Resectability and agreement between surgeons:

Review of CT- and MRI- scans of the CELIM study (Multicenter randomized trial of cetuximab/FOLFOX versus

cetuximab/FOLFIRI in unresectable liver metastases).

Wolf Bechstein,1 Hauke Lang,2 Claus-Henning Köhne,3 Fabio Parisi,4 Hans-Rudolf Raab,3 Andrea Frilling,5 Ralf Konopke,6 Jürgen Weitz,7

Christian Stroszczynski,6 Gunnar Folprecht6

1University Hospital Frankfurt, Germany, 2University Hospital Mainz, Germany, 3 Klinikum Oldenburg, Oldenburg, Germany, 4New York University, N.Y., U.S., 5University Hospital Essen, Germany,

6University Hospital Carl Gustav Carus, Dresden, Germany, 7University of Heidelberg, Dpt. of Surgery, Heidelberg, Germany

Abstract 4091

Background

• Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004)

• Resectability of colorectal liver metastases depends on technical resectability and prognostic factors

• Number of liver metastases is an important prognostic factor and pts with > 4 liver met’s were excluded from neoadjuvant trial for resectable liver metastases (Nordlinger, Lancet 2007)

• In primary non-resectable liver metastases, resection rate correlates with response to chemotherapy

• Few data are available on achievement of resectability due to chemotherapy and on the agreement between surgeons regarding resectabilty

• Cetuximab increases response rates when added to FOLFIRI or FOLFOX (Van Cutsem NEJM 2009, Bokemeyer JCO 2009)

• The CELIM study compared tumor response and resectability rates in patients with unresected liver metastases receiving neoadjuvant treatment with cetuximab plus FOLFIRI or FOLFOX6

Patient selection

Patients with non-resectable colorectal liver metastases

Definition of non-resectability:– ≥ 5 liver metastases and/or– liver metastases that are technically non-resectable

defined by local surgeon in cooperation with local radiologist (amount of functional liver tissue remaining, infiltration of non-resectable structures)

Expected resectability after response to chemotherapy was not an inclusion criterion

No extrahepatic disease

Karnofsky PS ≥ 80% and adequate hepatic, renal, and bone marrow function

Metastases histologically confirmed

Patients with simultaneous liver metastases were eligible if the primary tumor was resected ≥ 1 month prior to chemotherapy

Informed consent; no prior chemotherapy (except adjuvant chemotherapy ≥ 6 months ago); no concurrent immunotherapy, chemotherapy or hormone therapy; no previous malignancy other than colorectal cancer, basal cell carcinoma, or pre-invasive carcinoma of the cervix; no inflammatory bowel disease; no relevant coronary heart disease

Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)

without extrahepatic metastases

FOLFOX6 + cetuximab FOLFIRI + cetuximab

Randomization

Biopsy: EGFR screening

FOLFOX6

EGFR IHC 0

closed early

Stratification:technically non-resectable / ≥ 5 liver metastasesstaging with PETEGFR IHC

FOLFOX6: oxaliplatin 100 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²FOLFIRI: irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²Cetuximab: 400 mg/m², then 250 mg/m² weekly

5-FU, 5-fluorouracil; FA, folinic acid; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry;

PET, positron emission tomography.

Patients with non-resectable colorectal liver metastases(technically non-resectable / ≥ 5 liver metastases)

without extrahepatic metastases

Biopsy: EGFR screening

Randomization

FOLFOX6 + cetuximab FOLFIRI + cetuximab

Primary endpoint: Response

Therapy: 8 cycles (~ 4 months)

Evaluation of resectability

Technically non-resectable

4 additional therapy cycles

Technically resectable

Resection

Therapy continuation for 6 cycles (~ 3 months)

EGFR, epidermal growth factor receptor.

Patient characteristics

    FOLFOX6 + FOLFIRI + All

    cetuximab cetuximab patients

n=56 n=55 n=111 

       

Median age (y.) 65.1 62.0 63.3

Sex      

male 64% 64% 64%

KRAS status (n=99)      

wild-type   70% 71% 71%

Primary tumor site      

rectal cancer 38% 51% 44%

Adjuvant chemotherapy      

yes 11% 22% 16%

Patient characteristics

  FOLFOX6 + FOLFIRI + All

  cetuximab cetuximab patients

n=56 n=55  n=111

Number liver metastases      

<5   23% 31% 27%

5-10   55% 49% 52%

>10   20% 15% 17%

NA   2% 5% 4%

Prior liver resection      

yes 16% 9% 13%

NA, not available

Efficacy: confirmed response

  FOLFOX6 + FOLFIRI + All

  cetuximab cetuximab patients

n=53 n=53 n=106

CR/PR 68% 57% 62%

95% CI 54-80% 42-70% 52-72%

SD 28% 30% 29%

PD 4% 13% 8%

Responses confirmed by 2nd CT scan according to RECIST or by resection

Chi square test for comparison between FOLFOX6+cetuximab vs FOLFIRI+cetuximab: p would be 0.23

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, CT, computed tomography

Confirmed response by subgroups

  KRAS KRAS EGFR EGFR

  wild-type mutant IHC + IHC -

n=67 n=27 n=77 n=29

CR/PR 70% 41% 60% 69%

95% CI 58-81% 22-61% 48-71% 49-85%

Responses confirmed by 2nd CT scan according to RECIST or by resection

Chi square test for comparison between KRAS wild-type vs KRAS mutant: p < 0.01

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CT, computed tomography;

EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; CI, confidence interval

Liver resections

  FOLFOX6 + FOLFIRI + All

  cetuximab cetuximab patients

n=53 n=53 n=106

R0 resections 38% 30% 34%

R1-resection or resection with RFA 2% 8% 5%

RFA 9% 6% 8%

Total: R0 / R1 resection / RFA 49% 43% 46%

RFA, radio frequency ablation

Resections in pts with KRAS wild-type tumors: 22/67 pts (33%)

Perioperative morbidity / mortality 

Chemotherapy+ cetuximab 

n=45 (%)

All morbidity 16 (36%)

Median stay in hospital 13 days

Median stay on intensive care unit 2.0 days

Mechanical ventilation > 1 day 4 (9%)

Operative revisions 3 (7%)

Bleeding 2 (4%)

Hepatic failure 1 (2%)

Pleural effusion 6 (13%)

Wound infection 4 (9%)

Biliary leakage 2 (4%)

Renal failure 1 (2%)

Urinary tract infection 2 (4%)

Two post-operative deaths (4%):

Gram-negative sepsis – 8 days postop (right hemihepatectomy, FOLFOX + cetuximab arm)

Multiorgan failure – 75 days postop (two-staged liver resection, FOLFOX + cetuximab arm)

Blinded surgical review

A blinded surgical review performed for CT/MRI at baseline and at 4 months:

CT / MRI scans were presented by a radiologist to 5-6 liver expert surgeons of participating centers in two workshops.

CT, computed tomography; MRI, magnetic resonance imaging

S

SS

S

S

CT/MRI scans

R

Surgical review

- CT / MRI scans were evaluated by the surgeons without knowing when the scan was taken (before or after chemotherapy) and without clinical data

- Surgeons allocated scans to:resection / exploration / chemotherapy preferred / non-resectable

- Surgeons were blinded to the votes of the other participants.

- 181 scans reviewed / 171 scans evaluable

- Paired scans (baseline and follow-up) available for 68/106 ptsActual resection rate in this subgroup 34%, response rate 60%

- Following imaging review:22/68 scans (32%) judged resectable at baseline41/68 scans (60%) judged resectable at follow-up (p<0.01)

Waterfall plot of resectability at baseline

100%

50%

0%

50%

100%| | | | | | | - | - | | | | | - - | - - | | | - | | | | | | - - -

Patient

rese

ctab

le

no

n -

res

ecta

ble

Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red.

Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”

Waterfall plot of resectability after chemotherapy

100%

50%

0%

50%

100%| | | - | | | | - | | - | | | - | | - | | - - | | - | | | - - | | -

Patient

rese

ctab

le

no

n -

res

ecta

ble

Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red.

Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”

Resectability according to imaging

increased by 28% (32% → 60%)

p<0.01

Patterns of voting of the individual surgeons

Votes for “resectable”/”exploration” are in green, “chemotherapy preferred” in yellow and for “unresectable” in red.

Blinded review of patient MRI and CT scans at baseline and follow-up revealed large variation between reviewers in the decision making process.

1 2 3 4 5 6 7

1   73%(135)

60%(136)

60%(132)

61%(62)

71%(65)

78%(64)

2 4%(135)

  64%(166)

60%(161)

70%(69)

64%(89)

67%(86)

3 3%(136)

2%(166)

  55%(164)

56%(68)

76%(92)

62%(89)

4 15%(132)

17%(161)

5%(164)

  76%(67)

62%(91)

63%(88)

5 8%(62)

14%(69)

3%(68)

18%(67)

     

6 5%(65)

2%(89)

4%(92)

4%(91)

    65%(89)

7 2%(64)

2%(86)

2%(89)

15%(88)

  4%(89)

 

Agreement and critical disagreement

“Agreement” (grey/green) show the percentage of agreement between two individual surgeons with the categories “resection/exploration”, “chemotherapy preferred” and “unresectable”. Total rate in all decisions is 64.5%

“Critical disagreement” means the proportion of contrary votes (one surgeon for “resection/exploration”, the other for “unresectable”) The total rate in all pairs is 6.8%

The numbers in brackets mean the evaluable images per surgical pair.

“Critical” disagreement

Ag

reem

ent

Reviewer

• High response rates induced by cetuximab plus either FOLFOX or FOLFIRI:– 70% confirmed response in KRAS wild-type patients

• Resections among patients with initially non-resectable liver metastases: – 34% R0 liver resection– 46% R0 or R1 liver resection and/or RFA

• Perioperative morbidity/mortality comparable to experience from literature

• Resectability according to imaging review improved significantly following treatment with cetuximab plus FOLFOX or FOLFIRI

• Cetuximab plus FOLFOX or FOLFIRI are good options for conversional chemotherapy for KRAS wild-type patients(Europe, not approved in U.S.)

• Although, as demonstrated here, there is heterogeneity between different surgeons in treatment decisions, this rarely results in the need for a surgical second opinion within experienced centers

Conclusions

We thank...

• All patients and their relatives

• All investigators at the study sites University Hospital Dresden Klinikum Oldenburg University Hospital Vienna University Hospital Tübingen University Hospital Göttingen University Hospital Munich Rechts der IsarKlinikum Passau Krankenhaus der Barmherzigen Brüder TrierUniversity Hospital / NCT Heidelberg University Hospital Würzburg University Hospital Frankfurt Klinikum CelleUniversity Hospital Essen Klinikum Magdeburg University Hospital Mannheim Klinikum AscherslebenKlinikum Essen-Mitte

• The companies which supported this studyMerck-Serono, Sanofi-Aventis, and Pfizer