La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott. Amedeo Pancotti Ospedale Mazzini – Teramo 07 A PRILE.

Presentazioni simili


Presentazione sul tema: "Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott. Amedeo Pancotti Ospedale Mazzini – Teramo 07 A PRILE."— Transcript della presentazione:

1 Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott. Amedeo Pancotti Ospedale Mazzini – Teramo 07 A PRILE 2011 I L C ARCINOMA DEL C OLON -R ETTO M ETASTATICO TAVOLA ROTONDA T ERAPIA DI I LINEA

2 2010 NCCN Guidelines: Advanced/mCRC Patient Can Tolerate Intensive Therapy First LineSecond LineThird Line FOLFOX ± bevacizumab FOLFOX ± cetuximab* CapeOx ± bevacizumab CapeOx ± cetuximab* FOLFIRI + bevacizumab FOLFIRI ± cetuximab* 5-FU/leucovorin + bevacizumab Panitumumab FOLFOXIRI (2B) FOLFIRI Irinotecan FOLFIRI + cetuximab* (2B) Irinotecan + cetuximab* FOLFOX CapeOx Irinotecan + cetuximab* FOLFOX CapeOx Irinotecan Irinotecan + cetuximab* Clinical trial BSC *Patients with wild-type KRAS only. In patients who cannot tolerate combination, consider either single-agent cetuximab (wild-type KRAS only) or single-agent panitumumab (wild-type KRAS only); cetuximab and panitumumab should not be used in combination. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V

3 Obiettivi della prima linea Risposta obiettiva immediata (malattia curabile, potenzialmente resecabile) Migliore risposta obiettiva (malattia incurabile aggressiva ->paziente sintomatico) Trattamento a lungo termine (malattia incurabile indolente -> paziente asintomatico)

4 Le caratteristiche del paziente guidano il processo decisionale Performance status Età Comorbidità Estensione della malattia Obiettivi del trattamento: palliative vs potentially curative Precedente trattamento adiuvante entro 1 anno Funzionalità dorgano: epatica e renale Ipertensione non controllata Rischio di sanguinamento KRAS status

5 Goals of Treatment: Paziente sintomatico vs asintomatico CHOICE OF FIRST-LINE MCRC THERAPY BASED ON TREATMENT GOALS FOR THE PATIENT [1] – Paziente asintomatico, malattia indolente – Considerare età del paziente, comorbidità, qualità di vita, preferenza del paziente, costi del trattamento – Paziente sintomatico, malattia aggressiva – Chemioterapia (doppiette o triplette) con agenti biologici quando possibile per ottenere un rapido tumor shrinkage e remissione dei sintomi 1. Adam R, et al. Ann Oncol. 2010;21:

6 Goals of Treatment: trattamento curativo vs palliativo Intento curativo nei pazienti con malattia metastatica limitata al fegato o al polmone, potenzialmente suscettibili di chirurgia curativa, quindi candidati ad una terapia neoadiuvante aggressiva Intento palliativo nei pazienti con coinvolgimeto di più organi o di sedi non trattabili chirurgicamente (peritoneo, linfonodi) con lobiettivo di migliorare la qualità di vita

7 Ruolo della terapia adiuvante Progressione entro 12 mesi dalla terapia adiuvante suggerisce una resistenza del tumore alla terapia 1. NCCN. Clinical practice guidelines in oncology: colon cancer Recommended [1] First-line Treatment Choices for Patients Progressing < 12 mos after adjuvant FOLFOX> 12 mos after adjuvant FOLFOX, adjuvant 5-FU/LV, or adjuvant capecitabine FOLFIRI ± bevacizumab FOLFIRI ± cetuximab or panitumumab (KRAS wild type only) All active chemotherapy regimens

8 KRAS Gene Status ~ 40% dei tumori del colon-retto presentano mutazione del gene KRAS [1] – Mutazioni nei codoni 12 e 13 dellesone 12 [2] – Mutazioni del codone 61 determinano una proteina KRAS costituzionalmente attiva Scarsa risposta agli agenti diretti verso EGFR [2] – Linibizione EGFR potrebbe essere evitata da attivazione costitutiva KRAS a valle [1] 1. Lièvre A, et al. Oncogene. 2010;29: Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49.

9 Comorbidità: Ipertensione Bevacizumab - Associato con una maggiore incidenza (10% to 15%) di ipertensione di grado 3/4 - Non dovrebbe essere utilizzato in pazienti con mCRC con ipertensione severa o non controllato dalla terapia - Associato con un maggior rischio di stroke e/o eventi tromboembolici – Soprattutto in pazienti 65 anni

10 Rischio di sanguinamento Bevacizumab è associato al rischio di – Sanguinamenti e complicanze – Ritardata guarigione delle ferite – Perforazione GI Raccomandazioni [1] – intervallo di almeno 4-6 settimane dallultimo trattamento con bevacizumab e la chirurgia – Intervallo di almeno 6-8 settimane post-intervento prima di somministrare bevacizumab – Non dovrebbe essere somministrato a pazienti con storia di recentiemorragie o emottisi 1. NCCN. Clinical practice guidelines in oncology: colon cancer

11 Comorbidità Le comorbidità possono avere un impatto significativo sulla scelta del trattamento di I linea Esempi – Lutilizzo di oxaliplatino potrebbe essere limitato in pazienti con neuropatia diabetica o insufficienza renale in anamnesi – Lutilizzo di irinotecano potrebbe essere limitato in pazienti con storia di malattie intestinali, che hanno ricevuto precedentemente radioterapia sulla pelvi, con storia di malattie epatiche (epatite virale o cirrosi) con ridotta funzionalità epatica – Pazienti con malattie cardivascolari potrebbero presentare una cardiotossicità correlata allutilizzo di fluoropirimidine

12 Come trattare I pazienti con le seguenti opzioni terapeutiche? Chemioterapia FOLFOX FLOX FOLFIRI 5-FU/LV or capecitabine FOLFOXIRI CapeOX (XELOX) CapeIRI (XELIRI) IROX Irinotecan Targeted Therapy Bevacizumab Cetuximab Panitumumab NCCN. Clinical practice guidelines in oncology: colon cancer

13 n RR 56%15%54%4% Median PFS (months) Median PFS (months) for sequence Median overall survival (months) Tournigand C, et al. J Clin Oncol. 2004;22: Arm A FOLFIRI FOLFOX6 Arm B FOLFOX6 FOLFIRI FOLFIRI vs FOLFOX: no difference in first-line efficacy

14 Falcone A, et al. J Clin Oncol 2007; 25: RR, 41% v 66%; P.0002 RR confirmed by an external panel was 34% versus 60% (P.0001). median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P.0006; median OS, 16.7 v 22.6 months; HR, 0.70; P.032). Conclusions of Author: in patients with few chances to achieve a three-drug exposure in a sequential strategy Three Drugs combinations

15 Targeting VEGF(R) Recombinant humanized monoclonal IgG1 moAb Recognizes VEGF-A and blocks VEGF function Recombinant humanized monoclonal IgG1 moAb Recognizes VEGF-A and blocks VEGF function

16 IRINOTECAN-based regimen and BEVACIZUMAB Hurwitz H, et al. N Engl J Med 2004;350:2335–42

17 BICC-C Trial, 1 st line MCRC Irinotecan-based Chemotherapy + Beva First-line mCRC (n=115) FOLFIRI + Bevacizumab n=56 CapeIri + Bevacizumab mIFL + Bevacizumab n=59 First-line mCRC (n=430) FOLFIRI n=144 CapeIri n=145 mIFL n=141 Fuchs CS, et al. J Clin Oncol 2007;25:4779–86

18 BICC-C Study What is the best 5FU and Irinotecan-based regimen with Bevacizumab? FOLFIRI

19 AVIRI trial Sobrero, et al. Oncology 2009;77:

20 N016966: Study Design Randomized phase III trial XELOX + Placebo (n = 350) Unresectable mCRC with no previous systemic therapy for mCRC and no previous oxaliplatin or bevacizumab (N = 1401) XELOX + Bevacizumab (n = 350) FOLFOX4 + Placebo (n = 351) FOLFOX4 + Bevacizumab (n = 350) 1. Saltz LB, et al. J Clin Oncol. 2008;26: OXALIPLATIN-based regimen and BEVACIZUMAB

21 Saltz LB, et al. J Clin Oncol. 2008;26: PFS significantly increased with addition of bevacizumab to chemotherapy XELOX is not inferior to FOLFOX-4 in First Line Colorectal Cancer

22 ARIES: Study Design Community-based prospective observation cohort study 244 sites, 43 states in US FOLFOX + Bev (n = 739) FOLFIRI + Bev (n = 191) First-line mCRC (N = 1550 enrolled) PFS OS Bendell JC, et al. GI ASCO Abstract 480.

23 ARIES Study: Clinical Efficacy Endpoint, MosFOLFOX + Bev (n = 72) FOLFIRI + Bev (n = 73) PFS OS Bendell JC, et al. GI ASCO Abstract 480.

24 Targeting EGFR Expression of EGF Receptors Ligands Bind EGF Receptor Dimerization TGF- EGF Extracellular Binding Domain Transmembrane Lipophilic Segment Intracellular Protein Tyrosine Kinase Domain Activation of Signal Transduction chimeric human/murine immunoglobulin G1 (IgG1) MAB targeting the EGFR Antibody Binds Receptor Internalized

25 CRYSTAL trial: Study design Stratification factors: – Regions – ECOG PS Populations – Randomized patients n=1217 – Safety population n=1202 – ITT population: n=1198 FOLFIRI irinotecan (180 mg/m 2 ) + 5-FU 400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks Cetuximab + FOLFIRI Cetuximab IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly + irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks R EGFR-expressing metastatic CRC Van Cutsem E, et al. N Engl J Med 2009; 360:

26 KRAS Status in Response to Cetuximab CRYSTAL: randomized, multicenter phase III trial [1] – Significant improvement in PFS with addition of cetuximab to FOLFIRI vs FOLFIRI alone for first-line mCRC treatment Retrospective analysis of CRYSTAL [2] – Included only subset of KRAS-evaluable patients (N = 540) 1. Van Cutsem E, et al. N Engl J Med. 2009;360: Van Cutsem E, et al. ASCO Abstract 2.

27 KRAS Status in Response to Cetuximab Retrospective analysis of CRYSTAL [1] – PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS 1. Van Cutsem E, et al. ASCO Abstract 2. OutcomeWild-Type KRAS (n = 348) Mutated KRAS (n = 192) Median PFS, mos FOLFIRI + cetuximab FOLFIRI HR0.68*1.07 ORR, % FOLFIRI + cetuximab FOLFIRI *P =.017; P =.75; P =.0025

28 Kaplan–Meier Estimates of PFS and OS in the Wild-Type– KRAS Population mPFS 9.9 vs 8.7 Van Cutsem E, et al. N Engl J Med 2009; 360: mOS 24.9 vs 21.0

29 Bokemeyer C, et al. J Clin Oncol 2009; 27:663-71

30

31 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 – PFSHR: 0.66 (P <.0001) – OSHR: 0.81 (P =.0062) 1. Bokemeyer C, et al. ASCO Abstract Van Cutsem E, et al. N Engl J Med. 2009;360: Bokemeyer C, et al. J Clin Oncol. 2009;27:

32 Panitumumab Inhibition of EGF binding to EGFR This may lead to: Cell proliferation Cell survival Angiogenesis Metastatic spread EGF, TGFα or other ligands binding to EGFR A fully human* lgG2 monoclonal antibody to EGFR High affinity, K D = 5 x M Inhibits ligand-induced EGFR tyrosine phosphorylation Panitumumab Inhibits Ligand Binding to EGFR and Dimerization

33 PRIME Study: KRAS Status in Response to Panitumumab Randomized, global, open-label, phase III trial Douillard JY, et al. J Clin Oncol. 2010;28: Panitumumab 6.0 mg/kg q2w + FOLFOX4 q2w (n = 593) FOLFOX4 q2w (n = 590) Stratified by ECOG PS (0-1 vs 2) and geographic region (Western Europe, Canada, and Australia vs all other locations) Patients with previously untreated mCRC (N = 1183)

34 PRIME Study: Efficacy Results PFS significantly improved with FOLFOX4 + panitumumab only in wild- type KRAS patients Worse PFS outcome with panitumumab addition in mutated KRAS patients Douillard JY, et al. J Clin Oncol. 2010;28:

35 PRO E CONTRO DEI FARMACI BIOLOGICI Anti-VEGF Rallenta la crescita tumorale Aumenta la PFS Profilo di tossicità ± favorevole Possibilità di utilizzo fino a progressione Possibilità di mantenimento Non attivo in monoCT No biomarcatori predittivi (VEGF epithelial and stromal expression; Microvascular density; VEGF and VEGFR SNPs; VEGF plasma levels) Perde efficacia nelle successive linee di trattamento Scarso effetto su tasso di risposta Anti-EGFR Attivo anche come agente singolo Aumenta il tasso di risposta Efficace in tutte le linee di trattamento Biomarcatore predittivo convalidato Modesto incremento di PFS e OS Tossicità cutanea (Interruzione del trattamento, riduzione di dose, compromissione dellefficacia del trattamento)

36 Can Genetic Polymorphisms Guide Chemotherapy for Metastatic CRC ? FOLFOX – ABCG2 34 G>A: rare transporter gene FOLFIRI – UGT1A1 7/7 genotype regimen specific? Capecitabine – Differential metabolism not understood

37 Predicting Oxaliplatin Efficacy Genomic DNA from 180/238 patients on C80203 (FOLFOX vs FOLFIRI ± cetuximab) Genotype transporter genes involved in irinotecan and oxaliplatin clearance – ABCC2, ABCC4, ABCG2, SLCO1B1, SLC22A1, SLC22A2 Association of genotype with response and toxicity Result – ABCG2 34 G>A associated with response to FOLFOX, resistance to FOLFIRI but not to toxicity McLeod HL, et al. ASCO Abstract 3513.

38 Patients With Reduced UGT1A1 Activity Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of irinotecan treatment A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele Heterozygous patients (carriers of one variant allele and 1 wild-type allele, which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses Irinotecan [prescribing information].

39 FOCUS Trial Patients with previously untreated CRC (N = 2135) Molecular substudy (n = 1188)* Fluorouracil + Irinotecan (n = 175) Fluorouracil + Oxaliplatin (n = 172) Irinotecan (n = 184) Fluorouracil + Irinotecan (n = 95) Fluorouracil + Oxaliplatin (n = 108) First-line therapySecond-line therapy *152 patients missing data for primary endpoint. Fluorouracil (n = 688) C B A Braun MS, et al. J Clin Oncol. 2009;27:

40 Marker/FunctionVariantAt Risk GTDrug Effected Hypothesized Impact ActivityToxicityOther ABCB1/cellular efflux3435 C to TTTIrinotecan clearance DPYD/detoxification IVS14 + 1G to A (*2A) VariantsFluorouracil active metabolite ERCC2/DNA repair35,931 A to CCCOxaliplatin DNA repair GSTP1/detoxification313 A to GAAOxaliplatin detoxification MLH1/DNA repair-93 G to AAA Fluorouracil Irinotecan Oxaliplatin DNA repair MTHFR/folate pool, modifies FU response 667 C to TTTFluorouracil-- TYMS/target for FU metabolite 1494: 6 bp insertion+/+Fluorouracil-- expression ER: VNTR 28 bp2R/2RFluorouracil-- expression UGT1A1/detoxification VNTR: 6 or 7 TA repeats (*28) 7/7Irinotecan detoxification XRCC1/DNA repair23,885 G to AAA Irinotecan Oxaliplatin DNA repair FOCUS: Polymorphisms Potentially Predictive of Toxicity and/or Efficacy Braun MS, et al. J Clin Oncol. 2009;27:

41 EGFR antibodies – KRAS mutational status – BRAF mutational status VEGF antibody efficacy Combining EGFR and VEGF antibodies Toward Personalized Therapy of CRC: Who Will Benefit From Targeted Therapy?

42 SubgroupPR, % P Value Mutant KRAS (n = 34)6.011 Wild-type KRAS (n = 79) Mutant BRAF (n = 11)0.011 Wild-type BRAF (n = 68) KRAS and BRAF Mutational Status and EGFR Inhibitors KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGFR Di Nicolantonio F, et al. J Clin Oncol, 2008;26:

43 KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGFR Small subset of patients – N = 113 – 22 of 68 patients (32%) with WT KRAS and WT BRAF responded to treatment with EGFR inhibitor KRAS and BRAF Mutational Status and EGFR Inhibitors (Contd) Di Nicolantonio F, et al. J Clin Oncol, 2008;26:

44 Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC): Results of the translational study on the PETACC 3-EORTC SAKK trial Roth A, Oral Abstrct Session 2010 ASCO Annual Meeting

45 Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC): Results of the translational study on the PETACC 3-EORTC SAKK trial Roth A, Oral Abstrct Session 2010 ASCO Annual Meeting

46 Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on the PETACC 3-EORTC SAKK trial Sabine Tejpar, Oral Abstract Session 2010 ASCO Annual Meeting

47 Mutant KRAS and BRAF gene expression profiles in colorectal cancer: Results of the translational study on the PETACC 3- EORTC SAKK trial

48 Untreated advanced or mCRC (N = 1500) Bevacizumab followed by FOLFOX or FOLFIRI q2w Cetuximab followed by FOLFOX or FOLFIRI q2w One cycle = 8 wks Open-Label Phase III Study Screen for eligibility Send tumor tissue block to SWOG PCO Register Patient CALGB/SWOG Study Design ClinicalTrials.gov. NCT Randomize patients with Wild-type KRAS tumor

49 Patients with metastatic colorectal cancer and ECOG 1 (N = 1053) Oxaliplatin-CT + Bevacizumab + Panitumumab (n = 413) Oxaliplatin-CT + Bevacizumab (n = 410) Irinotecan-CT + Bevacizumab + Panitumumab (n = 115) Irinotecan-CT + Bevacizumab (n = 115) PACCE Trial: Chemotherapy + Bevacizumab ± Panitumumab Hecht JR, et al. J Clin Oncol. 2009;27:

50 Outcome, mosCT + Bevacizumab + Panitumumab CT + Bevacizumab HR (95% CI) Oxaliplatin cohort (n = 413)(n = 410) Median PFS ( ) Median OS ( ) Irinotecan cohort (n = 115) Median PFS ( ) Median OS ( ) PACCE: PFS and OS for Ox-CT and Iri-CT Hecht JR, et al. J Clin Oncol. 2009;27:

51 I Proposta: pazienti con buon PS e KRAS mut In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens – FOLFOX – XELOX – FOLFIRI – XELIRI In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens – FOLFIRI – XELIRI Bevacizumab is the biologic agent of choice

52 II a Proposta: pazienti con buon PS e KRAS wild-type In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens – FOLFOX – XELOX – FOLFIRI – XELIRI In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens – FOLFIRI – XELIRI

53 Bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab are reasonable biological agents to consider as part of the treatment regimen In patients who are potentially surgically resectable, cetuximab may be the optimal biological agent as it yields increased response rates when combined with cytotoxic chemotherapy II b Proposta: pazienti con buon PS e KRAS wild-type

54 III Proposta: pazienti con scarso PS e KRAS mut In previously untreated patients, fluoropyrimidine monotherapy is appropriate – 5-FU/LV – Capecitabine Bevacizumab is the biologic agent of choice in the absence of contraindications

55 IV Proposta: pazienti con scarso PS e KRAS wilde type In previously untreated patients, fluoropyrimidine monotherapy is appropriate – 5-FU/LV – Capecitabine Consider using bevacizumab or the anti-EGFR antibodies cetuximab or panitumumab

56 CONCLUSIONI Obiettivi terapeutici Continuum of care Terapia di conversione Polimorfismi genetici Nuovi fattori predittivi e prognostici Gene expression profile A NEW ERA: INDIVIDUALIZED THERAPY


Scaricare ppt "Dott.ssa Alessandra Santomaggio U.O.C. Oncologia Medica Dipartimento di Oncologia Direttore: Dott. Amedeo Pancotti Ospedale Mazzini – Teramo 07 A PRILE."

Presentazioni simili


Annunci Google