1. Preoperative/neoadjuvant treatment of CRC liver metastases
Markus Moehler

2. >350 Certified Colon Cancer Centers
.. but how good are they in reality ?

3. The collaboration makes the difference Surgery of liver metastases
can achieve long-term DFS
Even in Germany, >4000 patients are undertreated with CRC liver metastases
100 80 60
neoadjuvant
Chemo + OP 40
Chemo 20
30% !
BSC
Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

4. The collaboration makes the difference Surgery of liver metastases
can achieve long-term DFS
100 80 60
neoadjuvant
Chemo + OP 40
Chemo 20
30% !
BSC
Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

5. The collaboration makes the difference
Our
metastatic
CRC patients
survive
>4 years
100 80 60
neoadjuvant
Chemo + OP 40
Chemo 20
30% !
BSC
Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

6. Mainz University Cancer Center
Center of excellence for CRC liver metastases
First center of excellence and competence
General, Visceral & Transplant Surgery (AVTC

7. Mainz University Cancer Center

8. Mainz University Cancer Center
Outreach / Regional Network
To ensure the highest quality of cancer care for each patient at every place and any time

9. Mainz University Cancer Center
Outreach / Regional Network
Oncology Center (n=2)
Hospital (n=12)
Organ-specific Cancer Center (n=3)
Practicing Oncologist (n=22)

10. Mainz University Cancer Center
Outreach / Regional Network
UCT Network Communication
Virtual „central entry portal“
Password-protected area
Information of trials, SOPs ...
Contact information at a glance
UCT hotline
Tumor Board participations
In person or via telecommunication
„Flying UCT oncologist“
Outreach / Regional Network

11. Therapeutic Options in Metastatic Disease
Colorectal cancer
Resection ?
Resection ?
Resection ?
Therapeutic Options in Metastatic Disease

12. Prognostic factors in CRC liver metastases neoadjuvant chemotherapy
Resection after
neoadjuvant chemotherapy
Technical Resectability
Functionality of
Remnant Liver tissue
Involved Struktures/Segments

13. Prognostic factors in CRC liver metastases
Technical Chemotherapy
Technical Resectability
Functionality of
Remnant Liver tissue
Involved Struktures/Segments

14. Prognostic factors in liver metastases
Technical Chemotherapy
Number /size
Lymphnode status
Disease-free Interval
CEA levels
Technical Resectability
Functionality of
Remnant Liver tissue
Involved Struktures/Segments

15. Prognostic factors in CRC liver metastases
Technical Chemotherapy
Conversion- chemotherapy („neoadjuvant“)
Technical Resectability
Techniques
presented by Dr. Tagkalos
Morbidität
Komplikationsrisiko
Keine Resektionen

16. Response and Resection rates
Prognostic factors in CRC liver metastases
Studies with
neoadjuvant
focus
met. CRC
Response and Resection rates
Jones, Folprecht Eur J Cancer 2014

17. Chemo+EGFR vs. Chemo +VEGF RAS wt
RAS mutated
RAS Wildtype
Chemotherapy
with
biologicals
is better
Anti-VEGF
Anti-EGFR

18. Chemo+EGFR vs. Chemo +VEGF RAS wt
n RR PFS OS
FOLFIRI/Cetux %
FOLFIRI/Beva %
Heinemann, Lancet Oncol HR 0.93 HR 0.70 p=0.017

19. Chemo+EGFR vs. Chemo +VEGF RAS wt
n RR PFS OS
FOLFIRI/Cetux %
FOLFIRI/Beva %
Heinemann, Lancet Oncol HR 0.93 HR 0.70 p=0.017
FOLFOX/Pani 88 64%
FOLFOX/Beva 82 61%
Schwartzberg, JCO HR 0.65 HR 0.63 p=0.058

20. Chemo+EGFR vs. Chemo +VEGF RAS wt
n RR PFS OS
FOLFIRI/Cetux %
FOLFIRI/Beva %
Heinemann, Lancet Oncol HR 0.93 HR 0.70 p=0.017
FOLFOX/Pani 88 64%
FOLFOX/Beva 82 61%
Schwartzberg, JCO HR 0.65 HR 0.63 p=0.058
Chemo/Cetux %
Chemo/Beva %
Lenz, ESMO p< HR 1.1 HR 0.9

21. Chemo+EGFR vs. Chemo +VEGF RAS wt
n RR PFS OS
FOLFIRI/Cetux %
FOLFIRI/Beva %
Heinemann, Lancet Oncol p=0.18 HR 1.06 HR 0.77 p=0.017
FOLFOX/Pani %
FOLFOX/Beva %
Schwartzberg, JCO HR 0.84 HR 0.62 p=0.009
Chemo/Cetux % resected: 82 pts (14.2%)
Chemo/Beva % resected: 50 pts (8.9%)
Venook, ASCO/WCGIC/ESMO p< p<0.01

22. FOLFOXIRI combinations
n RR PFS OS
FOLFOXIRI/Bev %
FOLFIRI/Bev %
Loupakis, NEJM p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054
Progression free survival Overall survival

23. Background: Resectability is often missed
Retrospective reviews suggest that careful patient selection is still a major challenge
 CELIM (Chemo+Cetux) and Prodige-14 (Chemo + Cetux/Beva) report potential/real secondary resections of 50% and higher in LLD
The reported metastatic resection rate in FIRE-3 was 13% in ITT.
The new ESMO consensus guideline does not limit surgery and/or ablations to single-organ metastatic disease.
Therefore investigation of a mixed cohort appears important.
Ychou M. et al. Prodige1$/ACCORD 21 (METHEP-2), J Clin Oncol 34, 2016 (suppl; abstr 3512).
Folprecht G et al. Lancet Oncol 2010

24. After combination- therapy
Background (CELIM)
- Improving resectability in mCRC-
Untreated mCRC
32%
+28%
After combination- therapy
60%
Folprecht G, et al. Lancet Oncol 2010

25. Probability of survival months since start of treatment
Background
FIRE-3 (all comers!)
Events n/N (%)
Median
(months)
95% CI
― FOLFIRI + Cetuximab
107/199
(53.8%)
33.1
24.5 – 39.4
― FOLFIRI + Bevacizumab
133/201
(66.2%)
25.0
23.0 – 28.1
HR (95% CI: 0.54 – 0.90)
p (log-rank)=
1.0
0.75
Probability of survival
0.50
0.25
Δ = 8.1 months
0.0 12 24 36 48 60 72
months since start of treatment
* KRAS and NRAS exon 2, 3 and 4 wild-type
Stintzing S, …Moehler M, et al. Lancet Oncol. 2016 25 25

26. Review-Process
448 patients, central, blinded for treatment and other reviewers
Baseline vs best response images were evaluated in pairs
Information given to reviewers during assessment:
metachronous (incl. disease-free interval) vs. synchronous
disease spread (as noted in CRF)
primary in place
8 surgeons, 3 medical oncologists
Definition of resectability: ≥50% votes for resectability

27. FIRE-3, Assessment of resectability
Time
Tumor Nadir
Baseline
Lethal tumor load
DpR
Definition of resectability: ≥50% votes for resectability
8 surgeons, 3 medical oncologists
448 patients, central, blinded for treatment and other reviewers

28. FIRE-3, Resectability at baseline
100%
Intention
Not resectable
Conversion possible
(maybe only abd. lesions)
Abdominal lesions resectable
(+- periop. Chemo)
R0-resection
(with periop. Chemo)
50%
50%
100%
21.7%
Median kappa‘ coefficient for inter-rater reliability: 0.56

29. FIRE-3, Resectability at best response
100%
Intention
Not resectable
Abdominal lesions resectable
(+- locoreg. therapy)
R0-resection inlc. Locoregional therapy all lesions
R0-resection all lesions
50%
50%
100%
53.1%
Median kappa‘ coefficient for inter-rater reliability: 0.66

30. Resectability according to organ-involvement Evaluation at „baseline“
„best response“
Metastatic spread
[CRF]
One-organ disease
N=186
N=186
Two-organ disease
N=155
N=155
Three-organ disease
N=80
N=80
Percentage with unresectable disease
Percentage with resectable disease

31. Review (best response)
vs. study-reports

32. Impact of treatment-site
Percentage
Difference in resection rate university vs. others: P=0.02 (Fisher‘s exact test)

33. FIRE-3: Survival with/without resection:
Group
OS (95% CI), months
Resectable +resected
51.3 ( )
Resectable + not resected
30.8 ( )
Not resectable
18.6 ( )

34. The center makes the difference:
Mainz UCT
Survival CTX + anti-EGFR vs CTX + anti-VEGF: 47 vs 20 months
Möhler, Thomaidis et al. J Cancer Res Clin Oncol (2015)

35. The collaboration makes the difference
Our
metastatic
CRC patients
survive
>4 years
100 80 60
neoadjuvant
Chemo + OP 40
Chemo 20
30% !
BSC
Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

36. The collaboration makes the difference
Our
metastatic
CRC patients
survive
>4 years
LIMITATIONS
in daily practice
Co-morbidities (in ECOG 0/1 pts)
Unclarities with lesions ( lymph nodes and lung)
Suspected vs. proven peritoneal lesions (Information not always exactly available)
Patient’s wish
Available liver-specific MRI/PET-CT scans may have changed some recommendations
Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

37. We all make the difference !
Resectability can be increased from 22% at baseline to 53% at best response
CTX improves resectability even in patients with >1-organ disease.
Potential resections were evaluated as “easier” and the potential clinical benefit as “greater” at best response.
Resection-rates will be highest in university-hospitals and lowest in private practice: collaboration necessary !
Regular and pre-planned assessment of mCRC-patients with specialized surgeons in high-volume institutions may help to increase resection rates.

38. We all make the difference !
Expanding bounderies for our patients
New molecular diagnostics (NGS, Liquid biopsies)
Multidisciplinary teams with high clinical impact
From palliative therapy into potential cure
From non-resectable into resectable tumors
Immunotherapy for adjuvant and advanced indications

39. for all your commitment and enthusiasm !!
Thank you very much
for all your commitment and enthusiasm !!