Pieter Tanis, chirurg Academisch Medisch Centrum, Amsterdam Orde in de volgorde bij synchrone levermetastasen bij een colorectaal carcinoom Pieter Tanis, chirurg Academisch Medisch Centrum, Amsterdam

Mulitmodality treatment stage IV CRC Synchronous CRCLM Cure Radiotherapy Chemotherapy Surgery Local ablation Stereotactic RTx SIRT

Gereviseerde richtlijn colorectaal carcinoom 2014

Gelijktijdig opereren van de primaire tumor en synchrone metastasen is geen standaard bij patiënten met synchrone levermetastasen. De werkgroep is van mening dat deze behandeling na zorgvuldige selectie in centra met veel ervaring op zowel colorectale chirurgie als leverchirurgie kan worden overwogen.

Het medisch beleid bij synchrone levermetastasen en extrahepatische afwijkingen is niet eenduidig. Niveau 4: D Mening van de werkgroep Er zijn aanwijzingen dat overleving bij gelijktijdig opereren van primaire tumor en synchrone metastasen vergelijkbaar is met opereren van synchrone levermetastasen na 2 of 3 maanden. Niveau 3: C Yin 2013 (39); Li 2013 (26); Slesser 2013 (34) …..Timing is afhankelijk van expertise van het centrum.

Geen perioperatieve chemotherapie bij resectabele metastasen Inductiechemotherapie met targeted agent bij potentieel resectabele metastasen EORTC 40983; Nordlinger et al. Lancet Oncol 2013

Level of evidence Only cohort studies Expert centers

Multidisciplinary team discussion Individualize!

Background Timing of multimodality treatment in stage IV CRC Biological behaviour of the tumour Loss of control at the primary site Loss of control at metastatic site(s) Treatment related toxicity Preventing completion of treatment Worsening physical condition / immune status leading to disease progression

Biological behaviour prognostic implications of response to neo-adjuvant chemotherapy Adam Ann Surg 2004

Biological behaviour Failure to complete 2-stage liver resection Chua JSO 2012

Induction chemotherapy Responses occur early… …Toxicity occurs later Kishi et al. Ann Surg Oncol 2010)

Decision making Primary tumour characteristics Right vs left sided / rectum Symptomatic / asymptomatic Locally advanced Type of liver metastases Resectable vs potentially resectable Minor (1-2 segments) vs major or complex resection Requiring two-stage hepatectomy / PVE Patient condition / comorbidities

Timing issues Timing of chemotherapy in curable CRC stage IV Start of multimodality treatment (induction before synchronous resection) In between treatment modalities (primary - metastatic surgery; metastatic - primary surgery; PVE – liver resection; RTx - surgery) Timing of radiotherapy in stage IV rectal cancer Short vs long course Before or after induction chemotherapy Timing of surgery for the primary tumour Complicated primary (obstruction / perforation) Simultaneous or staged resection Timing of surgery for metastases Preceding primary tumour resection (‘reversed’ / ‘liver first’) Multi-stage resections

Vena porta embolisatie CAVE tumorgroei Overlevingseffect onafhankelijk van resectabiliteit na PVE Fischer JAMA Surg 2013

Implications of anastomotic leakage after LAR in stage IV N = 123 pts resected with curative intent 3y OS 72% Multivariate analysis for overall survival 3y OS 32% Factors identified as significant in univariate analysis for Overall Survival (OS) Overall leak rate 6.5% Smith JD et al. Ann Surg Oncol. 2013

Traditional treatment resectable synchronous CRCLM Radiotherapy Resection primary CRC Resection LM adjuvant chemotherapy

‘Liver first’ approach advanced synchronous CRCLM (Fong score 3 or higher) Induction Chemotherapy 3-6 courses RT N=13 primary rectal cancer RT for T3 and/or N+ stage Resection LM Resection primary CRC adjuvant chemotherapy N=9 two-stage hepatectomy with right PVE / PVL N=7 simultaneous resection N=5 not completed the programme 1 died of sepsis during chemotherapy 2 disease progression 1 rapid regrowth of LM, no rectal surgery Mentha BJS 2006 Mentha Dig Surg 2008

Two-stage hepatectomy combined with primary tumour resection Karoui BJS 2010

Treatment strategies for synchronous CRCLM the MD Anderson experience RT Resection primary CRC Interval chemotherapy (69%) Resection LM Classic N=72 Livermetastases: median no. 3 (1-10), median max diameter 3 (1-10), bilobar 60% Induction chemotherapy (26%) RT Combined resection of primary CRC and liver metastases Simultaneous N=43 Livermetastases: median no. 2 (1-10), median max diameter 2 (1-12), bilobar 30% Induction chemotherapy Resection LM Interval chemotherapy (59%) RT Resection primary CRC Liver first (Reverse) N=27 Livermetastases: median no. 3 (1-10), median max diameter 4 (2-11), bilobar 63% Brouquet JACS 2010

Treatment strategies for synchronous CRCLM the MD Anderson experience Bouquet JACS 2010

Treatment strategies for synchronous CRCLM the MD Anderson experience Combined/ Simultaneous N=43 Classic N=72 Reverse / Liver first N=27 R0 resection primary 95% 94% 93% Resection >2 liver segments 35% 66% 89% RFA 9% 33% 19% R0 resection metastases 86% 85% 90-day mortality 5% 3% 4% Major complications 17% 7% Adjuvant chemotherapy 77% 64% 78% Bouquet JACS 2010

Treatment strategies for synchronous CRCLM the MD Anderson experience Bouquet JACS 2010

5x5 Gy followed by chemotherapy Dutch M1 study Primary rectal cancer + synchronous resectable metastases in 1 or 2 organs Surgery Rectum & liver / lung SCRT 5x5 Gy 2x CAPOX + bevacizumab 4x CAPOX + 3x bevacizumab week 1-2 3-7 8 9-20 23 26 Re-staging CT Re-staging CT Van Dijk et al, Ann Oncol 2013

Dutch M1 study - interim results Conclusions Primary endpoint: radical resection and/or RFA of primary tumour and metastatic lesions in 72% 64 % 2-year recurrence 80% 2-year survival Locoregional control: 26% pCR 2/36 local recurrence at a median of 32 months Van Dijk et al, Ann Oncol 2013

Induction chemotherapy first – rectal cancer 3-year OS 59% Gall Colorectal Dis 2014

prognostic factors relevant for decision making Number of metastases Bulky primary tumor Capussotti Ann Surg Oncol 2007

major hepatectomy

Synchronous versus staged resection meta-analysis ¶ = In favour of simultaneous Major hepatectomy series In favour of staged =primary first Lykoudis BJS 2014

Synchronous versus staged resection meta-analysis The median MINORS score was 10, with incomplete follow-up and outcome reporting accounting primarily for low scores. Conclusion: None of the three surgical strategies for synchronous colorectal liver metastases appeared inferior to the others.

Synchronous versus staged resection meta-analysis Intraoperative blood loss Colorectal Dis 2013

Synchronous versus staged resection meta-analysis Hospital stay Colorectal Dis 2013

Synchronous versus staged resection meta-analysis Overall complications Colorectal Dis 2013

Synchronous versus staged resection meta-analysis Overall survival Disease free survival Colorectal Dis 2013

Synchronous versus staged resection meta-analysis Selection criteria for patients undergoing simultaneous or delayed resections differs resulting in a discrepancy in the metastatic disease severity being compared between the two groups. The comparable intra-operative parameters, post-operative complications and survival found between the two groups suggest that delayed resections may result in better outcomes. Simultaneous resections can only be recommended in patients with limited hepatic disease until prospective studies comparing similar disease burdens between the two resection groups are available.

Minimally invasive approaches Simultaneous laparoscopic approaches (near) pCR rectal primary Local excision ‘Wait and see’ protocol

One-stage total laparoscopic major hepatectomy + colorectal resection Ando Surg Today 2013 Spampinato Surg 2013

Decision making Asymptomatic primary Major hepatectomy (>2 segments) Need for induction chemotherapy “Low risk” primary resection + minor hepatectomy (laparoscopic) simultaneous resection (laparoscopic) liver first approach Radiotherapy / chemotherapy Symptomatic primary Resection primary CRC (+minor liver resection) (laparoscopic) liver resection Radiotherapy / chemotherapy Decompressing stoma / stent Chemotherapy Simultaneous / staged resection

Conclusies Orde in de volgorde van CRCLM Geindividualiseerd beleid Simultaan: ‘minor’ leverresectie met ‘laag risico’ primaire tumor Staged (‘liver first’): ‘major’ leverresectie / ‘hoog risico’ primaire tumor Inductie / interval chemotherapie ter voorkoming ziekteprogressie Meer mogelijkheden met laparoscopisch gecombineerde procedures / rectumsparende behandeling