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patients with up-front resectable isolated liver metastases. In a
randomized controlled trial accruing from 2000 to 2004,
Nordlinger et al. compared peri-operative chemotherapy (six
cycles of FOLFOX4 before and six cycles after) with partial
hepatectomy to partial hepatectomy alone for patients with 1–4
colorectal liver metastases (Nordlinger et al. 2008). The initial
report, published in 2008, found an improvement in per protocol three-year progression free survival in the peri-operative
chemotherapy group (36% vs 8%, p = 0.04) (Nordlinger et al.
2008). Of the 182 patients initially randomized to peri-operative chemotherapy, 40% had a partial response, 38% had stable
disease, and 7% had progression of disease (Nordlinger et al.
2008). The final report published in 2013, however, demonstrated no difference in five-year overall survival (51% in the
perioperative chemotherapy group, 49% in the surgery only
group) (Figure 3) (Nordlinger et al. 2013). The CHARISMA
trial (ClinicalTrials.gov ID NCT04513457) which enrolled 967
patients from 2010 to 2020, is comparing the outcomes of neoadjuvant oxaliplatin-based chemotherapy followed by surgery
versus surgery alone in high-risk patients with resectable isolated colorectal liver metastases (Van Der Stok et al. 2016).
Results of this study have yet to be published. The approach we
recommend is a selective use of neoadjuvant chemotherapy.
For patients with a high risk of recurrence, such as those with a
high clinical risk score (discussed in more detail below), particularly patients with synchronous disease, and those with a
lymph-node positive primary, neoadjuvant therapy can also be
justified.
In comparison to patients who present with isolated resectable liver metastases, there is a clear role for using chemotherapy in patients with initially unresectable disease to
facilitate potential R0 resection in the future. In the FIRE-3
trial, patients with unresectable RAS wild type metastatic
colorectal cancer were randomized to FOLFIRI with either
cetuximab or bevacizumab; in a subgroup analysis of patients
liver limited disease, 29/133 (22%) patients underwent hepatic
resection with curative intent with a median overall survival of
56 months (Holch et al. 2018), which was significantly longer
than patients who did not undergo hepatic resection (HR 0.55,
p = 0.03) (Holch et al. 2018). In a similar study, the CRYSTAL
randomized controlled trial compared FOLFIRI ± cetuximab
in patients with RAS wild type metastatic colorectal cancer;
10/89 (11%) with liver limited disease ultimately underwent R0
resection (Köhne et al. 2016). In the CELIM trial, patients with
either technically unresectable or >5 colorectal liver metastases
were randomized to cetuximab with FOLFOX6 or FOLFIRI. In
this study, resectability rates increased from 22/68 (32%) at
baseline to 41/68 (60%) after receipt of chemotherapy, and
49/106 (46%) patients ultimately underwent R0 resection or R1
and/or ablation (Folprecht et al. 2010). In this study, assessment
of resectability was evaluated by seven participating surgeons,
and agreement amongst all seven surgeons occurred in only
65% of decisions (Folprecht et al. 2010). Thus, indications to
proceed with hepatic resection in these types of patients is
nuanced and subject to debate, highlighting the importance of
a multi-disciplinary discussion (Folprecht et al. 2010).
Chemotherapy-Associated Liver Injury (CALI)
While the advent of more effective chemotherapy regimens has
increased the number of patients with hepatic colorectal metastases who are eligible for curative-intent surgical resection,
multiple chemotherapeutic agents have been found to cause
histopathologic hepatic changes ranging from steatosis to more
severe steatohepatitis, sinusoidal injury, and nodular regenerative hyperplasia. The types chemotherapy-associated liver
Figure 3 Kaplan-Meier curves of overall survival in all randomly assigned patients (A) and all eligible patients (B) per treatment group of patients with
1–4 colorectal liver metastases. Peri-operative chemotherapy = six cycles of FOLFOX4 before and six cycles after partial hepatectomy. Surgery
only = Partial hepatectomy alone. Adapted from Nordlinger et al. (Nordlinger et al. 2008, 2013).
19 MANAGEMENT OF METASTIC LIVER CANCER 357
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injury (CALI) have varying effects on postoperative morbidity
and mortality and appear to be regimen specific. Clinical features include hepatic fatty infiltration and splenomegaly from
portal hypertension, which can both be recognized on preoperative axial imaging, and refractory thrombocytopenia
(Figure 4). The damage can progress to fibrosis and cirrhosis of
the liver. The thrombocytopenia is consumptive and not related
to bone marrow suppression. Therefore, it is not corrected even
when chemotherapy is stopped.
Steatosis is characterized by accumulation of fat in hepatocytes, while steatohepatitis consists of steatosis associated with
inflammatory foci and enlargement (ballooning) of hepatocytes (Kleiner et al. 2005). Whereas 5-FU has been associated
with steatosis, which that is generally considered less clinically
significant, irinotecan has been linked to steatohepatitis which
is associated with increased rates of postoperative liver insufficiency and mortality. In a study of 248 patients receiving preoperative chemotherapy followed by resection of colorectal
liver metastases, 20% of patients who received irinotecan were
found to have steatohepatitis. Patients with steatohepatitis had
significantly higher 90-day mortality compared with patients
without steatohepatitis (14.7% v 1.6%, OR=10.5, P = .001)
(Vauthey et al. 2006). A systematic review and meta-analysis
by the international CALI consortium found that severe steatosis was not significantly associated with postoperative
overall or major morbidity but was related to a decreased rate
of liver surgery-specific complications (OR 0.52, p = .05). In
contrast, patients with steatohepatitis had increased rate of
postoperative liver surgery-specific complications (OR 2.08,
p = .012) (Zhao et al. 2017).
Oxaliplatin is associated with sinusoidal obstruction syndrome (SOS), which has been associated with perioperative
morbidity and encompasses several different histopathologic
lesions including sinusoidal dilatation, nodular regenerative
hyperplasia (NRH), peliosis, and centrilobular fibrosis (RubbiaBrandt et al. 2010; Soubrane et al. 2010). Among these, NRH is
of particular concern given its increased risk of postoperative
liver failure and portal hypertension (Viganò et al. 2015). In a
study of 406 patients undergoing liver resection after chemotherapy between 2000 and 2012, NRH was identified in 87/406
(21%) of patients, and was more often found in patients after
treatment with oxaliplatin (21% vs. 8%, p = 0.003). NRH was an
also independent predictor of postoperative liver failure (9%
with NRH vs. 2% without, p = .02), especially those with higher
grades of NRH (grade 2 – 14.3%; grade 3 – 25%) after major
hepatectomy (Viganò et al. 2015). Conversely, the addition of
bevacizumab to oxaliplatin appears decrease both incidence
and severity of SOS and NRH (Ribero et al. 2007b; RubbiaBrandt et al. 2010; Viganò et al. 2015). Rubbia-Brandt et al.
found that in 274 patients who underwent resection of colorectal liver metastases after oxaliplatin therapy, 54% had
moderate/severe SOS, 25% developing NRH. In patients treated
with oxaliplatin and bevacizumab the incidence of moderate/
severe SOS and NRH were both significantly lower (31% vs.
62%, p<0.01; 11% vs. 29%, p<0.01, respectively) (RubbiaBrandt et al. 2010).
The impact of the number of neoadjuvant chemotherapy
cycles on liver regeneration remains unclear. While some
studies have described lower regeneration rates after more than
six cycles of treatment, other studies have not found such
Figure 4 Typical radiologic findings for chemotherapyassociated steatohepatitis. CT of the abdomen demonstrates
steatosis of the liver as indicated by the liver being darker than
the spleen. Splenomegaly is also seen. The third part of the
triad that characterizes this syndrome is a thrombocytopenia
due to increased clearance of platelets by the spleen.
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differences. Another consideration is the time interval between
completion of chemotherapy and hepatic resection and the
types of chemotherapy, as mentioned earlier. Many patients
subjected to second- and third-line therapies remain candidates for liver resection, whereas in years past, most patients
failing first-line therapy were unlikely to be offered surgery.
Thus, CALI has become increasingly more commonplace, and
therefore is important to recognize.
Portal Vein Embolization and Preoperative
Imaging
The development of CALI is not purely academic, as it may
lead to additional interventions including preoperative portal
vein embolization (PVE) to grow the future liver remnant
(FLR) before resection. PVE is discussed in more detail under
the Interventional Radiology section of this chapter but is
reviewed here in brief here from the surgeon’s perspective,
along with data related to pre-operative imaging.
Originally, clinicians suggested using PVE when the planned
remnant liver after resection was less than 25% of total
functional liver (Hemming et al. 2003). The safe cut-off for
major hepatectomy was then moved to 20% future liver remnant for patients with otherwise normal livers that had not
been exposed to chemotherapy (Kishi et al. 2009). Shindoh
et al. later reported on a series of 194 patients undergoing major
hepatectomy and found that pre-operative chemotherapy
beyond 12 weeks was significantly associated with post-hepatectomy liver insufficiency (Shindoh et al. 2013c). In patients
with an FLR less than 30%, post-hepatectomy liver insufficiency occurred in only two patients, both with chemotherapy
durations more than 12 weeks, but all patients with a FLR
greater than 30% survived (Shindoh et al. 2013c). Thus, at this
time cut-off values of 20% FLR for otherwise normal livers, and
30% FLR for livers exposed to chemotherapy are generally used
when considering major hepatectomy and the risk of post-hepatectomy liver insufficiency and failure. Degree of hypertrophy
and growth rates after PVE also serve as predictors of outcome
after major hepatectomy (Leung et al. 2014). This was demonstrated by Leung et al., who reported that no patients in their
series of 153 patients experienced liver failure when growth
rate was greater than 2.66%/week (Leung et al. 2014). Low
growth rates however were highly predictive of post-hepatectomy liver failure.
Pre-operative imaging is critical to any discussion regarding
assessment of FLR since the goal of surgical intervention is to
address known metastatic disease. While practice varies, the
evidence suggests that the best methods for detection of colorectal liver metastases are contrast enhanced multi-phase
computed tomography (CT) scan and magnetic resonance
imaging (MRI). Current generation helical CT with contrast
enhancement of vasculature is invaluable in determining
number of lesions, relationship to lesions of vascular structures,
and potential involvement of neighboring organs. MRI, however, has been shown to be more sensitive than CT for lesions
smaller than 10mm (Niekel et al. 2010). Further, contrast agents
such as gadoxetic acid are increasingly being used to identify
metastatic lesions. Gadoxetic acid (marketed as EOVIST in the
United States (Eovist (gadoxetate disodium) solution label –
Accessdata.fda.gov 2010)) is taken up by hepatocytes, allowing
combined dynamic imaging and hepatocyte-specific imaging in
one examination (Zech et al. 2007). Sensitivity for identifying
colorectal liver lesions using gadoxetate contrast enhanced MRI
has been reported to be 90–95% vs 72–75% for multi-phase
contrast enhanced CT scan (Granata et al. 2019). The CAMINO
study is an international multicenter prospective study evaluating whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM (Görgec et al. 2021).
At this time, in our practice, we generally obtain both contrast
enhanced CT and MRI pre-operatively given the value of both
imaging modalities.
18
F-fluorodeoxyglucose positron emission tomography
(FDG-PET) exploits the glucose-avid nature of colorectal cancers to image tumors. It was previously reported patients with
hepatic colorectal metastases who were assessed by FDG-PET
prior to liver resection had higher resectability, lower recurrence, and improved long-term survival (Strasberg et al. 2001)
because of its ability to detection of extrahepatic disease, such
as nodal, peritoneal, lung, or bone metastases. It is inferior to
CT or MRI for detection of liver lesions because the normal
liver is also a glucose-avid tissue and therefore the background
is often too high (Akhurst et al. 2005).
Key Take Home Messages
• All patients with colorectal liver metastases should be evaluated by a surgical team within the context of a multidisciplinary
environment.
• Resection of colorectal liver metastases is the standard of
care for patients with resectable disease since it prolongs
survival and has the potential for cure.
• Parenchymal sparing and minimally invasive approaches are
appropriate for colorectal liver metastasectomy.
• Strategies including portal vein embolization and two-stage
hepatectomy can be employed for initially inadequate future
liver remnant.
Areas for Further Research
• Timing of systemic therapy for patients who present with
resectable colorectal liver metastases is subject to debate.
• Pushing the limits of resection with high-risk procedures,
such as Associated Liver Partition and Portal vein ligation for
Staged hepatectomy (ALPPS) is subject to debate.
19 MANAGEMENT OF METASTIC LIVER CANCER 359
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Trusted Links for Further Reading
• Stewart CL, Warner S, Ito K, et al. Cytoreduction for colorectal
metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When
does it palliate, prolong survival, and potentially cure? Curr Probl
Surg. 2018 Sep;55(9):330–379. doi: 10.1067/j.cpsurg.2018.08.004.
Epub 2018 Oct 4. PMID: 30526930; PMCID: PMC6422355.
• Raoof M, Haye S, Ituarte PHG, Fong Y. Liver Resection
Improves Survival in Colorectal Cancer Patients: Causal-effects
from Population-level Instrumental Variable Analysis. Ann Surg.
Oct 2019;270(4):692–700. doi:10.1097/sla.0000000000003485
• Margonis GA, Buettner S, Andreatos N, et al. Prognostic
Factors Change over Time after Hepatectomy for Colorectal
Liver Metastases: A Multi-institutional, International Analysis
of 1099 Patients. Ann Surg. 2019 Jun;269(6):1129–1137. doi:
10.1097/SLA.0000000000002664. PMID: 31082912.
• Nordlinger B, Sorbye H, Glimelius B, et al; EORTC GastroIntestinal Tract Cancer Group; Cancer Research UK;
Arbeitsgruppe Lebermetastasen und–tumoren in der
Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO);
Australasian Gastro-Intestinal Trials Group (AGITG); Fédération
Francophone de Cancérologie Digestive (FFCD). Perioperative
FOLFOX4 chemotherapy and surgery versus surgery alone for
resectable liver metastases from colorectal cancer (EORTC
40983): long-term results of a randomized, controlled, phase 3
trial. Lancet Oncol. 2013 Nov;14(12):1208–15. doi: 10.1016/
S1470-2045(13)70447–9. Epub 2013 Oct 11. PMID: 24120480.
• Melstrom LG, Warner SG, Woo Y, et al. Selecting incision-dominant cases for robotic liver resection: towards outpatient hepatectomy with rapid recovery. HepatoBiliary Surgery and Nutrition.
2018–04-01 2018;7(2):77–84. doi:10.21037/hbsn.2017.05.05
Systemic Chemotherapy
S. Lindsey Davis
First-line Therapy for Metastatic Disease
For nearly four decades the treatment of choice for colorectal
cancer was fluorouracil (5-FU) and leucovorin (LV). The
average response rate was 20% and the average median survival
was 12 months (Saltz et al. 2000). In the 1980s, a topoisomerase
inhibitor, irinotecan, demonstrated tumor responses in pretreated patients with colorectal cancer. Then a study comparing
5-FU with or without irinotecan in chemotherapy-naïve patients
reported higher response rates and a significant survival
advantage for the irinotecan-containing regimen (Douillard et
al. 2000; Rougier et al. 1998). In this study, a continuous infusion 5-FU with LV and irinotecan was associated with a median
survival of 17 months with the three-drug combination vs 14.1
months with 5-FU / LV alone (Douillard et al. 2000).
The next drug to show activity in treating colorectal cancer was
oxaliplatin. Infusion of 5-FU and LV combined with oxaliplatin
(FOLFOX) as first-line therapy produced response rates of approximately 50% (de Gramont et al. 2000; Giacchetti et al. 2000). In an
intergroup phase III trial (Goldberg et al. 2004), metastatic colorectal cancer patients were randomized to FOLFOX versus bolus
irinotecan/5-FU/LV (IFL). The study demonstrated a significant
increase in response rate, time to progression and median survival
for FOLFOX versus IFL with 45% responding to FOLFOX with a
19.5 month median survival (Goldberg et al. 2004).
The order in which these regimens should be administered
remains unclear. In the Tournigand study, FOLFOX followed
by FOLFIRI (infusional of 5-FU/LV/irinotecan) compared to
FOLFIRI followed by FOLFOX produced similar median survivals of 21.5 and 20.6 months, respectively (Tournigand et al.
2004). Similarly, a phase III study evaluating FOLFIRI versus
FOLFOX4 in the first line setting was associated with similar
overall response rates, median time to progression, and overall
survival (Colucci et al. 2005).
Oral capecitabine has also been evaluated as substitute for
infusional 5-FU in combination with oxaliplatin in the
treatment of metastatic colorectal cancer. Multiple studies have
confirmed comparable efficacy between the CAPOX and
FOLFOX regimens, though potential for increased toxicity
with capecitabine (Guo et al. 2016). This is especially true in the
US population related to regional differences in capecitabine
tolerability (Haller et al. 2008). The efficacy of the combination
of oral capecitabine and irinotecan as compared to the FOLFIRI
regimen has been shown to be similar in a number of clinical
trials (Guo et al. 2014). However, in the US population this
combination was associated with a significant increase in toxicity and decrease in PFS as compared to FOLFIRI (5.8 vs 7.6
months; p = 0.015) (Fuchs et al. 2007).
Triplet combination therapy of 5-FU, oxaliplatin and leucovorin in the FOLFOXIRI regimen has also been compared to
two-drug regimens with 5-FU and oxaliplatin or irinotecan.
The majority of these trials are associated with favorable progression free and overall survival results in the FOLFOXIRI
arm, at the expense of increased rates of high-grade toxicity
(Cremolini et al. 2020b).
The addition of biologic agents targeting vascular endothelial growth factor (VEGF) and epidermal growth factor
receptor (EGFR) to first-line chemotherapy regimens has
led to further improvement in survival outcomes. AntiEGFR monoclonal antibodies cetuximab and panitumumab are effective in patients with RAS wild-type tumors,
but not those with RAS mutations (KRAS exon 2, 3, 4 or
NRAS exon 2, 3, 4) (Sorich et al. 2015). Increasingly, the
site of origin of the primary tumor is being recognized as
an additional predictor of response within the RAS
wild-type population. The phase III CALGB/SWOG 80405
trial demonstrated an increased overall survival in patients
with RAS wild-type left-sided primary tumors (originating
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in the splenic flexure to rectum) treated with cetuximab
rather than bevacizumab (39.3 vs 32.6 months, HR 0.77),
but improved survival in patients with right-sided primary
tumors (originating in the cecum to the hepatic flexure)
treated with first-line bevacizumab as compared to firstline cetuximab (29.2 vs 13.6 months, HR 1.36) (Venook et
al. 2016). The underlying mechanism of this “sidedness” is
being further explored but thought related to the varied
molecular characteristics of colorectal cancers across primary disease sites.
For those patients with RAS mutant tumors or RAS wild-type
tumors originating in the right side of the colon, bevacizumab
is the targeted therapy of choice. The benefit of bevacizumab
was first documented in combination with the IFL regimen,
with improved response rate (45% vs 35%) and overall survival
(20 vs 16 months). However, with more modern chemotherapy
backbone regimens these improvements have not been as pronounced, as demonstrated in a pooled analysis of bevacizumab
trials which documented overall survival of 19.8 vs 17.6 months
in patients receiving regimens with and without bevacizumab
(Hurwitz et al. 2013). In addition, the increased risk of bleeding,
clotting, and impaired wound healing related to bevacizumab
must be considered with this agent.
Two trials have demonstrated that simultaneous addition
of both EGFR and VEGF targeted therapies to cytotoxic chemotherapy regimens is associated with inferior progression
free survival, and thus these combinations are not recommended, even in a RAS wild-type population (Tol et al. 2009)
(Hecht et al. 2009).
In the small subset of patients (3–6%) with metastatic colorectal cancer who have deficient mismatch repair (dMMR) or
high microsatellite instability (MSI-H) tumors, the first-line
treatment of choice is immune checkpoint inhibitor therapy
rather than cytotoxic chemotherapy regimens. This is based
on results from the KEYNOTE-177 trial demonstrating
improved progression free survival (16.5 vs 8.2 months) with
PD-1 inhibitor pembrolizumab vs chemotherapy with an
oxaliplatin- or irinotecan-containing regimen in this population
(Andre et al. 2020).
Later-line Therapy for Metastatic Disease
Options for additional therapy following progression on a firstline regimen depend on the initial regimen, as well as molecular characteristics of the tumor (Table 6). For those patients
who received an oxaliplatin-based regimen up-front, an irinotecan-based regimen is typically selected, and vice versa
(Tournigand et al. 2004). For those treated with FOLFOXIRI,
the best second-line chemotherapy regimen is not established,
but addition of a VEGF or EGFR inhibitor may be considered
in combination with cytotoxic chemotherapy according to the
targeted therapy utilized in the first line setting and RAS mutation status.
In this population, as well as those who have progressed on
separate oxaliplatin- and irinotecan-based regimens, both
multi-kinase inhibitor regorafenib and trifluridine-tipiracil
are also options for treatment. Regorafenib was associated
with a modest, though statistically significant improvement in
overall survival as compared to best supportive care (6.4 vs 5
months, HR 0.77) in the CORRECT trial (Grothey et al. 2013).
Similarly, trifluridine-tipiracil was associated with a statistically significant increase in overall survival of 7.1 vs 5.3
months with best supportive care (HR 0.68) (Mayer et al.
2015). Subsequently, trifluridine-tipiracil has been combined
with bevacizumab with an improved overall survival of the
combination vs trifluridine-tipiracil alone (9.4 vs 6.7 months,
HR 0.55) (Pfeiffer et al. 2020).
Additional therapies have shown benefit for patients with
particular molecular characteristics beyond the first-line
setting. For patients with RAS wild-type, BRAF V600E mutant
disease, the combination of cetuximab plus encorafenib provides improved overall survival of 9.3 vs 5.9 months in
patients treated with irinotecan or FOLFIRI plus cetuximab
(HR 0.61). In patients with RAS wild-type disease that is
human epidermal growth factor receptor 2 (HER2) positive,
trastuzumab plus lapatinib, or pertuzumab may be considered based on data from the HERACLES (Sartore-Bianchi et
al. 2016) and MyPathway studies (Meric-Bernstam et al.
2021). For the rare patient with tropomyosin receptor kinase
Table 6 Molecular targeted therapies for the treatment of metastatic colorectal cancer.
Regimen Line of therapy Molecular alteration Incidence in colorectal
Cetuximab
Panitumumab
Cetuximab/encorafenib Second line and beyond BRAF V600E mutant 3–10%
Pembrolizumab First line and beyond MSI high, dMMR 3–6%
Trastuzumab/lapatinib
Trastuzumab/pertuzumab
Larotrectinib
Entrectinib
cancer
First line and beyond RAS Wild type 50–70%
Second line and beyond HER2 overexpression 3–5%
Second line and beyond NTRK fusion 0.5–1%
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(TRK) fusion-positive disease (0.5–1%), TRK inhibitors
including larotrectinib and entrectinib are favored following
first-line treatment (Demetri et al. 2022; Hong et al. 2020).
These treatment options demonstrate the importance of
broad testing of tumor for somatic mutations in all patients
with metastatic colorectal cancer.
Systemic Therapy for Patients with Initially
Unresectable Hepatic Metastases
In patients with liver-limited metastatic disease for whom surgical resection is not initially feasible, systemic therapy is typically
recommended to help downstage disease, as well as to assess the
biology of the metastatic cancer. The benefit of one cytotoxic regimen over another has not been proven in this setting. The higher
response rates associated with FOLFOXIRI make this a
consideration for a patient population able to tolerate the toxicity
of this regimen. Data from a pooled analysis of trials evaluating
the FOLFOXIRI/bevacizumab regimen in the setting of initially
unresectable hepatic metastatic disease demonstrated an overall
response rate of 69%, which led to surgical conversion in 39.1% of
patients and R0 resection in 28.1% (Tomasello et al. 2017).
The role of biologic targeted therapies in combination with
cytotoxic regimens is also not well-defined in this setting.
Minimal improvement in resectability rate, from 6.1% with
oxaliplatin-based chemotherapy alone to 8.4% with the addition
of bevacizumab, was demonstrated in a randomized trial of
1401 patients with unresectable hepatic metastases (Saltz et al.
2008). However, in a randomized trial of patients with RAS
mutant metastatic colorectal cancer, patients who received
FOLFOX/bevacizumab had a higher objective response rate of
55% as compared to 37% in those who received chemotherapy
alone, with R0 resection rates of 22.3 and 5.8 percent, respectively (Tang et al. 2020). The increased risk of relevant toxicities
and need for a period of approximately six weeks off bevacizumab therapy prior to surgery must be taken into consideration
when considering bevacizumab in this setting.
Initial studies of cetuximab plus FOLFOX and FOLFIRI
indicated a small improvement in surgical resectability in
cetuximab-treated patients (Bokemeyer et al. 2009; Van Cutsem
et al. 2009). However, the subsequent New EPOC trial evaluating FOLFOX with or without cetuximab for patients with
resectable liver-only metastases demonstrated an inferior progression free survival (22.2 v 15.5 months) and overall survival
(81.0 v 55.4 months) for patients who received combination
treatment with cetuximab, and is not recommended in this
setting (Bridgewater et al. 2020).
Table 7 Drugs for hepatic arterial infusion (HAI).
Drug Half-life
Fluorouracil (5-FU) 10 5–10-fold
5-fluoro-2-deoxyuridine
(FUDR)
Bischlorethylnitrosourea
(BCNU)
Mitomycin C <10 6–8-fold
Cisplatin 20–30 4–7-fold
Adriamycin (doxorubicin
hydrochloride)
Table 8
Rationale for hepatic arterial infusion (HAI).
1 Liver metastases perfused by hepatic artery; normal liver by portal
vein.
2 Some drugs extracted by liver during first pass; less systemic toxicity.
3 Liver may be only site of metastatic disease; stepwise pattern of
metastatic progression.
(min)
<10 100–400-fold
<5 6–7-fold
60 2-fold
Estimated
increased
exposure via
HAI
Additionally, certain drugs are largely extracted by the liver during
the first pass through the arterial circulation, which results in high
local concentrations of the drug with minimal systemic toxicity. In
1978, Ensminger and colleagues demonstrated that 94–99% of
floxuridine (FUDR) is extracted by the liver during the first pass,
compared to 19–55% of 5-FU. Drugs with a high total body
clearance and short plasma half-life are more useful for hepatic
infusion (Table 7) (Ensminger et al. 1978). The liver is often the
first and only site of metastatic disease and it is possible that hematogenous spread occurs via the portal vein to the liver, and then
from the liver to other organs. Therefore, aggressive treatment of
metastases confined to the liver may prolong survival. Rational for
hepatic artery infusion therapy is described in Table 8.
Regional hepatic arterial therapy can be delivered using either
an intra-arterial catheter connected to an external pump or a fully
implanted pump. Early studies with percutaneously placed
hepatic artery catheters produced high response rates, but clotting of the catheters or the hepatic artery, duodenal ulcers, and
bleeding from around the catheters (Tandon et al. 1973) led physicians to abandon this method. The development of a fully
implanted pump allowed long-term hepatic artery infusion (HAI)
with a lower incidence of complications (Ensminger et al. 1981).
Toxicity of Hepatic Arterial Infusion
Hepatic Arterial Infusion (HAI)
Liver metastases are perfused almost exclusively by the hepatic
artery, while the normal liver hepatocytes derive their blood
supply mostly from the portal vein (Breedis and Young 1954).
The most common adverse effects of HAI FUDR therapy are
gastrointestinal ulceration and biliary sclerosis. The bile ducts
derive their blood supply almost exclusively from the hepatic
artery (Northover and Terblanche 1979), and thus are also
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perfused with high doses of chemotherapy through HAI.
Myelosuppression, nausea, vomiting, and diarrhea do not
occur with HAI therapy using FUDR. If diarrhea does occur,
shunting to the bowel should be suspected (Gluck et al. 1985).
Clinically, biliary toxicity is manifested as elevations of aspartate transaminase, alkaline phosphatase, and bilirubin. In the
early stages, hepatic enzyme elevations will return to normal
when the drug is withdrawn and the patient is given a rest
period, though can become permanent. Therefore, careful monitoring of liver function tests is necessary to avoid this toxicity.
In patients who develop jaundice, an endoscopic retrograde
cholangiopancreatogram (ERCP) may demonstrate lesions
resembling idiopathic sclerosing cholangitis. The strictures
may be focal and present at the hepatic duct bifurcation, and
therefore drainage procedures may be helpful.
Hepatic Arterial Infusion for Unresectable
Metastatic Colorectal Cancer
In the Cancer and Leukemia Group B (CALGB) trial, metastatic colorectal cancer patients were randomized to either HAI
FUDR, LV, and dexamethasone, or to intravenous 5-FU plus
LV. The primary endpoint was survival, and a statistically
significant survival advantage was seen with HAI relative to
systemic 5-FU/LV (24 vs. 20 months, p = 0.0034). The response
rate was also higher in the HAI arm at 48% versus 25% (p =
0.001), as was the hepatic disease-free survival (9.8 vs. 7.3
months, p = 0.034) (Kemeny et al. 2006). Other endpoints
concerned correlation of survival with tumor biology,
assessment of clinical response and toxicity, and economic
analysis (Kemeny et al. 2003). Quality of life using the Rand
36-Item Health Status Profile, Memorial Symptom Assessment
Scale, and other instruments demonstrated an improvement in
physical functioning in the HAI group (Kemeny et al. 2006).
Additional trials evaluating more modern chemotherapy
regimens including oxaliplatin and irinotecan followed. In a
phase I study of HAI FUDR and systemic irinotecan in 46
pretreated patients, the combination was found to be safe and
tolerable at the maximum tolerated dose, with a response rate
of 74% observed, and median overall survival of 20 months
(Kemeny et al. 2001). A subsequent phase I trial identified the
combination of HAI FUDR and systemic m-FOLFOX6 as safe
and tolerable, with overall response rate of 68.6% for hepatic
metastases and overall survival of 25 months in 35 patients (Li
et al. 2014). Additional phase I studies evaluating various
combinations of systemic and hepatic arterial infusion regimens have generally identified this overall strategy as safe and
tolerable. The combination of HAI FUDR and systemic chemotherapy with cetuximab was evaluated in a multicenter
phase II trial which was significant for median OS of 35.2
months and no toxicity concerns (Levi et al., 2016). However,
the addition of systemic bevacizumab to chemotherapy with
oxaliplatin- or irinotecan-based regimens was associated with
greater biliary toxicity in a phase II trial (Kemeny et al. 2011).
There are currently no randomized data comparing systemic
chemotherapy ± HAI FUDR, though clinical trials evaluating
such are currently ongoing. Retrospective data comparing
systemic chemotherapy with or without HAI FUDR in patients
with hepatic metastatic colorectal cancer demonstrated an
overall survival of 32.8 vs 15.3 months (p<0.001) (Dhir et al.
2017), though low rates of conversion to resection and shorter
than expected survival in the chemotherapy alone cohort limit
interpretation of these results (Karanicolas and Ko 2017).
Conversion to resectability has been evaluated in colorectal
cancer patients with unresectable hepatic metastases treated
with HAI FUDR and systemic chemotherapy. In a phase I trial
of HAI FUDR and systemic oxaliplatin and irinotecan in
patients with extensive hepatic metastatic disease, 47% of all
patients and 57% of treatment-naïve patients underwent
complete resection (Kemeny et al. 2009). In a phase II trial of
49 patients with unresectable colorectal cancer liver metastases, an overall response rate of 76% was seen, with 47%
achieving conversion to resection at six months (D’Angelica et
al. 2015). These results are favorable when compared to historically reported outcomes with chemotherapy alone, but no
randomized data exist.
Adjuvant HAI
Once metastases grow beyond 3mm, they obtain their blood
supply from arterial circulation, while the normal hepatocytes
continue to receive blood flow from the portal vein (Archer
and Gray 1989). With hepatic resection of liver metastases,
residual disease, if present, may be 2–3mm in diameter, and
therefore derive its blood supply from the hepatic artery.
Based on this rationale, randomized trials have been performed to address the question of the utility of adjuvant therapy
with HAI after liver resection. At Memorial Sloan-Kettering
Cancer Center (Kemeny et al. 1999), patients were randomized
after liver resection to HAI FUDR plus dexamethasone and
systemic 5-FU +/–LV, or systemic chemotherapy alone. The
primary endpoint of survival at two years was significantly
increased with HAI plus systemic chemotherapy (86% vs. 72%,
p = 0.03). An update with a median follow-up time of 10 years
revealed a 10-year survival of 40% for the HAI + systemic
therapy group and 27% for the systemic therapy-alone group.
The two-year time to hepatic recurrence was also increased in
patients treated with HAI plus systemic therapy and was 90%
and 60%, respectively (Kemeny and Gonen 2005). Median time
to hepatic recurrence had not been reached in the HAI +
systemic therapy arm, but was 32.5 months in patients treated
with systemic therapy (p = 0.01). The overall progression-free
survival was 31.3 months versus 17.2 months (p = 0.02)
(Kemeny and Gonen 2005).
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The Eastern Cooperative Oncology Group (ECOG) and
Southwest Oncology Group (SWOG) conducted a prospective
trial of hepatic resection alone versus resection followed by
HAI (FUDR) and systemic infusional 5-FU (Kemeny et al.
2002). Only patients with three or less hepatic metastases were
enrolled, and because patients were randomized prior to resection, 29 patients were found to be ineligible at the time of surgery. For the 75 patients who entered the study, the primary
endpoint of four-year disease-free survival was significantly
longer with HAI plus systemic therapy versus resection alone,
58% and 34%, respectively (p = 0.039). The study was not powered for overall survival, but the five-year survival rate was 58%
for the HAI and systemic group and 40% for the resection-only
group (Kemeny et al. 2002).
The combination of FUDR with systemic capecitabine and
oxaliplatin chemotherapy has also been evaluated in a phase II
study of 55 patients. In this trial, patients received alternating
courses of HAI FUDR and dexamethasone weeks 1 and 2, and
systemic therapy with capecitabine and oxaliplatin weeks 4
and 5. The primary endpoint of the trial was met with a twoyear overall survival of 88% (Alberts et al. 2010). A randomized
phase III trial to further evaluate this regimen, NASBP C-09,
was unfortunately terminated early due to low accrual.
Data from a prospectively maintained database of patients
with liver-limited metastatic colorectal cancer who underwent
resection and treatment with systemic chemotherapy with or
without HAI FUDR at Memorial Sloan Kettering has been evaluated for survival comparisons. In this population, HAI was
administered in the pre- and/or post-operative setting, and all
patients received pre- and/or post-operative systemic chemotherapy. Of 2368 total patients, 1442 received modern systemic
chemotherapy regimens. The 10-year overall survival in this
group was 67 months for those who received and 47 months for
those who did not receive HAI. The hazard ratio adjusted by propensity score was 0.67 (P<0.001) (Groot Koerkamp et al. 2017).
Key Take Home Messages
• In patients with metastatic colorectal cancer, trials with triplet
combination therapy using 5-FU, oxaliplatin and irinotecan
show improved progression free and overall survival compared
to two-drug regimens with 5-FU and oxaliplatin or irinotecan,
at the expense of increased rates of high-grade toxicity.
• Addition of biologic agents should be made based on site of primary tumor; overall survival increased with addition of cetuximab
vs bevacizumab for RAS wild type left-sided primary tumors,
whereas the reverse was found for right-sided primary tumors.
• FOLFOX with or without cetuximab for patients with resectable liver-only metastases demonstrated an inferior progression free survival for patients who received combination
treatment with cetuximab; therefore, cetuximab is not recommended in this setting.
• In the small subset of patients with metastatic colorectal cancer who have deficient mismatch repair or high microsatellite
instability tumors, the first-line treatment of choice is immune
checkpoint inhibitor therapy rather than cytotoxic chemotherapy regimens.
• Hepatic artery infusion with systemic chemotherapy can be
used in patients with liver limited colorectal metastases who
are unresectable and in the adjuvant setting.
Areas for Further Research
• The underlying mechanisms explaining differences in regimen responsiveness of right versus left sided colorectal cancer
metastases is being further explored.
• There are currently no randomized data comparing systemic
modern chemotherapy with or without hepatic artery infusion
therapy for patients with liver limited unresectable colorectal
metastases in patients. Trial enrollment sizes are small for evaluation of adjuvant hepatic artery infusion therapy.
Trusted Links for Further Reading
• Venook AP ND, Innocenti F, et al. Impact of primary tumor
location on overall survival and progression-free survival in
patients with metastatic colorectal cancer: Analysis of CALGB/
SWOG 80405. Journal of Clinical Oncology. 2016;3504(34S).
• Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in
Microsatellite-Instability-High Advanced Colorectal Cancer. N
Engl J Med. Dec 3 2020;383(23):2207–2218. doi:10.1056/
NEJMoa2017699.
• Bridgewater JA, Pugh SA, Maishman T, et al. Systemic chemotherapy with or without cetuximab in patients with resectable
colorectal liver metastasis (New EPOC): long-term results of a
multicentre, randomised, controlled, phase 3 trial. Lancet Oncol.
Mar 2020;21(3):398–411. doi:10.1016/S1470-2045(19)30798–3.
• Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases
from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039–
48. doi: 10.1056/NEJM199912303412702. PMID: 10615075.
Interventional Radiology
Lisa Liu & Jonathan Lindquist
Locoregional Therapies to Induce Future Liver
Remnant Hypertrophy and Improve Perioperative Outcomes
Complete surgical resection remains the first-line treatment for
metastatic cancer to the liver, and is potentially curative with
long-term survival benefit. However, up to 70–80% of patients
are not candidates for surgical resection. One major potential
barrier to surgical resection eligibility is inadequate future liver
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remnant (FLR) volume, which greatly increases the risks of
postoperative liver failure and liver failure related mortality.
One of the strongest predictors of a patient’s risk for poor
perioperative outcomes is a small FLR percentage in relation to
total functional liver volume (Kubota et al. 1997). Therefore,
patients with a tumor burden requiring a large volume resection are at increased risk for liver failure. As discussed above
under Surgical Therapy, for patients with normal liver function,
a minimum of ≥20% FLR is the recommended threshold for
safe resection, with some institutions preferring a cutoff of
≥20–30% (Dixon et al. 2021; Kishi et al. 2009; Vauthey and
Mizuno 2017). Patients with chemotherapy-associated liver
injury (CALI) or Child-Pugh A cirrhosis are at greater risk for
postoperative liver failure in comparison to patients with
normal liver function (Dixon et al. 2021). Therefore, for
patients with steatosis and/or exposure to hepatotoxic chemotherapy, a minimum of ≥30% FLR is recommended for safe
resection (Shindoh et al. 2013b; Vauthey and Mizuno 2017;
Zorzi et al. 2007). For Child Pugh A cirrhotic patients with
limited functional hepatic reserve, the recommended threshold
increases to ≥40% (Azoulay et al. 2000; Clavien et al. 2007;
Kubota et al. 1997; Vauthey and Mizuno 2017). For patients
that do not meet these recommendations, locoregional and
surgical therapies can be used to induce FLR hypertrophy to
decrease their perioperative risks and thus bridge to surgical
resection. In practice, FLR is calculated using volumetric software to analyze cross-sectional imaging such as CT or MRI.
Mathematical calculations have been developed in an attempt
to standardize FLR for body surface area and body (Ribero et
al. 2008; Vauthey et al. 2002). Rate of growth following portal
vein embolization (PVE) and degree of hypertrophy after PVE
have also been shown to have prognostic value (Ribero et al.
2007a; Shindoh et al. 2013a).
Portal Vein Embolization
In the mid-1980s, Makuuchi was the first to describe using preoperative portal vein embolization (PVE) to atrophy the portion of
the liver planned for resection and induce compensatory hypertrophy of the planned remnant liver (Madoff et al. 2005). PVE can
also function as a “stress test” by providing a preoperative demonstration of the remnant liver’s capacity for regeneration, which
may be impaired in the setting of liver injury or poor liver
functional reserve. Over a period of 2–8 weeks, PVE is expected to
increase FLR volumes by approximately 40%, though individual
patient characteristics can cause great variability in outcomes.
The oldest method of PVE involved an open surgical
approach with direct puncture of the ileocolic vein; this has
largely been supplanted by the minimally invasive imageguided percutaneous transhepatic approach. There are two
main ways to access percutaneously: through the ipsilateral
lobe that is targeted for resection versus the contralateral lobe
that is the future liver remnant. The ipsilateral approach
minimizes risk of causing iatrogenic damage to the future liver
remnant but requires thoughtful planning to avoid accessing
through tumor and risking tumor seeding. Additionally, the
ipsilateral approach requires the interventional radiologist to
intravascularly navigate more acute angles in order to appropriately position the catheter at the embolization target.
Accessing contralateral is technically easier to navigate the
catheter to the target but may increase the risk of injuring the
future liver remnant from access attempts. A variety of embolic
materials can be used to occlude the portal veins, such as coils,
plugs, and particles. N-butyl cyanoacrylate glue has shown to
have the best effect on FLR hypertrophy in recent studies (Ali et
al. 2021; Luz et al. 2021).
General risks of PVE regardless of ipsilateral or contralateral
approach include bleeding such as subcapsular hematoma and/
or hemoperitoneum, infection such as cholangitis and/or
hepatic abscess, bile duct damage and potential leak, damage to
liver function, non-target embolization or migration of embolic
coils or plugs, non-target portal vein thrombosis, and inadequate hypertrophy. Overall the risk profile for PVE is low. The
Society of Interventional Radiology published quality improvement guidelines in 2010 recommending staying below a
threshold of 11% morbidity and 6% major complications for
PVE. A 2008 meta-analysis of 1088 patients who underwent
PVE demonstrated only a 2.2% morbidity and 0% procedurerelated mortality, keeping well within those parameters
(Abulkhir et al. 2008).
As discussed above under Surgical Therapy, for patients with
bilobar metastatic disease, a two-stage hepatectomy (TSH)
approach may be an option to try to downstage to a potentially
curative resection. In the first stage, tumor within the FLR is
treated typically with surgical resection or thermal ablation. Once
the FLR is free of viable tumor, the next goal is for PVE to increase
the FLR volume before the second stage resection, especially since
most of these patients also undergo neoadjuvant hepatotoxic chemotherapy, thereby increasing their perioperative risks.
While the majority of patients who undergo preoperative
PVE successfully continue on to surgical resection, up to
30–40% of patients are not able to bridge to resection due to
progression of liver tumor burden while waiting for hypertrophy (Sandström et al. 2018a). Not only is a lack of tumor
control a concern during this waiting period, PVE may contribute to progression of disease (Hoekstra et al. 2013).
Embolizing the portal inflow can instigate a compensatory
increase in ipsilateral hepatic arterial inflow, also known as
the hepatic artery buffer response. Studies have suggested in
patients with colorectal metastases that PVE is associated
with increased tumor growth rate, mitotic rate, and proliferation index Ki67 (de Graaf et al. 2009; Hoekstra et al. 2012;
Simoneau et al. 2015). Recently hepatic vein embolization
has been described in combination with portal vein embolization. This may improve degree of FLR hypertrophy and
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improve kinetic growth rate (Guiu et al. 2016; Hwang et al.
2015; Le Roy et al. 2017; Niekamp et al. 2020). Further study
of this technique is ongoing.
Associating Liver Partition and Portal vein ligation for Staged
hepatectomy (ALPPS) was originally designed to induce rapid
FLR growth rate, thereby decreasing the time interval to
complete surgical resection. Compared to PVE or portal vein
ligation (PVL) alone, the combination of liver partitioning and
PVL achieves greater hypertrophy percentages of segments 2
and 3 in a shorter amount of time – only 1–2 weeks (Sandström
et al. 2018a). However, given the controversial safety profile
and lack of evidence for long term survival benefits as discussed above in more detail under Surgical Therapy, ALPPS
currently is not commonly practiced.
Radiation Lobectomy
Transarterial radioembolization of the tumor-bearing lobe
with radioactive microspheres has been described as a method
of inducing FLR hypertrophy and provides concomitant tumor
control (Malhotra et al. 2019; Gaba et al. 2009; Gabr et al. 2019;
Teo and Goh 2015). Radioembolization, also known as selective
internal radiation therapy (SIRT) is a catheter-directed infusion of radioactive microspheres.
90
Yttrium-90 (Y90) is the
most commonly used isotope, though other isotopes such as
166
Holmium (Ho166) can be used. Y90 is a pure beta-emitter
with maximal tissue penetration range of 1 cm, allowing for
local high intensity radiation. Historically, SIRT has been used
as a salvage therapy for unresectable advanced colorectal liver
metastatic disease (Jakobs et al. 2008). As an adjunctive therapy
to first-line systemic chemotherapy, SIRT has been demonstrated to be a useful tool for tumor control in patients with
colorectal liver metastases (Lewandowski et al. 2014). The neoadjuvant potential for SIRT was first described in 2008 when
Jakobs et al. reported a case series of patients with colorectal
liver metastases who had unilobar radioembolization. These
patients had expected ipsilateral lobe atrophy, but also had contralateral lobar hypertrophy of 21% 30 days post-SIRT (Jakobs
et al. 2008). Gaba et al. also described this phenomenon in
patients with primary liver cancer and named the technique
“radiation lobectomy” (Gaba et al. 2009). In contrast to palliative lobar radioembolization, radiation lobectomy is performed
with the ultimate goal of curative surgical resection. Higher
radiation doses are generally given to improve FLR hypertrophy (Entezari et al. 2021).
Radiation lobectomy provides the benefit of synchronous
tumor control, but with the drawback that the rate of hypertrophy is slower than PVE (Gaba et al. 2009; Jakobs et al. 2008;
Vouche et al. 2013). Radiation lobectomy related volumetric
changes progress at a linear time-dependent rate, with continuous gradual hypertrophy until maximum FLR volumes are
reached at nine months post procedure (Vouche et al. 2013).
Patients with colorectal liver metastases are thought to have a
similar pattern of hypertrophy after radiation lobectomy to
those with primary liver cancer (Vouche et al. 2013). A 2012
animal study using swine models offered further insight by
prospectively comparing hypertrophy after PVE and Y-90
lobectomy at three- and six-month follow-up intervals. PVE
was associated with more rapid hypertrophy over one month
that then plateaued, while Y90 lobectomy demonstrated a
gradual yet persistent rate of hypertrophy with the volume gain
of both groups converging at the 3–6 month follow-ups. Degree
of hypertrophy has been shown to be closely related to absorbed
radiation dose in the treated lobe (Liebl et al. 2021). Care must
be taken not to overestimate the relatability of animal study
results to predictions of human outcomes, even though these
findings certainly corroborate Vouche et al.’s findings in their
human patient population. In 2021, Bekki et al. published a retrospective comparison between radiation lobectomy and PVE
in human patients with HCC, hypertrophy was followed out to
six months with imaging and demonstrated greater hypertrophy with Y90 lobectomy of 63% compared to 26% in the
PVE group. The PVE group did have a higher resectability rate
of 85% compared to 64% in the Y90 group, with tumor progression as the most common reason to not pursue surgery, however the Y90 group also had 18% of patients not pursue surgery
due to complete tumor control. Complete response per RECIST
criteria was achieved in 50% of the Y90 lobectomy group
(Bekki et al. 2021).
While the interest in radiation lobectomy has grown since
first described, data remains limited with few comparative
investigations. Additionally, most studies focus on primary
liver cancer patients, primarily HCC. Patients with secondary
liver cancer are likely to respond differently for a multitude of
reasons including differences in comorbid liver conditions (less
likely to be cirrhotic, though more likely to be exposed to hepatotoxic chemotherapies), differences in tumor pathophysiology, and differences in treatment pathways. Garlipp et al.
performed a retrospective comparison using matched pair
analyses PVE and Y90 lobectomy in patients with colorectal
metastatic liver disease, however hypertrophy outcomes were
compared at a short one month follow-up which led as expected
to PVE being associated with greater hypertrophy compared to
Y90 lobectomy (Garlipp et al. 2014). In 2020, Kurilova et al.
described two patients with colorectal liver metastases who
both failed PVE with insufficient FLR increase. The first patient
underwent Y90 multisegmentectomy for a target radiation
dose of 120 Gy 5 months after PVE and experienced a 13% FLR
increase and partial tumor response, which allowed for the
patient to proceed to right extended hepatectomy (Kurilova
et al. 2020). This patient developed a solitary lung metastasis
one-year post-resection and passed away 32 months post-Y90
without evidence of recurrent hepatic disease. The second
patient underwent right lobar Y90 with a targeted dose of 120
Gy two months after PVE and experienced a 59% FLR increase
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