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346 3 HEPATOBILIARY AND PANCREAS CANCER
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Carcinoma: 2018 Practice Guidance by the American Association
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• Lubel, J. S., Roberts, S. K., Strasser, S. I., Thompson, A. J.,
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& Shackel, N. 2021. Australian recommendations for the
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• Asia-Pacific Primary Liver Cancer Expert Association
Annual Board Meeting Report 2021
19 Management of Metastic Liver
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Cancer
Camille Stewart1, Felix Ho1, Yuman Fong2, S. Lindsey Davis3, Lisa Liu4, Jonathan
4
Lindquist
1
Department of Surgery, University of Colorado School of Medicine, Aurora, Colorado
2
Department of Surgery, City of Hope National Medical Center, Duarte, California, USA
3
Department of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado
4
Department of Interventional Radiology, University of Colorado School of Medicine, Aurora, Colorado
5
Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina, USA
, Pooja Karukonda5, Christopher Willett5 & Brian Czito
5
The liver is the most common site for blood-borne metastasis
from colorectal cancers, and is the dominant metastatic disease
site just prior to death (Stewart et al. 2018). Until the early
1980s, it was generally accepted that hepatic metastases from
colorectal cancer represented just one site in a wide systemic
dissemination of tumor, and partial hepatectomy was rarely
used as treatment. Since then, numerous studies have shown
that resection can prolong survival and potentially provide
cure. Surgical excision for hepatic metastases from colorectal
cancer is now considered standard therapy for patients with
metastases isolated to the liver. In the next section, we will
summarize the data supporting such therapies, as well as
clinical parameters that influence outcome. Since acceptance of
surgery as a local therapy for this disease, a number of other
local therapies have emerged as effective treatment options for
hepatic metastases. The data supporting use of ablative, radioembolic, and radiation therapies will also be presented. These
tissue-sparing local treatments for hepatic colorectal metastases have further extended treatment possibilities.
Recent advancements in chemotherapies and biologic therapies have also contributed to effective treatment for hepatic
colorectal metastases and extended the possibility for cure.
Patients previously beyond curative therapies can be converted
by systemic therapies to becoming resectable. Those not resectable for cure are effectively treated by systemic and regionally
delivered therapies, including hepatic artery infusion pump
therapy, to achieve extension of life. In the following sections
we will also present the current approach of palliative neoadjuvant, and adjuvant systemic and regional infusion therapies.
The combined advances in surgery, systemic and regional infusion therapies, along with radiation, radioembolization, and
ablative therapies have transformed this disease from uniformly and immediately fatal to an increasingly curable one.
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
Surgical Therapy for Colorectal Liver
Metastases
Camille Stewart, Felix Ho & Yuman Fong
Introduction
The liver is the most common site for distant metastasis from
colorectal cancers. Single institutional studies have suggested
that one-quarter of patients will be found to have hepatic
metastases synchronous with their colorectal primary, and
nearly half of patients will develop metachronous liver metastasis colorectal resection (Ekberg et al. 1987). Specifically for
patients presenting with stage IV disease, a recent study based
on the SEER database found that 72% of these patients resented
with liver metastases at the time of diagnosis (Ituarte et al.
2022). Liver resection, however, is only performed for the
minority of these patients (<10%) (Raoof et al. 2019). Untreated
colorectal metastasis to the liver uniformly results in death
within months (Oxley and Ellis 1969). If liver disease is unresectable, it generally dominates the clinical picture until death;
83% of patients die with liver disease, and 49% of patients have
the liver as the dominant metastatic disease at the time of death
(Stewart et al. 2018). Even with the best current systemic
chemo- and biologic therapies, median survival of unresected
disease is less than less than 2.5 years (Cremolini et al. 2020a;
Cunningham et al. 2004; Hurwitz et al. 2004; Saltz et al. 2000).
Abundant data accumulated over many decades have definitively demonstrated that partial hepatectomy can be curative
treatment for colorectal liver colorectal metastases (Creasy
et al. 2018a; Wagner et al. 1984; Wilson and Adson 1976). We will
review these data in this chapter. The patient selection criteria,
preoperative work-up, and clinical determinants of outcome will
be presented in the context of current multimodality treatment.
While the bulk of discussion on chemotherapy will be presented
in the chapter on systemic and regional therapy for this cancer, we
will summarize the issues related to perioperative use of chemotherapy as it relates to surgical outcome and conduct.
347
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Natural History
Metastatic colorectal cancer has an incidence of 9.8 per
100,000 individuals; patients specifically with liver metastases
make up 7.1 per 100,000 (Ituarte et al. 2022). The incidence of
metastatic colorectal cancer is higher in males (11.7) and
African Americans (14.6) (Ituarte et al. 2022). Many studies in
the twentieth century examined the outcome of untreated
hepatic colorectal metastases. Median survival is 5–10 months
(Table 1). Outcome is clearly related to tumor burden
(Bengmark and Hafstrom 1969; Bengtsson et al. 1981; Wood
et al. 1976). While the one-year survival was only 5.7% for
patients with widespread liver disease, 60% of patients with
solitary metastasis were alive at one year and these patients
with solitary metastases had a mean survival of 25 months
(Wood et al. 1976). Wood et al. compared the survival of 13
unresected patients with technically resectable disease with
100 patients with unresectable disease. For these 13, the 1-, 3-,
and 5-year survival was 77%, 23%, and 8%, compared with
15%, 0, and 0 for the unresectable group (Wood et al. 1976).
Wagner et al. reported the 3- and 5-year survival for untreated
resectable disease to be 14% and 2%, compared with 4% and 0
for unresectable disease (Wagner et al. 1984). Stangl et al.
reported six independent determinants of survival in patients
with untreated colorectal liver metastases: % liver volume
replaced by tumor, grade of malignancy, presences of extrahepatic disease, mesenteric lymph node disease, carcinoembryonic antigen value, and age (Stangl et al. 1994).
Regardless of these factors, five-year survival for untreated
disease is extremely rare.
Similar conclusions were found in older case-control studies.
Wilson and Adson (Wilson and Adson 1976) compared 60
patients with resection to 60 patients with a comparable
number of lesions and extent of disease not subjected to resection. The five- and ten-year survivals of resected patients were
25% and 19%, while no unresected patient survived five years.
Two other case-control studies had almost identical results
(Scheele et al. 1991; Wagner et al. 1984). These data, combined
with extensive data documenting long-term survival after hepatectomy, have led to general acceptance of hepatectomy as an
effective treatment for liver colorectal metastases, even though
no randomized trial comparing systemic therapy alone to surgery with or without systemic therapy has ever been
performed.
Results of Resection for Colorectal Liver
Metastases
Many studies have been published demonstrating resection
of liver metastases from colorectal primaries is safe and
effective (Simmonds et al. 2006). Results from retrospective
and prospectively gathered data show that even without
randomized controlled trial data, hepatectomy is superior to
systemic treatment alone (Table 2). The reason is that virtually no one under medical management lives more than five
years. A population based study from the California Cancer
Registry comparing colorectal liver mastectomy rate and
survival by medical service area demonstrated a 24-month
survival gain for patient’s whose treatment choices were
influenced by rates of resection in their geographic area
(Raoof et al. 2019). This translated into increasing survival
105% at 1 year, 223% at 2 years, 375% at 3 years, and 370% at
5 years (Raoof et al. 2019). This study highlights the importance of patient referral to a multidisciplinary team that
includes hepatobiliary surgery, since this statistically
improves three- and five-year overall survival (Lordan et al.
2009). Further, while African Americans with colorectal liver
metastases have a 17% higher hazard of death compared to
Caucasian patients, this difference is lost when examining
patients who have undergone liver resection for colorectal
liver metastases (Thornblade et al. 2020). It should also be
noted that disease-specific survival of patients who die of
liver metastasis (17.3±1.5 months) is shorter than for those
who die of other intra-abdominal disease (29.7±4 months;
p<0.0001), intrathoracic disease (39.3±5 months; p<0.0001),
or brain metastasis (35.6±5.3 months; p<0.0001). As such,
Table 1 Natural history of liver metastasis from colorectal cancer.
Study Number of
Bengmark 1968 (Bengmark and Hafstrom 1969) 173 – 5.7 0 0
Oxley 1969 (Oxley and Ellis 1969) 640 27 4 1
Wood 1976 (Wood et al. 1976) 113 6.6 15 3 1
Wagner 1984 (Wagner et al. 1984) 252 – 49 7 2
Scheele 1990 (Scheele et al. 1990) 921 – – – 0
Stangl 1994 (Stangl et al. 1994) 484 7.5 31 2.6 1
– Data not specified.
patients
Median
(months)
1 yr % 3 yr % 5 yr %
Table 2 Results of hepatic resection for metastatic colorectal cancer.
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19 MANAGEMENT OF METASTIC LIVER CANCER 349
Study Number of
patients
Kato 2003(Kato et al. 2003) 585 – – 33 – –
Mutsaerts 2005 (Mutsaerts et al. 2005) 102 3 – – 29 – –
Wei 2006 (Wei et al. 2006) 423 2 93 – 47 28 53
House 2010 (House et al. 2010) 563 0.5 65 43
Hackl 2014 (Hackl et al. 2014) 374 87 32 18 52
Hallet 2016 (Hallet et al. 2016) 2320 64
Margonis 2016 (Margonis et al. 2016) 485
Neal 2017 (Neal et al. 2017) 488 2 48 30
Sasaki 2018 (Sasaki et al. 2018) 604 94 69 50 62
Margonis 2019 (Margonis et al. 2019) 1099 88 61 42
– Not specified.
hepatic resection alters not only length of survival but also
eventual cause of death, by allowing other, more indolent
sites of metastatic disease to become clinically evident and
important (Stewart et al. 2018).
Since all major series have demonstrated that hepatectomy
results in long-term survival for a proportion of patients, these
data are so compelling that randomized trials are both unethical and unnecessary. As safety of hepatectomy has improved,
clinicians have been increasingly willing to perform ever more
extensive resections and multi-phase operations to eradicate
tumor. In addition, as long-term outcomes improve due to
improving adjuvant therapies, clinicians have been extending
the indications for resection. Following is a review of the perioperative and long-term outcomes.
Operative
mortality%
1-year
survival %
3-year
survival %
5-year
survival %
10-year
survival %
Complication rates remain high because of the physiologic
stress of removing a significant portion of such a metabolically
and immunologically important organ as the liver. A recent
meta-analysis of 41 studies performed from 2003 to 2018,
including 12,817 patients who underwent surgical resection for
colorectal liver metastases reported post-operative complications occurred in 26%, and 19% were grade 3+ (Dorcaratto
et al. 2019). The types of complications were not listed. Of note,
however, was that patients who experienced a post-operative
complication had significantly lower five-year overall (HR 1.43,
95% CI 1.3–1.57) and disease-free survival (HR 1.38, 95% CI
1.27–1.49) (Dorcaratto et al. 2019).
In a study of the American College of Surgeons NSQIP database from 2014 to 2016, morbidity was 33% (Wiseman et al.
2019). In this study, types of complications were detailed; the
Perioperative Mortality and Morbidity
In the prior edition of this text published in 2009, the mortality
associated with an elective liver resection for colorectal metastases was reported as less than 5%, ranging from 1–7% (Doci
et al., 1991; Belli et al. 2002; Busuttil 1974; Choti et al. 2002;
Fong et al. 1999; Foster 1978; Hughes et al. 1986; Jamison et al.
1997; Kato et al. 2003; Minagawa et al. 2000; Mutsaerts
et al. 2005; Nordlinger et al. 1996; Rosen et al. 1992; Scheele et al.
1995a; Schlag et al. 1990; Wei et al. 2006; Younes et al. 1991)
(Table 2). The majority of those deaths were from perioperative
hemorrhage, liver failure, or sepsis. In 2010, a cohort of 1,600
was reported from Memorial Sloan Kettering, showing that
30-day mortality decreased from 2% for patients treated from
1985 to 1998 (n=1037) to 0.5% for those treated from 1999 to
2004 (n=563). More recently, 30-day mortality rates were again
reported as <1% from the American College of Surgeons NSQIP
database from 2014 to 2016 (Wiseman et al. 2019). Mortality
was associated with operative time >6 hours, use of the Pringle
maneuver, and biliary reconstruction.
two most common were blood transfusion within 72 hours
(16%), and surgical site infection (10%). Other common complications were readmission (9%), post-operative intervention
(8%), bile leak (6%), and post-operative liver failure (5%)
(Wiseman et al. 2019). Complications were more likely in
patients who underwent open operations, had operations >4
hours, those who underwent major hepatectomy, simultaneous
colectomy, and had tumor resection size >5 cm (Wiseman et al.
2019). Peri-operative mortality was 21/2832 (0.7%). Previously,
pulmonary complications were a significant source of morbidity for these patients. In 1985, Coppa et al. reported that
5–10% of pleural effusions may be sufficiently symptomatic to
require tube thoracostomy (Coppa et al. 1985), and in 1990,
Schlag et al. reported that pneumonia occurred in 5–22%
(Schlag et al. 1990). The risk of pulmonary complications have
now decreased substantially – pneumonia occurs in 3%, failure
to wean from the ventilator in 1%, and re-intubation in 2%
(Wiseman et al. 2019). Concordant with decreasing complications, length of hospitalization for colorectal liver metastasectomy has also decreased in the United States. We previously
reported the usual hospital stay in major centers after a major
Median
months
350 3 HEPATOBILIARY AND PANCREAS CANCER
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liver resection is generally less than two weeks (Fong et al.
2005). In contrast, the American College of Surgeons NSQIP
database study from 2014 to 2016, the mean length of stay was
only 6.3 days, and 95% of patients were discharged home
(Wiseman et al. 2019). This may be in part due to a difference
in approach that has evolved regarding sparing of parenchyma
(discussed in more detail under “Margin Status”).
Long-term Outcomes
A number of series now have sufficiently long follow-up for us
to be confident that 10-year survival after hepatectomy can be
expected in 20–30% of patients (Table 2) (Fong et al. 1999;
Minagawa et al. 2000; Wei et al. 2006). In House et al. recurrence free, disease free, and overall survival were compared for
patients treated before 1999, and from 1999 to 2004. These
authors found that patients with a low clinical risk score (<3)
had median disease specific survival before 1999 of 54 months;
this increased to 87 months for the later time period (House
et al. 2010). Patients with a clinical risk score of 3+, however,
had similar median disease specific survival regardless of time
period (House et al. 2010). This was similarly shown in a large
cohort study from Germany; patients who had <3 colorectal
liver metastases and underwent resection had improved 1, 5,
and 10-year overall survival compared to those with >3 (Hackl
et al. 2014).
Margin Status and Surgical Approach
It is largely believed that margin status impacts long-term oncologic outcomes for patients undergoing resection of colorectal
liver metastases. Questions arise here regarding method of
resection (anatomic wedge) and oncologic value of microscopic
margins (R1 vs R0). Traditionally, anatomic resections were
advocated for metastatic colorectal cancer because of the high
likelihood of a positive margin for wedge resections, but this is
no longer the case. In a classic series from Johannes Scheele,
wedge resections were associated with a positive margin rate of
19% (Scheele et al. 1995b). DeMatteo et al. reviewed resected
colorectal liver metastases from the Memorial Sloan-Kettering
Cancer Center and found that wedge resections had higher rates
of margin positivity when compared to anatomic segmental
resection (16 vs 8%) (DeMatteo et al. 2000). This translated into
a significant difference in median overall survival, favoring
those who underwent anatomic resection (38 vs 50 months)
(DeMatteo et al. 2000). This was likely due to the difficulty in
judging margins of the tumor deep in the parenchyma. Wedge
resections are also complicated by the fact that the transection
line tends to fracture at the interface of the hard colorectal
tumor and soft normal liver. Following the hepatic veins during
a segmental resection evolved to assist the surgeon in achieving
a negative margin. Later studies showed no difference between
wedge and anatomic resections for complications or one, three,
and five-year survival (Zorzi et al. 2006). A recent meta-analysis
of more than 2500 patients undergoing resection for colorectal
liver metastases concluded that both margin status and overall
survival were similar between the wedge and anatomic resections (Moris et al. 2017). This is likely due to expertise of surgeons at present for choosing to use either wedge or segmental
resections to achieve a low rate of margin positivity.
Regarding how margins should be assessed, Sadot et al.
examined 2368 patients who underwent hepatic resection for
metastatic colorectal cancer from 1992 to 2012, and found
that margin clearance of 1mm or more was associated with
improved overall survival, compared to those with sub-millimeter margin clearance (Sadot et al. 2015). In another smaller
case series of 334 patients from 2018, R1 resection again had
worse survival compared to those with negative margins (RR
3.2, 95% CI 2.0–5.2), but there was no difference for patients
with 0–1mm margins vs >1mm margins (Makowiec et al.
2018). R1 vs R0 status was important for patients with and
without neoadjuvant chemotherapy treatment (Makowiec
et al. 2018), but surprisingly did not affect one- and threeyear hepatic recurrence rates (R0 – 38%, 73% vs R1 – 36%,
68%, respectively) (Makowiec et al. 2018). Others have challenged the value/necessity of an R0 resection from an oncologic perspective. While some perform routine frozen margin
assessment with re-resection to negative margins if technically feasible (Makowiec et al. 2018), the value of re-resection
after identifying an R1 margin on frozen pathology has been
questioned. In a cohort of 332 patients, 74% had R0 resection,
18% had an R1 resection, and 7% initially had an R1 resection
identified on frozen section that was converted to an R0
resection by removal of additional tissue (Margonis et al.
2015a). In this study, margin status was not associated with
disease free survival, overall survival, or incidence of intrahepatic recurrence (Figure 1) (Margonis et al. 2015a). A
notable limitation of this study was the sample size, however,
making it difficult to detect differences in outcomes between
groups (Margonis et al. 2015a). The authors utilize selective
frozen margin assessment after rapid gross evaluation of the
specimen with our pathology colleagues. Frozen margins are
obtained if there is concern for margin involvement on rapid
gross assessment. During this time down-time, we place a
clean laparotomy pad (or baby laparotomy pad if minimally
invasive) in the resected bed to assess for bile leakage after
gross and frozen evaluation have been completed.
It should also be noted that minimally invasive surgery is
now within the standard of care for many operations,
including liver metastasectomy surgery. The Da Vinci robotic
surgical system uses technologically sophisticated equipment
to facilitate minimally invasive operations with wristed
A B
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1.00
0.80
R0
R1
R1>R0
19 MANAGEMENT OF METASTIC LIVER CANCER 351
1.00
0.80
R0
R1
R1->R0
0.60
0.40
0.20
Proportion of patients disease-free
0.00
Figure 1 Unadjusted recurrence free (a) and overall (b) survival of patients undergoing hepatic resection for colorectal liver metastases stratified by
margin status. Note that margin status was not associated with recurrence free or overall survival on multivariable analyses after adjusting for competing
risk factors (Margonis et al. 2015a/Springer Nature).
Log-rank: P = 0.93 Log-rank: P = 0.54
12 24 36
Time (months)
48 600 12 24 36
articulating instruments and three-dimensional visualization.
Liver surgery is increasingly being performed with the robotic
platform (Lafaro et al. 2020) which has certain advantages
over laparoscopic and open surgical techniques. Some of
these potential advantages include surgeon ergonomics,
enabling a minimally invasive approach for more superior
and posterior segment lesions, faster learning curve, superior
visualization, and facilitating the use of indocyanine green,
and the potential for use of intra-operative liver navigation
(Table 3). The patients who are best suited for a minimally
invasive approach are those who otherwise would undergo an
“incision dominant” open operation, where a large incision is
required to remove a small volume of liver parenchyma
(Stewart et al. 2021). Our group has reported previously that
0.60
0.40
Proportion of patients alive
0.20
0.00
Time (months)
48 600
minimally invasive techniques for liver metastasectomy,
which are beyond the scope of this chapter (Fong and
Blumgart 1997; Lafaro et al. 2020). In sum, given the known
benefits of minimally invasive surgery, including for liver surgery, and the technical advantages afforded by the robotic
surgical system, the authors recommend consideration for a
robotic approach in select patients, particularly those planned
for minor hepatectomy.
In conclusion, not only is there no doubt that resection prolongs survival in patients with isolated colorectal liver metastases, resection can produce cure from this stage IV cancer.
Surgical resection has therefore become standard therapy and
treatment of choice for metastatic colorectal cancer isolated to
the liver.
the majority of patients who undergo minor robotic liver
resections have hospitalizations of three days or less (Melstrom
et al. 2018) and that patients who undergo minor robotic liver
resections have fewer complications and shorter length of stay
compared to open operations, resulting in overall lower cost
(Stewart et al. 2021). We have previously reported complete
descriptions of surgical techniques related to open and
Pushing the Limits of Resection
There is a subset of patients anticipated to have an insufficient
future liver remnant after removal of all visible hepatic metastatic disease, who may otherwise be good surgical candidates.
For these patients, a number of techniques exist to augment the
Table 3 Advantages and limitations of robotic liver surgery (Stewart and Fong 2021/Springer Nature).
Advantages Limitations
• Surgeon ergonomics • Inability to palpate the liver
• Enables minimally invasive surgery for superior
and posterior liver segment resections
• Faster learning curve • Additional operative time to dock and undock
• Superior visualization, facilitates use of
indocyanine green imaging
• Potential for intra-operative liver navigation • Increased operative cost
• Increased incision size to remove larger specimens
may negate the benefits of smaller initial incisions
• Potential for argon gas vascular embolization
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anticipated future liver remnant (FLR) and stave off the dreaded
complication of post-hepatectomy liver failure. Some strategies
that have been employed for these patients are portal vein
embolization (discussed further below), portal vein ligation,
two-stage hepatectomy, and more recently Associated Liver
Partition and Portal vein ligation for Staged hepatectomy
(ALPPS) (Michal et al. 2020).
Two stage hepatectomy can be employed in patients who
present initially with unresectable bilobar disease due to an
insufficient future liver remnant. Often, the greater burden of
disease is resected first, occasionally with concomitant additional tumor ablation, portal vein ligation, and/or embolization
(Lam et al. 2013). The goal is to complete the second stage of
the hepatectomy to resect the remaining disease; however,
there is a risk of interval disease progression, continued inadequate FLR, portal venous injury/thrombosis, and patient death
after the first stage (Lam et al. 2013). In a meta-analysis from
2013, the authors found that 69–92% of patients progressed to
the second stage hepatectomy, and that median overall survival
for patients after the second stage was 24–44 months (Lam
et al. 2013). More recent publications show similar rates of noncompletion of the second stage and overall survival (Cunha
et al. 2019; Mor et al. 2019). ALPPS is a two-stage hepatectomy
variant, initially described in 2011 (Baumgart et al. 2011),
intended to induce rapid functional liver remnant hypertrophy,
enabling the second stage of the procedure to be performed in
7–14 days (Schnitzbauer et al. 2012). In the first operation of
this two-staged technique, segment 4 is completely devascularized by separating the liver parenchyma from the falciform
ligament (i.e., liver partition) and the right portal vein is ligated
(Torres et al. 2013). Early reports regarding this technique created concern regarding the high morbidity and mortality.
Traunt et al. reported on a series of 62 patients who underwent
ALPPS from 2011 to 2013, with 40% morbidity, including
many with complications after the first stage, and 13% mortality
(Truant et al. 2015). An ALPPS Risk Score was developed after
examining 528 patients, to facilitate identification of the 9%
patients who will have three-month or in-hospital mortality
after stage 1 surgery (Linecker et al. 2016). Factors increasing
risk before stage 1 of surgery were non-colorectal liver metastases and age >67 years old. Factors increasing risk before stage
2 surgery were complications after stage 1, elevated bilirubin,
and elevated creatinine (Linecker et al. 2016). More recently,
the LIGRO trial published in 2018 compared ALPPS to usual
two-stage hepatectomy with portal vein embolization in 100
non-cirrhotic patients with colorectal liver metastases treated
with neoadjuvant chemotherapy and responding or stable disease, requiring liver resection, but not resectable in one step
because of a future liver remnant/standardized total liver
volume ratio of <30% (Sandström et al. 2018b). They reported
a resection rate of 92% in the ALPPS arm compared to 57% in
the two-stage hepatectomy arm (P < 0.0001) (Sandström et al.
2018b). Of the 48 eligible patients in the ALPPS arm, 41 reached
a functional liver remnant (FLR) more than 30% within 7 days,
and another 3 reached a FLR more than 30% within 14 days
(92%). By comparison, in the two-stage hepatectomy group,
28/49 (57%) of the patients reached 30% FLR without tumor
progression; 14 (29%) patients after 7 days, 9 (18%) patients
after 4 weeks, and 5 (10%) patients within 7 weeks (Sandström
et al. 2018b). The 90-day mortality from the final intervention
for patients who completed treatment was 4 (9.1%) in the
ALPPS group and 3 (10.7%) in the two-stage hepatectomy
group (P = 0.64). Thus, mortality from this aggressive approach
remains much higher than patients who can undergo resection
in a single stage. The authors of the LIGRO trial did report,
however, that mortality was limited to patients with a MELD
score >9 or an ALPPS risk sore >5 before the second intervention (Sandström et al. 2018b). The first long-term oncologic
outcomes from ALPPS were published in 2020, and reported
90-day mortality of 4.9%, median overall survival of 39 months,
and recurrence free survival of 15 months (Petrowsky et al.
2020). Therefore, this approach may be considered within the
context of a multidisciplinary environment in a high-volume
hepatobiliary center with well-selected patients.
Liver transplant for non-resectable colorectal liver metastases has been attempted. In a series of 21 patients with nonresectable colorectal liver metastases treated with liver transplant
from 1983 to 1994 at the Medical University of Vienna, 3
patients had genetic and histologically negative lymph nodes
and experienced a median overall survival of 118 months
(Kappel et al. 2006). In 1991, a series from the University of
Cincinnati reported that liver transplant for liver metastases
had a 59% recurrence rate (Penn 1991). These authors concluded that liver transplant for metastatic disease generally
should not be performed. A prospective pilot study was conducted at Oslo University Hospital to further examine liver
transplant in 21 patients with nonresectable colorectal cancer
from 2006 to 2011 (Hagness et al. 2013). A third of patients
experienced a complication requiring intervention, and metastatic or local recurrence was detected in 19/21 patients after a
median of 6 months (Hagness et al. 2013). These authors later
compared outcomes of the patients who underwent liver transplant to patients who were treated with FLOX chemotherapy
with or without cetuximab in the NORDIC VII trial (Dueland
et al. 2015). For patients undergoing liver transplant, the fiveyear overall survival rate was 56% compared with 9% of patients
starting first line chemotherapy, however, patients had similar
disease-free survivals of 10 and 8 months, respectively. The
potential reason for this discrepancy between disease-free and
overall survival was thought by the authors to be a difference in
metastatic patterns of relapse and progression (Dueland et al.
2015). Additional randomized trials are underway to further
evaluate the utility of liver transplant for nonresectable colorectal liver metastases (Gorgen et al. 2018), but at the time of
19 MANAGEMENT OF METASTIC LIVER CANCER 353
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this writing, transplantation for nonresectable remains outside
the standard of care.
lower for these patients than patients undergoing initial
hepatic mastectomy, at 11–21% (Andreou et al. 2011; Fukami
et al. 2017; Neal et al. 2017). One study further classified these
patients into those who had effective salvage therapy, and
Sites of Recurrence and Re-resection
The patterns of recurrence in patients who are not cured by
hepatectomy have been well documented (Table 4). Since the
liver is a common site for recurrence after hepatectomy,
treatment of such recurrences constitutes an important part of
the overall treatment plan for patients.
As liver surgeons have become increasingly comfortable
with liver resections, an increasing number of repeat hepatec-
found that 25% of patients who underwent repeat hepatectomy achieved at least 36 months free of recurrent disease
(Butte et al. 2015). While undoubtedly these findings include
the effects of selection bias (these patients tend to be younger,
have negative margins from their first liver resection, and
have smaller tumors (Butte et al. 2015)), they nevertheless
demonstrate that repeat hepatectomy can be life-extending
when performed on a select cohort of patients.
tomies are being performed as treatment for recurrent disease. Table 5 summarizes the data for such repeat
Prognostic Variables and Scoring Systems
hepatectomies. These repeat hepatectomies are considered
safe, and in many modern series, five-year survival after second resection is reported to be over 40%. The number of
patients being treated with repeat hepatectomy has increased
over time, survival has been prolonged, and morbidity is
Table 4 Sites of initial recurrence after liver resection for colorectal metastasis.
Study n Recurrences Liver Liver and other Lung Colon/ Rectum
Clinical scoring systems are frequently used for predicting
outcomes in medicine. These scoring systems take into account
that patient outcomes such as morbidity and mortality are seldom
based on a single variable and generally are multi-factorial in
Nordlinger 1987 (Nordlinger et al. 1987) 80 51 (64) 21 (42) 13 (26) 11 (22) 11 (22)
Hohenberger 1990 (Hohenberger et al. 1990) 122 80 (66) 17 (14) 55 (45) – –
Hughes 1992 (Maeda et al. 1992) 607 424 (69) 149 (35) 42 (10) 73 (17) 33 (8)
Suzuki (Suzuki et al. 1997) 64 45 (70) 31 (48) – 16 (25) –
Butte 2015 (Butte et al. 2015) 952 594 (62) 157 (26) 167 (28) 9 (2)
Hallet 2016 (Hallet et al. 2016) 2320 1099 (47) 473 (43) 225 (20) 176 (16)
Fukami 2017 (Fukami et al. 2017) 282 193 (68) 78 (40) 47 (25)
Neal 2017 (Neal et al. 2017) 488 338 (69) 152 (31) 231 (47)
Gagniere 2020 (Gagnière et al. 2020) 1467 821 (56) 222 (27) 376 (46) 220 (27)
Takamoto 2020 (Takamoto et al. 2020) 296 247 112 (45)
n = number of patients (%).
Table 5 Results of repeat hepatic resections.
Author Resected Mortality 2-year survival 5-year survival
Elias 1993 (Elias et al. 1993) 28 1 (4) 30 –
Fong 1994 (Fong et al. 1994) 25 0 (0) 30 –
Yamamoto 1999 (Yamamoto et al. 1999) 75 0 (0) – 23
Muratore 2001 (Muratore et al. 2001) 29 1 (3) – –
Suzuki 2001 (Suzuki et al. 2001) 26 0 (0) – 31
Petrowsky 2002 (Petrowsky et al. 2002) 126 2 (2) – 43
Shaw 2006 (Shaw et al. 2006) 66 1 (2) – 44
Andreou 2011 (Andreou et al. 2011) 43 0 (0) 73
Butte 2015 (Butte et al. 2015) 160 65
Fukami 2017 (Fukami et al. 2017) 62 2 (5)
Neal 2017 (Neal et al. 2017) 71 0 (0) 48
Takamoto 2020 (Takamoto et al. 2020) 122 0 (0) 51
– Data not specified.
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nature. While physicians may have a working knowledge of
positive or negative influences on the outcomes, understanding
the most important variables and assessing the weight of these
variables in patients can be difficult. For the surgeon, challenges arise when determining who should be offered an operation and also when providing information regarding
prognosis, especially when patients are perceived to possess
both favorable and poor prognostic features. Beyond risk stratification, clinical scoring systems importantly facilitate communication between physicians and assist in patient selection
for participation in clinical research. As surgeons continue to
push the limits of their technical ability, the question “can an
operation be done?” shifts to “should an operation be done?”
Patients with colorectal cancer liver metastases openly lend
themselves to this type of stratification, since a percentage of
these patients will be cured with surgery, whereas a percentage
will likely incur little or no benefit (Stewart and Fong 2020).
The traditional TNM staging systems classifies all patients with
colorectal liver metastases in the same category: stage IV.
Clearly, however, the patient with a solitary metastasis found
four years after resection of a node-negative primary is very
different from a patient found with bilobar multiple metastases
synchronous to discovery of a node-positive primary.
Prognostic Factors
The stage of the primary is a major determinant of outcome; in
particular, regional nodal positivity is a powerful predictor of
recurrence (Fong et al. 1999; Hughes et al. 1989; Nordlinger et
al. 1996; Scheele et al. 1995a). Synchronous presentation of
liver metastases also predicts poor outcome (Ballantyne and
Quin 1993). Further, patients with right sided colonic primary
tumors have shorter median recurrence free survival compared
to those with tumors on the left (1.3 vs 1.7 years) and shorter
median overall survival (3.6 vs 5.2 years) (Creasy et al. 2018b).
Short disease-free interval between primary cancer and hepatic
metastases is associated with poor outcome (Hughes et al.
1986; Rosen et al. 1992). Other parameters associated with
poor outcome include large size of tumor (Hughes et al. 1986;
Stephenson et al. 1988), multiple tumors (Hughes et al. 1986;
Rosen et al. 1992), bilateral tumors (Hughes et al. 1986; Rosen
et al. 1992), and high carcinoembryonic antigen (CEA) levels
(Hughes et al. 1986; Rosen et al. 1992). As mentioned earlier,
margin status also plays a role in the oncologic outcome after
metastasectomy.
KRAS, NRAS, and BRAF mutational testing has become
important in the assessment of metastatic colorectal cancer,
since they serve as biomarkers for response to anti-EGFR
inhibitors (Douillard et al. 2013; Lievre et al. 2006). They also
serve prognostically for patients with colorectal liver metastases undergoing resection. A meta-analysis of 11 studies and
1833 patients with colorectal liver metastases who underwent
complete liver resection found that KRAS mutation and BRAF
mutation were associated with statistically shorter overall
survival (Lievre et al. 2006; Tosi et al. 2017). KRAS mutations
were found in 14–46% of patients, whereas BRAF was only
identified in 2% of patients (Tosi et al. 2017). The largest study
included in this meta-analysis included 334 patients, and
showed that KRAS mutation, lymph node metastases, CEA >30
ng/ml, and ablation were all independently associated with
decreased overall survival in this patient population (Margonis
et al. 2015b). KRAS mutant status is associated with more frequent micro-metastases and positive margins after resection
(Zhang et al. 2020). Another systematic review of 78 studies
including all patients with colorectal liver metastases and
details on KRAS, BRAF, PI3K, and TP53 was performed in
2018 (Tsilimigras et al. 2018). In this study, KRAS mutations
were identified in 25–52% of patients. A study of 4124 patents
who underwent hepatectomy for colorectal liver metastases
found that BRAF mutations were present in 35 (2%) of the
patients (Gagnière et al. 2020). These patients more often had
multiple synchronous tumors, and had a significantly lower
median recurrence free survival (10 vs 22 months, p<0.001),
and overall survival (40 months vs 81 months, p<0.001)
(Gagnière et al. 2020). It has also been reported that KRAS
mutant circulating cell-free tumor DNA is associated with
shorter overall survival, and that the combination of high
(>3.33%) KRAS mutant cell-free tumor DNA with CEA >4.5
ug/L best predicted shorter overall survival after surgery
(Polivka et al. 2020). Of note, there is a proportion of patients
with KRAS mutation discordance; one study reported 15.9% of
patients had discordant KRAS testing of the colorectal primary
and liver metastases (Ardito et al. 2021). Discordance can occur
both in patients with KRAS mutant and wild type colorectal
tumors (Ardito et al. 2021).
Scoring Systems
We recently reviewed scoring systems for colorectal liver
metastases (Stewart and Fong 2020). The time frame of
patients used to develop these scoring systems ranges from
1960 to 2016. Throughout this time the management of these
patients has changed significantly, however, most notably
with the advent of “modern” chemotherapy options, including
irinotecan, first approved in 2000, and oxaliplatin approved in
2002. These combinations of treatments doubled median
overall survival for metastatic colorectal cancer from 10 to 20
months (Kelly and Goldberg 2005). Antibody therapies
including drugs that target vascular endothelial growth factor
(VEGF), such as bevacizumab, and the epidermal growth
factor receptor (EGFR) pathway, such as cetuximab, came in
the 2000s–2010s. Further, immune checkpoint inhibitors
such as pembrolizumab have subsequently become used in
patients with microsatellite instability. The biological features
which are indications for use of these newer drugs have
known prognostic implications on their own (Wu 2018), as
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Fong scoring system
Colorectal cancermetastaticto
(B)(A)
1. 0
.8
lymph nodes
Disease-free interval from the
.6
primarytodiscoveryof the liver
metastases <12 months;
Survival
.4
Number of tumors in the liver >1;
Pre-operative CEA level >200
.2
ng/ml;
Size of the largest liver tumor >5
cm.
Figure 2 Fong Clinical Scoring System. Scoring system variables (A) and overall survival curve demonstrating stratification between groups (B) in Fong
et al. (1999)/Wolters Kluwer Health, Inc..
described in more detail below, thus significantly impacting
outcomes for these patients. The most common variables
included in scoring systems for predicting outcome after
0.0
12
24
36 48 600
Months
T-stage of primary tumor, and presence of bilobar tumors,
have all been included in various scoring systems (Stewart
and Fong 2020).
resection of colorectal liver metastases are pre-operative laboratory values (often CEA), tumor size, number of tumors,
nodal status of the primary colorectal tumor, and disease free
interval (Stewart and Fong 2020). These factors are all taken
into consideration with the Fong Clinical Risk Score (Figure
2), a frequently cited scoring system created in 1999 by Fong
et al., utilizing data of 1001 patients treated from 1985 to 1999
at the Memorial Sloan-Kettering Cancer Center (Fong et al.
1999). In this study, there was a 2.8% perioperative mortality
rate, and the five-year survival after liver resection was 37%.
The authors performed regression analyses to identify features that correlated with disease-free and overall survival,
resulting in the selection of five clinical criteria, each getting
one point: positive colorectal lymph nodes, disease-free
interval < 12 months, number and size of liver tumors, and
preoperative CEA level. When this scoring system was
applied, the five-year survival correlation coefficient was r
0.92; patients with 0 points had a five-year survival of 60%,
compared to 14% for patients with 5/5 points (Fong et al.
1999). This score was superior to prediction based on a
number of tumors alone and was considered more practical
than scores created by other authors, since all criteria could
generally be known prior to surgery (excluding patients with
planned synchronous resections). Other factors have since
been considered for inclusion in similar scoring systems,
including KRAS/NRAS status, progressive or stable disease
according to RECIST criteria, presence of extra-hepatic disease, tumor differentiation, location of primary tumor,
Neoadjuvant Use of Chemotherapy
Systemic therapies are an important part of the treatment
plan for patients with colorectal liver metastases and are
further described in the following section of this chapter
from the medical oncologist’s perspective. It should be
acknowledged, however, that in patients who are considered
potential surgical candidates, the surgeon plays a critical role
in determining the timing of systemic therapy. Further, che-
motherapy can affect the quality and function of the liver,
which may also be a factor when considering surgery. Thus,
the following data are presented for consideration when sur-
gery may be offered.
In a cohort study from Memorial Sloan Kettering from 1999
to 2004, 66% of patients received neoadjuvant chemotherapy,
and 65% received adjuvant chemotherapy (House et al. 2010).
2
=
In a cohort study from Johns Hopkins from 2003 to 2015, 79%
of patients received neoadjuvant chemotherapy and 35% also
received a biologic agent (Margonis et al. 2016). This trend has
persisted since then; in a study of the American College of
Surgeons NSQIP database from 2014 to 2016, 60% of patients
who underwent partial hepatectomy for colorectal liver metastases received neoadjuvant chemotherapy (Wiseman et al.
2019). Thus, use of chemotherapy prior to liver resection for
colorectal liver metastases is used quite commonly. Neoadjuvant
chemotherapy may be used to treat occult metastases, test
tumor biology, and has been shown to improve progression
free survival, but remains a subject of significant debate in
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