1. Terapia del cancro colorettale Carlo Barone Oncologia Medica Universit Cattolica del S. CuoreCenc oO ntric log oo

2. Argomenti Terapia adiuvante del cancro del colon Terapia del cancro del retto Terapia della malattia metastatica Metastasi epatiche ( polmonari) Metastasi multiple 3. Trials with Oxa: Adjuvant Setting TrialPtsTreatmentDataMOSAIC224 6FOLFOX-4 x 6 mos 5-FULV2 x 6 mos5-y DFS 6-y OS SafetyFLOX x 6 mos Bolus 5-FULV w x 6 mos5-y DFS SafetyXELOX x 6 mos Bolus 5-FULV w/q4w x 6 mos5-y-DFS Safety(NEJM 2004, ASCO 2005, ASCO 2007)NSABP C-07 2407 (JCO 2007) ASCO 2008ROCHE NO16968 (JCO 2007)1886 4. MOSAIC: 5-yrs DFS Updated3.8 7.5Andr T, et al. JCO 2009 5. MOSAIC Updated: OS 6 years2.5Andr T, et al. JCO 2009 6. MOSAIC OS Updated: 6 yrs, by stage p=0.9960.1%p=0.0294.4%Andr T, et al. JCO 2009 7. X-ACT updated: 5-Year DFS and OS Xeloda 5-FU/LV0.80.6Absolute difference at 5 years: 4.1%4 01234 5 YearsHR = 0.86 (95% CI 0.74-1.01) p = 0.06000.80.6Absolute difference at 5 years: 3.1%4 675-year OS (%) 71.4 68.41.0HR = 0.88 (95% CI 0.77-1.01) p = 0.0682OS estimateDFS estimate1.05-year DFS (%) 60.8 56.7(n = 1,004) (n = 983)80Twelves C, et al. ASCO GI 2008. Abstract 274.1234 5 Years678 8. NO16968 XELOXA Trial Primary endpoint: DFS XELOX 5-FU/LV1.0 0.8 0.6 0.4HR=0.80 (95% CI: 0.690.93) p=0.00450.2 0.0 0123 YearsITT population456 9. 3-year DFS: benefit with XELOX maintained over time 3-year DFS XELOX 5-FU/LV1.070.9% 66.5%0.8 at 3 years: 4.5%0.6 0.4 0.2 0.0 0123 YearsITT population456 10. 4-year DFS: benefit with XELOX maintained over time 3-year DFS 70.9% 66.5%XELOX 5-FU/LV1.04-year DFS 68.4% 62.3%0.8 at 3 years: 4.5%0.6 at 4 years: 6.1% 0.4 0.2 0.0 0123 YearsITT population456 11. 5-year DFS: benefit with XELOX maintained over time 3-year DFS 1.05-year DFS70.9% 66.5%XELOX 5-FU/LV4-year DFS 68.4% 62.3%66.1% 59.8%0.8 at 3 years: 4.5%0.6 at 4 years: 6.1% 0.4 at 5 years: 6.3%0.2 0.0 0123 YearsITT population456 12. NO16968 (XELOXA) and MOSAIC: DFS in stage III disease FOLFOX4 DFS(%)(%)3-yr 1NO16968LV5FU272.265.3XELOX 70.93-yr35-yr66.42XELOXNO16968 5-yr366.1 1.ITT population5-FU/LV 66.558.9HR (95% CI) 0.76(0.620.92)0.80 (0.690.93) p=0.0045 0.78(0.650.93) p=0.0055-FU/LV 59.8Andr et al. NEJM 2004; 2. Andr et al. 2009; 3. Haller et al. ESMO 2009 13. NO16968 (XELOXA) and MOSAIC: DFS in stage III disease Estimated probability 1.0NO16968 (XELOXA)1* XELOX MOSAIC2,3**FOLFOX43-yr DFS5-yr DFS(n=944)70.9%66.1%(n=672)72.2%66.4%0.80.60.4 01*Median observation time: 57.0 months **Median follow-up: 71.3 months Cross-trial comparison ITT population23 Years4561. Haller et al. ESMO 2009 2. Andr et al. NEJM 2004 3. Andr et al. JCO 2009 14. 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 15. Should patients with stage II colon cancer receive adjuvant therapy?Meta-analyses Direct evidence from randomized trials Identification of high risk patients 16. To B or Not To B? 17. QUASAR: Study designColon or rectal cancer Stage I-III Complete resection with no evidence of residual disease2x2 randomization to 5-FU with low- or high-dose LV and Lev or placeboClear 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 EObservation (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. 18. The QUASAR Trial100Observation (n=1622) Chemotherapy (n=1617)% of Patients80 60 40P = .02 5-year OS, Obs = 77.4% vs CT = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97)20 0012345Years QUASAR group Lancet 2007678910 19. DFS: High-Risk Stage II Patients only 1.0 0.9 0.8 FOLFOX-4 n = 286Probability0.7LV5FU25.0n = 2900.6 0.53-year5-year0.4FOLFOX-485.4%82.1%0.3LV5FU280.4%74.9%HR [95% CI]: 0.74 [0.52-1.06]0.27.20.1High-risk stage II defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, 3 mg/dl38%00,02Biliary stent11,4%00,05Kemeny et al, J Clin Oncol 2011 80. Adjuvant Systemic Treatment after Liver ResectionPower and Kemeny, JCO 2010 81. Mitry E, JCO 2008 82. Mitry et al, J Clin Oncol 2008 83. 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 84. Adjuvant CT after resection of metastases Studyn.TreatmentResultLorenz et al 98226HAI 5FU/FA 6 months vs Surgery aloneKemeny N et al 99 and 05156Sys 5FU+ HAI Flox + Dex vs Systemic 5FUImproved DFSKemeny M et al 0275Sys 5-FU + HAI Flox vs Surgery aloneImproved RFSLanger et al 02107Systemic 5-FU/FA 6 courses vs Surgery aloneTrend for improved DFS and OSPortier et al 06173Systemic 5-FU/FA 6 courses vs Surgery aloneImproved DFSMitry et al 08278Systemic 5-FU/FA 6 months vs Surgery aloneTrend for improved DFS and OSYchou et al 09306Systemic 5-FU/FA 6 months vs FOLFIRI 6 monthsNo difference in DFS or OSNo improved DFS or OS. 85. Post-operative, not pre-operative, CT impacts survival in single metachronous liver mts Retrospective analysis of 1.471 pts from MetSurg International RegistrySurgery vs pre-operative CT 5 yrs OS: 60% vs 60%, p =.57Adam et al, Ann Surg 2010Surgery vs post-operative CT 5 yrs OS: 36% vs 58%, p =.04 86. 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. 87. 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 88. Strategies in resectable liver metastases 89. Conversion to Resection of CRC Metastasis: an Optimal Treatment Goal COLORECTAL CANCER ~50% will develop metastases (synchronous or metachronous) 30-35% liver only metastases10-25% candidate for surgeryConvert?AIM: R0 RESECTION Cure rate: 20-30% 5 yrs survival: 40-60%75-90% non candidates for surgery PALLIATIVE THERAPY70-80% relapse within 2 yearsLeonard 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 90. 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 91. Survival after Liver Resection of CRC Mts Paul Brousse Hospital (Apr. 88 - Jul. 99) 91%100Survival (%)80Resectable : 335 Initially non resectable : 13866%P= 0.016048% 30%52%4033%2023%No Surgery 012345 6 Years78910Adam R et al. Ann Surg 2004 92. Adam R, J Clin Oncol 27. 2009 93. Conversion therapy: prospective phase II studies in non-resectable liver mts* ScheduleAuthorSelected PatientsN. of PatientsRR (%)Resezioni R0 (%)FOLFOX4AlbertsYes425230FFL4-10 cronoGiacchettiYes1515932FOLFOX4 + CetuximabGOIM2402No536021FOLFOX4 + CetuximabAndrNo437223FOLFIRIBaroneYes404833FolprechtNo196821FOLFOXIRIMasiNo747126FOLFOXIRIde la CamaraYes2126443FOLFOXIRIQuenetYes267335POCHERGarufiYes268360AIO+CPT-11 + Cetuximab* No extrahepatic metastases 94. Phase III studies in non-selected pts with PCT TreatmentN.RR (%)Mts resection (%)AuthorIFL FOLFOX IROX264 267 26531 45 351 4 4Goldberg, 20045FU/AF (AIO) 5FU/AF (AIO) + IRI216 21434 641 3Khne, 2005FOLFIRI FOLFOX109 11156 549 15Tournigand, 2004FOLFIRI FOLFOX178 18234 365,1 4,4Colucci, 2005XELOX FUOX171 17137 4610 12,9Diaz-Rubio, 2007FOLFIRI FOLFOXIRI147 13834 434 10Souglakos, 2006FOLFIRI FOLFOXIRI122 12241 666 (12 liver only) 15 (36 liver only)Falcone, 2007 95. Conversion therapy StudiesNRRResection (R0)20405070%2943%20404070%~20%200500 3060%824%Phase II Selected Phase II Non-selected Phase III Non-selectedFolprecht et al Ann Oncol 2005 96. Conversion Therapy: Resectability Correlates With Response Rate Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96; p=0.002)0.6Resection rate0.5 0.4Studies including nonselected patients with mCRC (solid line) (r=0.74; p