n d o f s t u d y u p Every 3 months (±28 days) until end of study • Study endpoints: PFS (1°); OS, ORR, resection rate, safety, exploratory biomarker analysis • No formal hypothesis testing was planned Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster); Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. ORR, objective response rate; mFOLFOX6, modified FOLFOX6
  • Analisi RAS dello studio PEAK PFS WT RAS WT KRAS esone 2 100 100 HR* = 0.84 (95% CI, 0.64–1.11) P = 0.22 80 70 60 50 40 30 20 90 Proportion event-free (%) Proportion event-free (%) 90 HR* = 0.66 (95% CI, 0.46–0.95) P = 0.03 80 70 60 50 40 30 20 10 10 0 0 0 4 8 12 16 20 24 Months Events n (%) 28 32 36 40 0 4 8 12 16 20 24 Months 28 32 36 40 Events n (%) Median (95% CI) months Median (95% CI) months Panitumumab + 100 (70) mFOLFOX6 (n = 142) 10.9 (9.7–12.8) Panitumumab + mFOLFOX6 (n = 88) 57 (65) 13.0 (10.9–15.1) Bevacizumab + 108 (76) mFOLFOX6 (n = 143) 10.1 (9.0–12.0) Bevacizumab + mFOLFOX6 (n = 82) 66 (80) 10.1 (9.0–12.7) Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster). *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4
  • Analisi RAS dello studio PEAK OS WT KRAS esone 2 WT RAS 90 80 80 Proportion alive (%) 100 90 Proportion alive (%) 100 70 60 50 40 30 20 HR* = 0.62 (95% CI, 0.44–0.89) P = 0.009 10 0 70 60 50 40 30 20 HR* = 0.63 (95% CI, 0.39–1.02) P = 0.058 10 0 0 4 8 12 16 20 24 28 32 36 40 44 Months Events n (%) 52 (37) 34.2 (26.6–NR) Bevacizumab + mFOLFOX6 (n = 143) 78 (55) 24.3 (21.0–29.2) 4 8 12 16 20 24 28 32 36 40 44 Months Events n (%) Median (95% CI) months Panitumumab + mFOLFOX6 (n = 88) 30 (34) 41.3 (28.8–41.3) Bevacizumab + mFOLFOX6 (n = 82) 40 (49) 28.9 (23.9–31.3) Median (95% CI) months Panitumumab + mFOLFOX6 (n = 142) 0 *Stratified Cox proportional hazards model; No formal hypothesis testing was planned; WT RAS, WT KRAS & NRAS exons 2/3/4; Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster). NR, not reached
  • Obiettivo sopravvivenza – Anti-angio Terapia Studio PFS OS IFL+B AVF2107 10.6 20.3 Fp+Ox+B* N016966 10.4 - XELOX+B N016966 9.3 21.4 FOLFOX+B N016966 9.4 21.2 FOLFOXIRI+B TRIBE 12.1 31 CT+B ML18147 5.7 11.2 1.6 1.4 FOLFIRI+A VELOUR 6.9 13.5 1.2 1.5 Regorafenib CORRECT 1.9 6.4 0.2 1.4 FOLFOX+B Di Giantonio 7.3 12.9 2.6 2.1 FOLFIRI+B FIRE III 10.3 25.0 * On-treatment Δ PFS Δ OS Δ rispetto al braccio di controllo
  • Obiettivo sopravvivenza Terapia personalizzata: Cet I linea Terapia Studio PFS OS FOLFIRI+C CRYSTAL 8.9 19.9 FOLFIRI+C KRAS wt CRYSTAL 9.9 23.5 FOLFOX+P KRAS wt PRIME 9.6 23.9 FOLFIRI+C ETS CRYSTAL 14.1 30.0 FOLFIRI+C FIRE III 10.0 28.7 FOLFIRI+C panRAS FIRE III 10.4 33.1 FOLFIRI+C panRAS CAPRI 11.3 - FOLFOX+P panRAS PRIME 10.1 26.0 FOLFOX+P panRAS PEAK 13 41.3
  • Obiettivo sopravvivenza Sequenza vs Terapia personalizzata XELOX+B OS: 21.4 m ML18147 ΔOS: 1.4 m VELOUR ΔOS: 1.5 m Regorafenib ΔOS: 1.4 m 22.8 m 24.3 m 25.6 m FOLFIRI+B FIRE III OS 25.0 m FOLFOXI+B Di Giantonio ΔOS: 2.1 m 27.1 m FIREIII FOLFIRI+C panRAS OS: 33.1
  • Classification of CRC based on correlation of clinical, morphological and molecular features Feature Group 1 (12%) Group 2 (8%) Group 3 (20%) Group 4 (57%) Group 5 (3%) MSI status H S/L S/L S H CIMP H H L Negative Negative +++ +++ ++ +/- +/- KRAS - + +++ ++ ++ BRAF +++ ++ - - - TP53 - + ++ +++ + Location R>L R>L L>R L>R R>L Serration +++ +++ + +/- +/- Mucinous +++ +++ + + ++ Poor diff +++ +++ + + ++ Methylation Jass JR, Hystopathology 2007
  • Colon cancer: genetic vs stage progression METASTASIS Lung Liver Skin Bone Ovary Peritoneum STAGING NORMAL TISSUE ADENOMA EARLY CARCINOMA (StageS I & II) Mucosa Submucosa Circular Muscle Longitudinal Muscle Pericolic Lymph Nodes Artery and Capillaries GENETIC PROGRESSION 20 - 40 years Mutation or loss Mutation Loss Mutation and loss Axin β-catenin APC B-RAF KRAS TGFβ−RII SMAD2/4 TP53 LATE CARCINOMA (Stages III & IV)
  • Multi-step colon-cancer progression NORMAL COLON EPITHELIA E-cadh β RAS Src ADENOMA PI3K K3 GS JNK β β Proteasome Ax in 1. Wnt/β-catenin Oncogenic Activation APC AKT 2. K-Ras Oncogenic Activation (other alterations) CARCINOMA Gro Lef Tcf/Lef genes OFF ON PROLIFERACION FOXO FOXO genes OFF ON QUIESCENCE PROLIFERATION QUIESCENCE, INVASION? PROLIFERATION DIFFERENTIATION 3. JNK activation? Stress or ligands METASTASIS Stage III & IV
  • Wnt/b-catenin & PI3k/Akt signalling crosstalk drives cancer cell fate NICHE WNT INHIBITORS OXIDATIVE ESTRESS GROWTH FACTORS RTK XAV939 β EGFR/PI3K/AKT INHIBITORS CETUXIMAB Proteasome Axin JNK APC RAS β β FOXO3a β PI3K API2 AKT GDC-0068 β Lef β ON PROLIFERATION ON FOXO3a APOPTOSIS CYCLE ARREST & METASTASIS CELL FATE
  • Small molecules to Inhibit Wnt/β-catenin Oncogenic Signal Small molecules Blocking antibodies Dr. Paul Polakis. Genentech Wnt LRP Fz TNK in Ax Dsh β C AP β β β K3 GS β β Lef ON Tcf/Lef genes Vitamin D Palmer HG et al Small molecules
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