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Preoperative/neoadjuvant 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.

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Preoperative/neoadjuvant treatment of CRC liver metastases Markus Moehler

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  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 0 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 0 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 0 Moehler, Thomaidis et al. J Cancer Res Clin Oncol 2015

  6. Mainz University Cancer Center Center of excellence for CRC liver metastases Firstcenter 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) PracticingOncologist (n=22)

  10. Mainz University Cancer Center Outreach / Regional Network UCT Network Communication • Virtual „centralentryportal“ • Password-protectedarea • Information oftrials, SOPs ... • Contactinformation at a glance • UCT hotline • Tumor Board participations • In personor via telecommunication • „Flying UCT oncologist“ Outreach / Regional Network

  11. Colorectal cancer Resection ? Resection ? Resection ? Therapeutic Options in MetastaticDisease

  12. Prognostic factors in CRC liver metastases 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 • Lymphnodestatus • Disease-freeInterval • 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. Prognostic factors in CRC liver metastases Response and Resection rates Studies with neoadjuvant focus Studies with met. CRC Jones, Folprecht Eur J Cancer 2014

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

  18. Chemo+EGFR vs. Chemo +VEGFRAS wt n RR PFS OS • FOLFIRI/Cetux17165%10.433.1 • FOLFIRI/Beva17160%10.2 25.6 • Heinemann, Lancet Oncol 2014 HR0.93HR 0.70 p=0.017

  19. Chemo+EGFR vs. Chemo +VEGFRAS wt n RR PFS OS • FOLFIRI/Cetux17165%10.433.1 • FOLFIRI/Beva17160%10.2 25.6 • Heinemann, Lancet Oncol 2014HR0.93HR 0.70 p=0.017 • FOLFOX/Pani8864%13.041.3 • FOLFOX/Beva8261%9.528.9 • Schwartzberg, JCO 2014HR 0.65HR 0.63 p=0.058

  20. Chemo+EGFR vs. Chemo +VEGFRAS wt n RR PFS OS • FOLFIRI/Cetux17165%10.433.1 • FOLFIRI/Beva17160%10.2 25.6 • Heinemann, Lancet Oncol 2014HR0.93HR 0.70 p=0.017 • FOLFOX/Pani8864%13.041.3 • FOLFOX/Beva8261%9.528.9 • Schwartzberg, JCO 2014HR 0.65HR 0.63 p=0.058 • Chemo/Cetux27069%11.432.0 • Chemo/Beva25654%11.331.2 • Lenz, ESMO 2014p<0.01 HR 1.1HR 0.9

  21. Chemo+EGFR vs. Chemo +VEGFRAS wt n RR PFS OS • FOLFIRI/Cetux295 62%10.028.7 • FOLFIRI/Beva297 58% 10.3 25.0 • Heinemann, Lancet Oncol 2014p=0.18HR1.06HR 0.77 p=0.017 • FOLFOX/Pani142 58%10.9 34.2 • FOLFOX/Beva14354% 10.1 24.3 • Schwartzberg, JCO 2014 HR 0.84 HR 0.62 p=0.009 • Chemo/Cetux57866%resected: 82 pts (14.2%) • Chemo/Beva55957%resected: 50 pts (8.9%) • Venook, ASCO/WCGIC/ESMO 2014p<0.02p<0.01

  22. FOLFOXIRI combinations n RR PFS OS FOLFOXIRI/Bev25265% 12.131.0 FOLFIRI/Bev 256 53% 9.7 25.8 Loupakis, NEJM 2014p<0.01 HR0.75 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. Background (CELIM) - Improving resectability in mCRC- • Untreated mCRC • 32% • +28% • After combination- therapy • 60% Folprecht G, et al. Lancet Oncol 2010

  25. Background FIRE-3 (all comers!) 1.0 0.75 0.50 Probability of survival 0.25 Δ = 8.1 months 0.0 48 12 60 36 24 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

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

  28. FIRE-3, Resectability at baseline Intention 100% 50% 50% 100% 21.7% Median kappa‘ coefficientfor inter-rater reliability: 0.56

  29. FIRE-3, Resectability at best response 100% Intention 50% 50% 100% 53.1% Median kappa‘ coefficient for inter-rater reliability: 0.66

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

  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 0 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) • Unclaritieswith 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 ! Expandingbounderiesforourpatients • New moleculardiagnostics (NGS, Liquid biopsies) • Multidisciplinaryteamswith high clinicalimpact • Frompalliative therapyinto potential cure • From non-resectableintoresectabletumors • Immunotherapyforadjuvantandadvancedindications

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

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