1. Dr Ip Man Yi, Zoe United Christian Hospital
The Evolution of Staged Hepatectomy in Treatment of Colorectal Liver Metastasis
Joint Hospital Surgical Grand Round
15 December 2018
Dr Ip Man Yi, Zoe
United Christian Hospital

2. Content Introduction Selection criteria for resection
Strategies to Increase Resectability
Two stage hepactectomy
ALPPS

3. Colorectal cancer with liver metastasis
Commonest cancer in Hong Kong, 3rd commonest cancer worldwide.
~50% of patients develop synchronous or metachronous liver metastases.
Surgical resection of colorectal liver metastasis (CRLM) can significantly improve 5-year survival to 40%.
Alberts SR et al 2008

4. Selection Criteria for Resection of CRLM
Anatomical criteria
Any liver tumors, irrespective of number or size, that can
Resected with microscopically clear margin (R0) achieved
Adequate future liver remnant (FLR>20%; >=2 segments) preserved
Vascular inflow/outflow/biliary drainage to remaining segments preserved
General criteria
Good performance status
Absence of untreatable extra-hepatic disease
Anatomical criteria
Number of lesions <=4
Tumor size <5cm
Resection margin >1cm
Previous guidelines recommend resection of CLM based on number of lesions <=4, tumor size <5cm, resection margin >1cm; such restrictions are outdated.
Contemporary international multidisplinary consensus guidelines and reviews defines resectable CLM simply as Any liver tumors, irrespective of number or size, that can Resected with R0 resection achieved, while preserved adequate functional liver remnant (FLR>=2 segments).
Steele G et al, Ann Surg 1989
Selection of patients for resection of CLM: expert consensus statement. Ann Surg Oncol 2006

5. By what is REMOVED
Old
By what REMAINS
New
Modern multidisplinary consensus defines resectable CRLM as tumors that can resected completely, leaving adequate liver remnant.
Decision on resectability has shifted from tumor burden in liver, to how much liver remnant remains after resection

6. Strategies to Increase Resectability
“Down-sizing” the tumor
Chemotherapy
“Up-Scaling” the surgery
Combination of resection and thermal ablation
Enhancement of hepatic reserve
Portal vein embolization
Two-stage hepatectomy
ALPPS procedure

7. Enhancement of hepatic reserve
Portal vein embolization (PVE)
Embolization of right portal vein induce left lobe hypertrophy
Enable a safer removal of liver tumors in those with borderline FLR
Two stage hepatectomy (TSH)
Two sequential liver resections to resect multinodular tumors irresectable by a single procedure
Allow time for liver regeneration in between
TSH includes a first stage in which FLR (the less affected lobe that will be designated the future liver remnant, usually the left lobe) is resected by either wedge resections and/or ablation.
An alternative technique, portal vein ligation (PVL), triggers a similar or better regenerative response than PVE. PVE and PVL are now routinely used in TSH to improve the rate of a successful R0 resection.
TSH + Portal vein embolization (PVE)
ALPPS
TSH + Portal vein ligation (PVL)
Makuuchi M, et al. Surgery 1990
Adam R, et al. Ann Surg 2000
Jaeck D et al. Ann Surg. 2004
Clavien PA et al. NEJM 2007

8. Illustration of TSH
Clavien PA et al. NEJM 2007

9. Outcomes of TSH
FLR Hypertrophy rates range from 27 to 39% after 4-8 weeks.
~2/3 patients can complete both stages of resection.
Prognosis is comparable to one stage resection, with ~30% 5-year-survival and the best result being 64% if both steps are completed in specialized centres.
Brouquet A, et al. J Clin Oncol 2011
Shindoh J, et al. JACS 2013
Lam VW, et al. HPB, 2013

10. Drawbacks of TSH
Possible risk of insufficient remnant liver hypertrophy.
 Postoperative liver failure due to “small-for-size syndrome”
Long time interval to achieve hypertrophy between the two surgical steps
19% to 28% of cases with disease progression and could not complete 2nd stage
Poor survival similar or even worse than patients treated with chemotherapy alone
Preventing curative resection
Postoperative liver failure due to “small-for-size syndrome”
Tsai S, et al. HPB 2010
Shindoh J, et al. JACS. 2013
Lam VW, et al. HPB, 2013

11. Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS)

12. What is ALPPS? 1-2 weeks later STAGE 1 STAGE 2
stage 1 right portal vein is sectioned and sutured (arrow in A)
the diseased hemiliver is transected along the falciform ligament and wrap by a bag. (B).
The rationale for using the bag is to avoid adhesions and obtain an easier removal of DH on surgical stage 2, as well as better drainage or identification of collections.
If affected by metastases, the FLR is cleaned up by wedge resections and/or intraoperative radiofrequency ablation
stage 2 (C), Hepatectomy is completed by removing atrophic DH after transecting the serving hepatic artery, hepatic duct and hepatic veins 
Zerial M et al, World Journal of Hepatology 2017

13. History of ALPPS
In 2007, Prof. Hans J Schlitt, from Germany, performed the first ALPPS in a patient with hilar cholangiocarcinoma.
In 2012, a case series of 25 patients from 5 German centers was published, including 14 patients with CRLM
Median FLR hypertrophy rate of 74% (range %) after 9 days (range 5-28 days)
100% resection rate
68% surgical morbidities, 12% 90-day mortality
Schnitzbauer AA et al, Ann Surg 2012

14. Mechanisms of liver regeneration in ALPPS
Moris D et al, World Journal of Gastroenterology. 2016
Parenchymal transection
The unique capacity of liver regeneration was described by ancient Greeks in the myth of Prometheus.
Adult hepatocytes can proliferate in response to injury.
Liver regeneration after ALPPS is a combination of portal flow changes by PVL and parenchymal transection that generate a systematic response inducing hepatocyte proliferation and remodeling. 
Rubens , Promethesus Bound, 1618

15. International ALPPS Registry [www.alpps.net]
1107 cases in the ALPPS Registry worldwide, up til August 2018
72% were CRLM
a platform was given to all to study actual results and to learn and further develop the method. 

16. International ALPPS Registry Review (2014)- Tumor type
GBCA= CA gallbladder; PHCC= Perihilar CholangioCA; IHCC=Intrahepatic cholangioCA; HCC=Hepatocellular carcinoma; NCRLM=Non Colorectal liver metastasis
Percentage %
ALPPS in CRLM has the potential to increase resectability rates in patients with high tumor load cases.
Caution should be called to use ALPPS for HCC, IHC, PHC in view of associated high morbidity and mortality.
1st International ALPPS Consensus Meeting 2015

17. However, the mortality and morbidity in ALPPS are important issues.
Advantages of ALPPS
Faster hypertrophy rate of liver remnant
Higher feasibility of complete resection with ALPPS
However, the mortality and morbidity in ALPPS are important issues.
Abrasi A et al. Transl Gastroenterol Hepatol. 2018

18. Are Operative Results and Oncologic Outcomes of ALPPS comparable to conventional Two-Stage Hepatectomy?

19. Meta-analysis of 9 studies during 2013-2016
Total 657 patients: ALPPS, n=186 vs TSH, n=471
Outcomes:
Postoperative FLR
Resectable rates
Mortality and Morbidity
Overall survival
Moris D et al.. World J Surg 2018

20. Conventional TSH ALPPS P value
FLR hypertrophy growth rate
slower
(3-4.4ml/day)
faster
( ml/day)
0.0006
Time to achieve final FLR
longer
( days)
shorter
(6-18 days)
<
Resection rate
75%
91%
0.03
Major morbidity
21%
30%
0.002
Mortality 7%
14%
0.04
1-year survival
94%
92%
1.0
1-year disease free survival
80%
67%
0.43
Moris D et al. World J Surg 2018

21. Only one prospective, multicenter RCT published
ALPPS vs TSH in patients with advanced CRLM
100 patients randomized
48 ALPPS and 49 TSH analysed
Outcomes
Primary – Resection rates (% of patients completed both stages)
Secondary – Complications, Mortality, Resection margin
Sandström P, et al. Ann Surg 2018

22. Complication (Clavien-dindo grade >=III) Negative margin in liver
LIGRO trial: Outcomes
ALPPS group
TSH group
Odds ratio, P value
Resection rates
(44/48) = 92 %
(28/49) = 57 %
8.25 ( ), P<0.0001
Complication (Clavien-dindo grade >=III)
(19/44) = 43 %
(12/28) = 43 %
1.01 ( ), P=0.99
90-day Mortality
(4/48) = 8.3 %
(4/44) = 9.1 %
(3/49) = 6.1 %
(3/28) = 10.7 %
1.39 ( ), P=0.68
0.83 ( ), P=0.82
Negative margin in liver
(34/44) = 77 %
(16/28) = 57 %
2.55 ( ), P=0.11
ALPPS for patients with CRLM resulted in a higher resection rate
Comparable 90-day mortality rate, complication rate, negative resection margins in liver in both groups
Sandström P, et al. Ann Surg 2018

23. Technical variations of ALPPS
Portal vein
Liver parenchyma
Partial ALPPS
Ligation
Incomplete transection
ALTPS
Partial transection + tourniquet
RALPP
Complete, Radiofrequency -induced necrosis
Hybrid ALPPS
Embolization
Complete, surgical
Refinements in technique was proposed in the hope to improve safety of the ALPPS procedure.
Partial ALPS = partial partition up MHV
Tourniquet ALPPS = a tourniquet was fixed along the future resection line to minimize the blood flow between the lobes
Hybrid ALPPS = combines parenchymal transection with PVE
Mono-segmental ALPPS = only one segment comprises the FLR 
➢No technical variation of the ALPPS transection technique can currently be recommended as superior.

24. Future directions of ALPPS
Patient selection?
Very small FLR and high tumor load
Rescue ALPPS for patients who failed PVE
Long term oncological outcomes of ALPPS?
Studies reported high risk for recurrence and early tumor progression.
3-year overall survival of 64.3 %
82 % recurrence rate after a median follow-up of 22.5 months
Rescue ALPPS = splitting of the liver along the main portal fissure after a radiological PVE that did not allow satisfactory liver hypertrophy
whether a better possibility of tumor resection, ultimately translates into better survival.
Oldhafer et al. revealed that ALPPS for patients with CRLM presented a high risk for recurrence and early tumor progression.
Lang et al. reported a 3-year overall survival of 64.3 %.
Bjo¨rnsson B et al reported 82 % recurrence rate after a median follow-up of 22.5 months from surgery, and an overall survival 1 year after stage-2 procedure of 83 and 59 % after 2 year.
Oldhafer KJ et al. World J Surg 2014
Lang SA et al. Langenbecks Arch Surg 2015
Bjo¨rnsson B et al, EJSO 2016

25. Portal Vein Embolization Hepatectomy + Thermal ablation
Extensive liver metastasis
Multi Unilobar
Multi Bilobar
Multi Bilobar
Remnant Liver <20-30% <=3 tumors, <=3cm >3 tumors, >3cm
Portal Vein Embolization
Studies consistently showed that even in the presence of these less favourable prognostic factors, surgical resection can improve long term survival. R0 resection is possible with bilobar tumors by one stage multiple site liver resection, combined resection and thermal ablation, or two-stage hepatectomy.
Hepatectomy + Thermal ablation
2-Stage Hepatectomy
ALPPS
Adam R, 1st ALPPS Meeting Hamburg 2015

26. Summary
Two-stage hepatectomy establishes a promising survival benefit in advanced CRLM.
ALPPS emerges
markedly induce FLR hypertrophy
increase complete resection rate
relatively high operative morbidity and mortality
unknown long term outcomes
Further study is warranted
Patient selection
Technical refinements
Long term oncological outcomes

27. Reference
Steele G, et al. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg. 1989;210(2):
Selection of patients for resection of CLM: expert consensus statement. Ann Surg Oncol 2006
Makuuchi M, et al: Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990; 107: 521–527
Adam R, et al. Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 2000; 232:777-85
Jaeck D et al; A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg. 2004;240(6):
Clavien PA et al. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356(15):
Brouquet A, Abdalla EK, Kopetz S, Garrett CR, Overman MJ, Eng C, Andreou A, Loyer EM, Madoff DC, Curley SA, Vauthey JN: High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol 2011; 10: 1083–1090.
Shindoh J, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg ;217(1):
Lam VW, et al. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013; 15: 483–491.
Tsai S, et al. Two‐stage strategy for patients with extensive bilateral colorectal liver metastases. HPB (Oxford). 2010;12(4):262-9.
Schnitzbauer AA et al, Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012; 255: 405–414.
Moris D et al, Mechanistic insights of rapid liver regeneration after associating liver partition and portal vein ligation for stage hepatectomy. World J of Gastroenterol. 2016; 22(33): 7613–7624.

28. Reference
Abbasi A, et al. Role of associating liver partition and portal vein ligation in staged hepatectomy (ALPPS)—strategy for colorectal liver metastases. Transl Gastroenterol Hepatol. 2018; 17;3:66.
Moris D et al: Operative results and oncologic outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) versus two-stage hepatectomy (TSH) in patients with unresectable colorectal liver metastases: a systematic review and meta-analysis. World J Surg 2018; 42: 806–815.
Sandström P,, et al. ALPPS improves resectability compared with conventional two-stage hepatectomy in patients with advanced colorectal liver metastasis: results from a Scandinavian multicenter randomized controlled trial (LIGRO Trial). Ann Surg 2018; 267:
Oldhafer KJ, et al ALPPS for patients with colorectal liver metastases: effective liver hypertrophy, but early tumor recurrence. World J Surg 2014; 38 (6):1504–1509
Lang SA, et al. Long-term results after in situ split (ISS) liver resection. Langenbecks Arch Surg 2015; 400(3):361–369.
Bjo¨rnsson B, et al. Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases–intermediate oncological results. Eur J Surg Oncol. 2016

29. THANK YOU Acknowledgement:
Dr TP Fung, Dr Derek Tam, & Division of Hepatobiliary surgery, UCH

30. ALPPS: Hong Kong experience
Largest case series in QMH, 42 patients, since 2013
Indication
HCC (90%) or CRLM (10%)
Preoperative FLR volume <30% ESLV
Central-locating tumor in right liver with sizeable non-tumorous liver to be sacrificed in right hepatectomy
Absence of complete right portal vein thrombosis
Child A cirrhosis
ICG clearance rate <20% at 15 mins

31. ALPPS: Hong Kong experience
Outcomes
FLR/ESLV ratio increase from 24.2% to 38.5%
Over a median of 6 days
100% resection rate
90-day mortality 7%, all due to liver failure