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Mario ScartozziClinica di Oncologia Medica
Ancona
HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT
TREATMENT OF METASTATIC DISEASE
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Bittoni, Giampieri et al, CROH 2012
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– 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
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– 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
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Not all liver metastases are created equal
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Bittoni, Giampieri et al, CROH 2012
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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
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BIOLOGICALLY
CHALLANGING
Colon Cancer: NOT all liver metastases are created equal
PFS/OS
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– 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
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– 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
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• 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
R
Nordlinger B, et al. Lancet 2008
FOLFOX4 for 6 cycles (12 wks)(n = 182)
Surgery FOLFOX4 for 6 cycles (12 wks)
Surgery(n = 182)
Colon Cancer: EORTC 40983 (the EPOC trial)
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Efficacy Results
No. ptsCT
No. pts Surgery
% absolute differencein 3-year PFS
Hazard ratio (confidence interval) p Value
All patients 182 182+7.2%
(28.1% to 35.4%)0.79
(0.62-1.02)0.058
All eligiblepatients
171 171+8.1%
(28.1% to 36.2%)0.77
(0.60-1.00)0.041
All resectedpatients
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%
Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.
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2012
Nordlinger et al
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Biol
ogic
als
Su
rgery
Ch
em
oth
era
py
Biologicals: How Do They Fit Into This Strategy?
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Colon Cancer: PFS in BEVACIZUMAB trials
Wagner et al. Cochrane Review ‘09
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Loupakis, Bria E et al. Cancer 2011
Colon Cancer: PFS in anti-EGFR trials
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BEVACIZUMAB: PFS on TREATMENT!
Saltz, et al. ASCO GI 2007
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TECHNICALLY
CHALLANGING
Colon Cancer: NOT all liver metastases are created equal
RR/R0/OS
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– 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
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– 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
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•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
What Do We Expect from Ideal Conversion Chemo?
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– 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
Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86.
Conversion Therapy: Liver Toxicities
REMEMBER: AS SOON AS….
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Folprecht et al. Ann Oncol ‘05
Rate of liver resectionfollowing CT
Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002)
▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line
△ Data from studies/retrospective analyses with “non selected pts”(r=0.74) (p<0.001), solid line
Selected pts(liver mets)
Not selected pts
Colon Cancer: Rate of Liver Resections/RR
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FOLFIRI122 pts
FOLFOXIRI122 pts
P value
Confirmed RR 34% 60% <0.0001
R0 surgery (all pts) 6% 15% 0.033
R0 surgery (liver only) 12% 36% 0.017
mPFS (months) 6.8 9.8 <0.001
mOS (months) 16.7 23.4 0.026
Falcone A, JCO ‘07 & Masi JNCI’10
FOLFIRI vs FOLFOXIRI: RESULTS
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Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
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Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
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Folprecht et al. Ann Oncol ‘05
Rate of liver resectionfollowing CT
Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002)
▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line
△ Data from studies/retrospective analyses with “non selected pts”(r=0.74) (p<0.001), solid line
K-RAS wt
Not selected pts
Colon Cancer: Rate of Liver Resections/RR
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Folprecht et al. Ann Oncol ‘05
Rate of liver resectionfollowing CT
Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002)
▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line
△ Data from studies/retrospective analyses with “non selected pts”(r=0.74) (p<0.001), solid line
Selected pts(liver mets)
Not selected pts
Colon Cancer: Rate of Liver Resections/RR
K-RAS wt
K-RAS mt
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Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
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Folprecht et al. Ann Oncol ‘05
Rate of liver resectionfollowing CT
Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002)
▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line
△ Data from studies/retrospective analyses with “non selected pts”(r=0.74) (p<0.001), solid line
Selected pts(liver mets)
Not selected pts
Colon Cancer: Rate of Liver Resections/RR
K-RAS wt
K-RAS mt
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Loupakis F, Bria E et al. Cancer 2011
Response Rate in anti-EGFR trials
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Response Rate in BEVACIZUMAB trials
Wagner et al. Cochrane Review ‘09
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A - Pretreatment B - Posttreatment
C - Pretreatment D - Posttreatment
CT Morphology vs RECIST
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CT Morphology vs RECIST to Determine Response on BEV
Computer Tomographic Tumor Characteristics
Morphology group Overall Attenuation Tumor-Liver Interface Pheripheral Rim of Enhancement
3 Heterogeneous III defined May be present
2 Mixed Variable If initially present, partially resolved
1Homogeneous and
hypoattenuatingSharp If initially present, completely resolved
Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
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
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0.0
Pro
por
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0.6 0.6
Morphologicresponse criteria RECIST
Log-rank p=0.009 Log-rank p=0.45
Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
0.8 0.8
50403020100 6050403020100
Patients with unresectable tumor
Months Months
No. at risk
Responders 30 30 26 16 6 2
Ronresponder 52 49 25 14 4 1
35 34 25 14 3 0
47 45 26 16 7 3
Response Evaluation: Morphology vs. RECIST
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Colon Cancer: NEVER (NEVER!) resectable
Bad, Bad luck…..PFS/OS/QoL
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Phase III randomized trials: gains in activity and efficacy in 1st line therapy
N° of patients RR PFS OS
Bevacizumab
Hurwitz 402 45 vs 35 10.6 vs 6.2 20.3 vs 15.6
No16966 700 38 vs 38 9.4 vs 8 nr
Cetuximab
Crystal 599 58 vs 40 9.9 vs 8.7 23.5 vs 20
COIN 2445 64 vs 57 8.6 vs 8.6 17 vs 17.9
Nordic 566 47 vs 46 7.9 vs 8.7 19.7 vs 20.3
Panitumumab
Prime 656 55 vs 48 9.6 vs 8 Ne vs 18.8
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Wagner et al. Cochrane Review ‘09
Overall Survival in BEVACIZUMAB trials
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Overall Survival in anti-EGFRs trials
Loupakis, Bria E et al. Cancer 2011
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N° of patients RR PFS OS
Bevacizumab
Giantonio 829 22.7 vs 8.6 7.3 vs 4.7 12.9 vs 10.8
Cetuximab
EPIC 1298 16.4 vs 4.2 4 vs 2.6 10.7 vs 10
Panitumumab
Peeters 597 35 vs 15 5.9 vs 3.9 14.5 vs 12.5
Phase III randomized trials: gains in activity and efficacy in 2nd line therapy
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Amado JCO 2008
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Amado JCO 2008
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CR
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PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients
Haz
ard
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io
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
First lineFirst line Second lineSecond line Salvage (single agent)Salvage (single agent)
AdjuvantAdjuvant
1.2
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2012
Arnold D, et Al
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2012
Arnold D, et Al
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2012
Arnold D, et Al
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2012
Arnold D, et Al
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AFLIBERCEPT
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2012
Allegra C, et Al
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2012
Allegra C, et Al
the VELOUR tr
ial
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2012
Allegra C, et Al
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GI 2009
Kopetz S et AL
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2012
Van Cutsem E, et al
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2012
Van Cutsem E, et al
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2012
Van Cutsem E, et al
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2012
Van Cutsem E, et al
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2012
Van Cutsem E, et al
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Baseline After 2 cycles
CT Response on REGORAFENIB
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Bittoni, Giampieri et al, CROH 2012
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Bittoni, Giampieri et al, CROH 2012