is there a benefit in resection of the primary tumor in synchronous metastatic colorectal carcinoma?...

Is there a benefit in resection ofthe primary tumor in synchronousmetastatic colorectal carcinoma?

Carmelo Pozzo

Oncologia MedicaUniversità Cattolica del Sacro CuorePoliclinico A. Gemelli – Rome, Italy

Mediterranean School of OncologyTHE CURRENT MANAGEMENT OF COLORECTAL CANCER

Roma 18 ottobre 2013

http://www.policlinicogemelli.it/b/?hw=5&b=62

30% synchronous metastasesAdditional ~50% will develop metastases

30–35% ‘liver only’ metastases

75–90% not resectable10–25% candidates for SURGERY

Aim: R0 resection

250,000 CRC cases/year (Europe)

Chu, et al. Clin Colorectal Can 2006; Kemeny, et al. NEJM 1999; Pozzo, et al. Oncologist 2008; Leichman. Surg Oncol Clin N Am 2007;

Leonard, et al. JCO 2005; Tomlinson, et al. JCO 2007; Van Cutsem, et al. EJC 200;

Initially resectable

Borderline resectable

Three potential scenarios when considering treatment options

Resection/Ablation of CRC liver metastases

• Accepted standard of practice (appropriately) despite a lack of randomized trials

• This is due to substantial cure rate (25%-40%) reported in initial series

• We accepted resection/ablation as a standard due to the realistic standard for cure

- Therefore, we need to accurately identify those patients who have a realistic chance for cure, and those who do not

Saltz L., Educational ASCO 2012

Overall survival probability after a first resection for colorectal liver metastases in 14,774 patients from the LiverMetSurvey

http://www.livermetsurvey.org, June 2011.

Overall survival probability after resection of initially resectable versus non resectable liver metastases in 10,940 patients in the LiverMetSurvey

http://www.livermetsurvey.org, June 2011.

Overall survival in advanced CRC: Is Surgery a plus?

0 1 2 3 4 50 1 2 3 4 5

100100

5050

00

% s

urvi

ving

% s

urvi

ving

Years after diagnosis of colorectal metastases

2011 chemotherapy alone2011 chemotherapy aloneMedian survival >25 monthsMedian survival >25 months5-yr survival 9%5-yr survival 9%

<1%<1%

19871987

2011 overall with addition of surgeryMedian survival ~40 months5 year survival 35 %

35%35%

Modified from Poston GJ. EJSO 2005; 31: 325-30http://www.livermetsurvey.org, June 2011

9%9%

19271927 19971997

3%3%

20112011

?50%?50%20172017

Changing Definition of Resectability

How many metastases?How many metastases? 4 < lesions, with unilobar location, 4 < lesions, with unilobar location, resectable resectable

How large?How large? < 5 cm resectable< 5 cm resectable

Extrahepatic disease?Extrahepatic disease? If none, resectableIf none, resectable

Old: What must come out?

Can R0 resection (negative margins) Can R0 resection (negative margins) be achieved? be achieved?

Can two contiguous liver segments be Can two contiguous liver segments be preserved?preserved?

Can adequate future liver remnant Can adequate future liver remnant (>20%) be preserved?(>20%) be preserved?

New: What will stay in?

Charnsangavej C, et al. Ann Surg Oncol. 2006; 13:1261-1268.

Modificato da Khatri, Petrelli e Belghiti, JCO 2005

Criteri convenzionali Criteri moderni

< 4 metastasi, unilobari


< 4 metastasi, unilobari Nessun limite (NeoCT, two-stage, RF)

Diametro < 5 cm




Diametro < 5 cm Nessun limite

Metastasi metacrone





Assenza di malattia extraepatica

Metastasi metacrone Metastasi sincrone e metacrone





Assenza di malattia extraepatica Exeresi di malattia extraepatica (adenopatie ilari, recidiva locale, mts polmonari)

Margine di resezione > 1 cm







Margine di resezione > 1 cm Margine < 1 cm, purchè negativo

Adeguato parechima residuo








Adeguato parechima residuo PVE o legatura portale


Resezione radicale









Resezione radicale Resezione radicale









Resezione radicale Resezione radicale

L’indicazione alla resezione epatica è data dalla fattibilità tecnica


Contraindications to hepatic resection in CRC patients: Oncosurgery Approach

Adam R et al., The Oncologist 2012;17:1225-1239

• Should the prospect of surgery influence the choice of first-line chemotherapy

• When should targeted therapies be used?• How many cycles before assessment of response and surgery?• Is there a maximum number of metastases for achieving potentially

curative surgery?• What to do when there is a complete response (no metastases)?• How should potentially resectable synchronous metastases be

managed?

Questions about liver metastases from colorectal cancer: Oncosurgery Approach

• How should potentially resectable synchronous metastases be managed?

– Chemotherapy or surgery first?– One- or two-stage surgical procedures?– Is liver surgery first a valid approach?

Questions about liver metastases from colorectal cancer: Oncosurgery Approach

• Surgical resection of the primary tumor, neoadjuvant chemotherapy (?), and then liver resection as a subsequent operation

• Colorectal primary tumor was the usual source of symptoms• Colorectal primary likely source of subsequent metastasis and thus should

be removed first (limited data)• Less morbidity and mortality, particularly when a major hepatectomy (> 3

segments) is needed • Early progression after removal of primary can select patients who do not

benefit of liver resection

Synchronous resectable liver metastases of colorectal cancer: Classical Approach

Only one randomized peri-operative trial:EORTC 40983 (the EPOC trial)

Phase III study: patients with CRC

and resectable liver metastases;

WHO/ECOG performance

score 0-2

(N = 364)

FOLFOX4 for 6 cycles (12 wks)

(n = 182)

Surgery(n = 182)

SurgeryFOLFOX4

for 6 cycles (12 wks)

http://www.sciencedirect.com/science/journal/01406736

EORTC 40983: Patients who received surgery and resection

EORTC 40983: RECIST Response After Pre-operative CT

12 Pts progressed during preop CT

• One further patient not eligible for RECIST response assess-ment progressed after 3 cycles

• 4 of 8 pts progressed after 3 cycles underwent resection

• 1 of 4 pts progressed after 6 cycles underwent resection

EORTC 40983: post-operative complications

EORTC 40983: PFS in eligible and resected patients

Nordlinger B et al, ASCO 2012, abstr. 3508

• Preferred in patients with limited hepatic disease (minor hepatectomy)• High risk patients with extensive metastatic disease, elderly, advanced

primary tumors tend to undergo sequential resections• Advantage of removing all of the macroscopic cancer during a single

operation• Prevents the delay of adjuvant chemotherapy• Simultaneous resections may leave behind undetected occult micro-

metastases (limited data)• Postoperative immunodeficiency associated with the primary can lead to

early tumor spread (limited data)• Primary tumor resection leads to the progression of the liver metastases

(limited data)• Few studies with bias in interpretation of simultaneous vs staged

Synchronous resectable liver metastases of colorectal cancer: Combined/Simultaneous Approach

Published Results of Simultaneous versus Staged Resection for Synchronous CRC Hepatic Metastasis

Martin R et al., J Am Coll Surg 2009;208:842–852

Outcome of simultaneous resectionsSynchronous resectable CRC liver mets

Slesser AAP, et al., Eur J Surg Oncol 2013.09.012

UK Hospitals,112 consecutive ptsFrom 2000 to 2012

36 simultaneous resect.76 sequential resect

No differences in intraoperative and postoperative complications

Outcome of simultaneous resectionssynchronous resectable CRC liver mets

Slesser AAP, et al., Eur J Surg Oncol 2013.09.012

3 yrs OS: 75% vs 64% p = 0.379 3 yrs DFS: 33% vs 32% p = 0.837

• The majority (70–90 per cent) metastatic disease at presentation is not suitable for curative resection

• A mutimodal approach including chemotherapy and aggressive surgical techniques such as extended or two-stage hepatectomy has been shown to improve resectability rates by 10–50 per cent

• The first stage focuses on the ‘easy’ side of the liver, leaving major hepatectomy for a second specific stage (higher morbidity and mortality)

• This approach reduces the number of procedures and optimizes administration of chemotherapy.

Synchronous resectable, borderline or unresectable liver metastases of colorectal cancer:Combined primary and two-stage hepatectomy

Combined first-stage hepatectomyand CRC resection in a two-stage hepatectomy strategy

Karoui M et al., British Journal of Surgery 2010; 97: 1354–1362

Two Institutions (French and Italian)

33 pts with bilobar metsFrom 2000 to 2008

Combined first-stage hepatectomyand CRC resection in a two-stage hepatectomy strategy

Karoui M et al., British Journal of Surgery 2010; 97: 1354–1362

- R0 resections 25/33 pts (67%)- Morbidity of first stage 21%, second stage 32%- Mortality second stage (liver-related) 4%

• Evidence from rectal cancer supporting preoperative chemoradiotherapy • Colonic stent has allowed palliation of symptoms (obstruction) so that

patients can be candidates for systemic chemotherapy at an early stage• Colorectal cancer is a chemosensitive disease, and thus there is a logic to

early systemic treatment• Potentially optimize the chance of R0 liver resection related to a better

survival• An early control of systemic (liver) disease can lead to a reduction of

probability of distant metastases and to better outcome

Synchronous liver metastases of colorectal cancer: Liver-first or Reverse Approach

Studies on Liver-First Approachfor synchronous CRC liver mets

Santhalingami J al., JAMA Surg. 2013;148(4):385-391


De Rosa A al., J Hepatobiliary Pancreat Sci (2013) 20:263–270


Santhalingami J al., JAMA Surg. 2013;148(4):385-391

Patient-based analysis comparingLiver-First and Combined approach

Skye C et al., J Am Coll Surg 2012.12.029

Four Institutions

1004 ptsFrom 1998 to 2011



Blue bar: overall complicationsRed bar: severe complicationsGreen bar: after minor resectionsTan bar: after major resections

No differences: all p= 0.05



No differences of complications between minor and major hepatectomy



No differences of complications in the logistic regression analysis



Only R0 resection is a predictors of survival



5 yrs Overall Survival 50.9 (44%) No differences regarding the approach (p =0.94)



In the Cox regression analysis for survival gender, rectal primary, number of mets, minor hepatectomy and combined resection and ablation are significat at univariate

Rectal cancer and Liver-First Approach


• Resection of the rectal primary is a significantly more challenging procedure by itself with well-established morbidity

• Patients with limited liver disease and small asymptomatic primary could benefit from a combined resection

• The extension of the primary tumor often do not allow a combine approach and require a neoadjuvant chemoradio

• In selected patients, where the primary rectal cancer is not a threat for bleeding, obstruction, or perforation, there is the option of addressing the hepatic disease first

• Need of selecting patients on biological features

Conclusions• Patients managed with a staged or simultaneous approach had similar

recurrence and overall survival• Both minor and major hepatectomy can be performed safely with low

morbidity and mortality as part of either a simultaneous or a staged operative strategy

• Few data available on Liver-First approach, though survival data are consistent across studies

• Laparoscopic rectal/colon simultaneous excision and/or other liver mets ablation technics should be further explorated

• Longterm outcomes among patients with sCRLM are dictated by biology (i.e. CEA, BRAF ?, RAS ? MSI, genomic, etc) not surgical strategy

Grazie per l’attenzione

is there a benefit in resection of the primary tumor in synchronous metastatic colorectal carcinoma?...

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