Preoperativeneoadjuvant treatment of CRC liver metastases Markus Moehler

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 BSC 30% ! 0 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 BSC 30% ! 0 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 BSC 30% ! 0 Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

Mainz University Cancer 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“

Colorectal cancer Resection ? Therapeutic Options in Metastatic Disease

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

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

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

Chemo+EGFR vs. Chemo +VEGF RAS wt • FOLFIRI/Cetux • FOLFIRI/Beva • Heinemann, Lancet Oncol 2014 n RR PFS OS 171 65% 10. 4 33. 1 171 60% 10. 2 25. 6 HR 0. 93 HR 0. 70 p=0. 017

Chemo+EGFR vs. Chemo +VEGF RAS wt • FOLFIRI/Cetux • FOLFIRI/Beva n RR PFS OS 171 65% 10. 4 33. 1 171 60% 10. 2 25. 6 HR 0. 93 HR 0. 70 p=0. 017 • Heinemann, Lancet Oncol 2014 • FOLFOX/Pani 88 64% 13. 0 41. 3 • FOLFOX/Beva 82 61% 9. 5 28. 9 HR 0. 65 HR 0. 63 p=0. 058 • Schwartzberg, JCO 2014

Chemo+EGFR vs. Chemo +VEGF RAS wt • FOLFIRI/Cetux • FOLFIRI/Beva n RR PFS OS 171 65% 10. 4 33. 1 171 60% 10. 2 25. 6 HR 0. 93 HR 0. 70 p=0. 017 • Heinemann, Lancet Oncol 2014 • FOLFOX/Pani 88 64% 13. 0 41. 3 • FOLFOX/Beva 82 61% 9. 5 28. 9 HR 0. 65 HR 0. 63 p=0. 058 • Schwartzberg, JCO 2014 • Chemo/Cetux 270 69% 11. 4 32. 0 • Chemo/Beva 256 54% 11. 3 31. 2 p<0. 01 HR 1. 1 HR 0. 9 • Lenz, ESMO 2014

Chemo+EGFR vs. Chemo +VEGF RAS wt • FOLFIRI/Cetux • FOLFIRI/Beva n RR PFS OS 295 62% 10. 0 28. 7 297 58% 10. 3 25. 0 p=0. 18 HR 1. 06 HR 0. 77 p=0. 017 • Heinemann, Lancet Oncol 2014 • FOLFOX/Pani 142 58% 10. 9 34. 2 • FOLFOX/Beva 143 54% 10. 1 24. 3 HR 0. 84 HR 0. 62 p=0. 009 • Schwartzberg, JCO 2014 • 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 FOLFOXIRI/Bev n 252 RR 65% PFS 12. 1 OS 31. 0 FOLFIRI/Bev 256 53% 9. 7 25. 8 Loupakis, NEJM 2014 Progression free survival p<0. 01 HR 0. 75 p<0. 01 HR 0. 79, p=0. 054 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. Prodige 1$/ACCORD 21 (METHEP-2), J Clin Oncol 34, 2016 (suppl; abstr 3512). Folprecht G et al. Lancet Oncol 2010

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

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 1. 0 Probability of survival 0. 75 HR 0. 697 (95% CI: 0. 54 – 0. 90) p (log-rank)= 0. 0059 0. 50 0. 25 Δ = 8. 1 months 0. 0 12 48 36 24 months since start of treatment * KRAS and NRAS exon 2, 3 and 4 wild-type 60 72 Stintzing S, …Moehler M, et al. Lancet Oncol. 2016

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 Lethal tumor load Baseline Dp. R Tumor Nadir Time 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 Intention 100% Not resectable 50% Conversion possible 1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 191 201 211 221 231 241 251 261 271 281 291 301 311 321 331 341 351 361 371 381 391 401 411 421 431 441 (maybe only abd. lesions) Abdominal lesions resectable (+- periop. Chemo) R 0 -resection 50% (with periop. Chemo) R 0 -resection 100% 21. 7% Median kappa‘ coefficient for inter-rater reliability: 0. 56

FIRE-3, Resectability at best response 100% Intention Not resectable 50% Abdominal lesions resectable 1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 191 201 211 221 231 241 251 261 271 281 291 301 311 321 331 341 351 361 371 381 391 401 411 421 431 441 (+- locoreg. therapy) R 0 -resection inlc. Locoregional therapy all lesions 50% R 0 -resection all lesions 100% 53. 1% Median kappa‘ coefficient for inter-rater reliability: 0. 66

Resectability according to organ-involvement Metastatic spread [CRF] Evaluation at „baseline“ 33. 3 Evaluation at „best response“ 33. 3 N=186 One-organ disease 66. 7 17. 4 Two-organ disease N=155 47. 7 N=155 52. 3 82. 6 10 33, 8 Three-organ disease N=80 66. 2 90 Percentage with unresectable disease Percentage with resectable disease

Review (best response) vs. study-reports

Percentage Impact of treatment-site 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 BSC 30% ! 0 Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

The collaboration makes the difference LIMITATIONS in daily practice Our metastatic CRC patients survive >4 years 1. Co-morbidities (in ECOG 0/1 pts) 2. Unclarities with lesions ( lymph nodes and lung) 3. Suspected vs. proven peritoneal lesions (Information not always exactly available) 4. Patient’s wish 5. 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 m. CRC-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

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