mario scartozzi clinica di oncologia medica ancona highlights in colorectal cancer management...

Mario ScartozziClinica di Oncologia Medica

Ancona

HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT

TREATMENT OF METASTATIC DISEASE

Bittoni, Giampieri et al, CROH 2012

– 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

Colon Cancer: what we already know

Not all liver metastases are created equal

Bittoni, Giampieri et al, CROH 2012

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

BIOLOGICALLY

CHALLANGING

Colon Cancer: NOT all liver metastases are created equal

PFS/OS

– 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: MULTIMODALITY management

• 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)

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.

2012

Nordlinger et al

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Biologicals: How Do They Fit Into This Strategy?

Colon Cancer: PFS in BEVACIZUMAB trials

Wagner et al. Cochrane Review ‘09

Loupakis, Bria E et al. Cancer 2011

Colon Cancer: PFS in anti-EGFR trials

BEVACIZUMAB: PFS on TREATMENT!

Saltz, et al. ASCO GI 2007

TECHNICALLY

CHALLANGING

Colon Cancer: NOT all liver metastases are created equal

RR/R0/OS

– 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: MULTIMODALITY management

•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?

– 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….

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

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

Cetuximab: CELIM & RR & R0 resection (LLD)

Folprecht et al. Lancet Oncology 2010

Cetuximab: CELIM & RR & R0 resection (LLD)

Folprecht et al. Lancet Oncology 2010

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

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

Cetuximab: CELIM & RR & R0 resection (LLD)

Folprecht et al. Lancet Oncology 2010

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

Loupakis F, Bria E et al. Cancer 2011

Response Rate in anti-EGFR trials

Response Rate in BEVACIZUMAB trials

Wagner et al. Cochrane Review ‘09

A - Pretreatment B - Posttreatment

C - Pretreatment D - Posttreatment

CT Morphology vs RECIST

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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Log-rank p=0.009 Log-rank p=0.45

Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.

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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

Colon Cancer: NEVER (NEVER!) resectable

Bad, Bad luck…..PFS/OS/QoL

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

Wagner et al. Cochrane Review ‘09

Overall Survival in BEVACIZUMAB trials

Overall Survival in anti-EGFRs trials

Loupakis, Bria E et al. Cancer 2011

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

Amado JCO 2008

Amado JCO 2008

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PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients

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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)

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Slide Courtesyof A Grothey

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Arnold D, et Al

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Baseline After 2 cycles

CT Response on REGORAFENIB

Bittoni, Giampieri et al, CROH 2012

Bittoni, Giampieri et al, CROH 2012