Preoperative/neoadjuvant treatment of CRC liver metastases Markus Moehler

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

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

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

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

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

Mainz University Cancer Center

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

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

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

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

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

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

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

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

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

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

Chemo+EGFR vs. Chemo +VEGF RAS wt n RR PFS OS FOLFIRI/Cetux 171 65% 10.4 33.1 FOLFIRI/Beva 171 60% 10.2 25.6 Heinemann, Lancet Oncol 2014 HR 0.93 HR 0.70 p=0.017

Chemo+EGFR vs. Chemo +VEGF RAS wt n RR PFS OS FOLFIRI/Cetux 171 65% 10.4 33.1 FOLFIRI/Beva 171 60% 10.2 25.6 Heinemann, Lancet Oncol 2014 HR 0.93 HR 0.70 p=0.017 FOLFOX/Pani 88 64% 13.0 41.3 FOLFOX/Beva 82 61% 9.5 28.9 Schwartzberg, JCO 2014 HR 0.65 HR 0.63 p=0.058

Chemo+EGFR vs. Chemo +VEGF RAS wt n RR PFS OS FOLFIRI/Cetux 171 65% 10.4 33.1 FOLFIRI/Beva 171 60% 10.2 25.6 Heinemann, Lancet Oncol 2014 HR 0.93 HR 0.70 p=0.017 FOLFOX/Pani 88 64% 13.0 41.3 FOLFOX/Beva 82 61% 9.5 28.9 Schwartzberg, JCO 2014 HR 0.65 HR 0.63 p=0.058 Chemo/Cetux 270 69% 11.4 32.0 Chemo/Beva 256 54% 11.3 31.2 Lenz, ESMO 2014 p<0.01 HR 1.1 HR 0.9

Chemo+EGFR vs. Chemo +VEGF RAS wt n RR PFS OS FOLFIRI/Cetux 295 62% 10.0 28.7 FOLFIRI/Beva 297 58% 10.3 25.0 Heinemann, Lancet Oncol 2014 p=0.18 HR 1.06 HR 0.77 p=0.017 FOLFOX/Pani 142 58% 10.9 34.2 FOLFOX/Beva 143 54% 10.1 24.3 Schwartzberg, JCO 2014 HR 0.84 HR 0.62 p=0.009 Chemo/Cetux 578 66% resected: 82 pts (14.2%) Chemo/Beva 559 57% resected: 50 pts (8.9%) Venook, ASCO/WCGIC/ESMO 2014 p<0.02 p<0.01

FOLFOXIRI combinations n RR PFS OS FOLFOXIRI/Bev 252 65% 12.1 31.0 FOLFIRI/Bev 256 53% 9.7 25.8 Loupakis, NEJM 2014 p<0.01 HR 0.75 p<0.01 HR 0.79,p=0.054 Progression free survival Overall survival

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

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

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 0.697 (95% CI: 0.54 – 0.90) p (log-rank)= 0.0059 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

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

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

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

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

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

Review (best response) vs. study-reports

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

FIRE-3: Survival with/without resection: Group OS (95% CI), months Resectable +resected 51.3 (35.9-66.7) Resectable + not resected 30.8 (26.6-34.9) Not resectable 18.6 (15.8-21.3)

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)

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

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

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.

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

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