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Mario Scartozzi Clinica di Oncologia Medica Ancona. HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE. Bittoni, Giampieri et al, CROH 2012. Colon Cancer: what we already know.
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Mario Scartozzi Clinica di Oncologia Medica Ancona HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE
Colon Cancer: what we already know • Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months • Probably FOLFOX = FOLFIRI and XELOX=FOLFOX(XELIRI has PHYLOSOPHICAL problems with toxicity) • Concept of all three drugs • Some patients with stage IV disease can be cured by an interdisciplinary approach
Colon Cancer: what we already know • Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months • Probably FOLFOX = FOLFIRI and XELOX=FOLFOX(XELIRI has PHYLOSOPHICAL problems with toxicity) • Concept of all three drugs • Some patients with stage IV disease can be cured by an interdisciplinary approach
Multimodality Management of CRC Liver Metastases • Neoadjuvant 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
Colon Cancer: NOT all liver metastases are created equal BIOLOGICALLY CHALLANGING PFS/OS
Colon Cancer: MULTIMODALITY management • Neoadjuvant 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
Colon Cancer: MULTIMODALITY management • Neoadjuvant 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
Colon Cancer: EORTC 40983 (the EPOC trial) • 364 patients randomized • Potentially resectable (≤ 4 liver metastases) • Goal: Improve PFS • Interim objective: Evaluate tumor response to perioperative CT • Perioperative CT (n = 182) • 159 (87.3%) underwent surgery • 151 (83.0%) resected • Surgery (n=182) • 170 (93.4%) underwent surgery • 152 (83.0%) resected FOLFOX4 for 6 cycles (12 wks) (n = 182) Surgery FOLFOX4 for 6 cycles (12 wks) R Surgery (n = 182) Nordlinger B, et al. Lancet 2008
Efficacy Results MOSAIC: 3-yr DFS for stage III: +7.2% Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.
2012 Nordlinger et al
Biologicals: How Do They Fit Into This Strategy? Biologicals Chemotherapy Surgery
Colon Cancer: PFS in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09
Colon Cancer: PFS in anti-EGFR trials Loupakis, Bria E et al. Cancer 2011
BEVACIZUMAB: PFS on TREATMENT! Saltz, et al. ASCO GI 2007
Colon Cancer: NOT all liver metastases are created equal TECHNICALLY CHALLANGING RR/R0/OS
Colon Cancer: MULTIMODALITY management • Neoadjuvant 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
Colon Cancer: MULTIMODALITY management • Neoadjuvant 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
What Do We Expect from Ideal Conversion Chemo? • High (anatomical) response rate • RR = goal 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
Conversion Therapy: Liver Toxicities • 5-FU: hepatic steatosis, associated with increased postoperative morbidity - yellow liver • Irinotecan: non-alcoholic steatohepatitis (especially in obese patients), can affect hepatic reserve and increase morbidity and mortality after hepatectomy - orange liver • Oxaliplatin: hepatic sinusoidal obstruction syndrome, does not appear to be associated with increased risk of perioperative death - blue liver • Both response rate and toxicity should be considered when selecting preoperative CT in patients with colorectal liver metastases REMEMBER: AS SOON AS…. Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86.
Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05
FOLFIRI vs FOLFOXIRI: RESULTS Falcone A, JCO ‘07 & Masi JNCI’10
Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010
Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010
Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05
Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line K-RAS mt ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05
Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010
Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line K-RAS mt ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05
Response Rate in anti-EGFR trials Loupakis F, Bria E et al. Cancer 2011
Response Rate in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09
CT Morphology vs RECIST A - Pretreatment B - Posttreatment D - Posttreatment C - Pretreatment
CT Morphology vs RECIST to Determine Response on BEV • 234 pts with CRC liver mets treated with chemo + BEV • 50 pts underwent hepatic resection • Three blinded radiologists evaluated response of liver mets according to • Standard RECIST criteria • Novel CT morphology criteria Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
Response Evaluation: Morphology vs. RECIST Patients with unresectable tumor Morphologicresponse criteria RECIST 1.0 1.0 0.8 0.8 0.6 0.6 Proportion surviving Proportion surviving 0.4 0.4 0.2 0.2 Log-rank p=0.009 Log-rank p=0.45 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Months Months Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
Colon Cancer: NEVER (NEVER!) resectable Bad, Bad luck….. PFS/OS/QoL
Phase III randomized trials: gains in activity and efficacy in 1st line therapy
Overall Survival in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09
Overall Survival in anti-EGFRs trials Loupakis, Bria E et al. Cancer 2011
Phase III randomized trials: gains in activity and efficacy in 2nd line therapy
PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients 1.2 1.0 0.8 0.6 Hazard ratio 0.4 NORDIC VII2 0.2 Study 1817 CRYSTAL5 Amado8 PRIME4 N01471 CO.179 COIN3 EPIC6 0 Adjuvant First line Second line Salvage (single agent) 1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. ASCO 2011; 5. Van Cutsem, et al. JCO 2011; 6. Langer, et al. ESMO 2008 7. Sobrero, et al. ASCO GI 2012; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008 Slide Courtesyof A Grothey
2012 Arnold D, et Al
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