Update On Current Problems in Colorectal Liver Metastasis

Current Problems in Surgery 54 (2017) 554–602
Contents lists available at ScienceDirect
Current Problems in Surgery
journal homepage: www.elsevier.com/locate/cpsurg
Update on current problems in colorectal

liver metastasis
Jeffrey Chakedis, MDa, Malcolm H. Squires, MD, MSa,
Eliza W. Beal, MDa, Tasha Hughes, MD, MPHa,
Heather Lewis, MDb, Anghela Paredes a,
Mazen Al-Mansour, MDa, Steven Sun, MDa,
⁎
Jordan M. Cloyd, MDa, Timothy M. Pawlik, MD, MPH, PhDa,
Introduction
The management of metastatic colon and rectal cancer has undergone significant evolution over
the last few decades. Due to advancements in chemotherapy, surgical techniques, and perioperative
care, the 5-year overall survival (OS) of patients with colorectal liver metastasis (CRLM) has now
improved to 35%-40%.1 Most significantly, the outcomes of patients with extensive disease have
improved with multimodality therapy. As the criteria for “resectable” disease have evolved, many
patients that might previously have been deemed unresectable are now treated with modern
chemotherapeutic regimens to down-stage disease, facilitate resection, and ultimately improve
survival. Although surgical “cure” remains a challenge, more and more patients are managed
successfully to allow for control of their disease, thus prolonging survival.
The vast majority of patients, even those with good prognoses, will ultimately develop
recurrence after aggressive medical and surgical treatment of CRLM. Based on a large multi-
institutional series of patients undergoing resection of CRLM, two-thirds of patients will recur in a
median time of 16 months: 43% with disease in the liver only, 35% with extrahepatic disease (EHD),
and 21% with combined sites of disease.2 Management of these patients is nuanced and complex, as
no single therapeutic modality is likely to be their only treatment.
Surgery for CRLM has become the standard of care, as it provides the best chance for durable
cure. Strategies to optimize patient treatment and selection in order to maximize the number of
From the aThe Ohio State University Wexner Medical Center, James Comprehensive Cancer Center, Columbus, OH; and
b
University of Colorado Health System, Fort Collins, CO
⁎
Address reprint requests to Timothy M. Pawlik, MD, MPH, PhD, Department of Surgery, The Urban Meyer III and
Shelley Meyer Chair for Cancer Research, The Ohio State University, Wexner Medical Center, 395 W 12th Ave, Suite 670,
Columbus, OH 43210.
E-mail address: tim.pawlik@osumc.edu (T.M. Pawlik).
http://dx.doi.org/10.1067/j.cpsurg.2017.10.002
0011-3840/& 2017 Elsevier Inc. All rights reserved.
J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602 555
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Fig. 1. Volume of yearly publications in PubMed using the search terms “colorectal liver metastases”.
patients with CRLM who are surgical candidates remain an important goal. Given that disease will
recur in up to 70% of patients after resection of CRLM, however, an improved understanding of
prognostic factors for disease recurrence or progression might permit a more personalized
treatment approach and an opportunity to optimize patient outcomes. In this review we highlight
the current controversies in the care of patients with CRLM and review the relevant literature of the
last 10 years, given the expansive increase in research on surgical strategies for CRLM (Fig 1).
Natural history of colorectal liver metastasis
Colon and rectal cancer is the fourth most common cancer diagnosis in the United States, with
135,000 new patients diagnosed annually.3 Of these, nearly 20%-25% of patients will present with
synchronous metastasic disease, and ultimately nearly 50% of patients with colorectal cancer will
develop liver metastases.4 Metastatic colorectal cancer has historically been associated with poor
survival. Without treatment, the median survival is less than 12 months, and the 5-year survival is
less than 10%.5 However, as resection of CRLM has become established as the standard of care and
modern chemotherapy regimens have evolved, there has been a substantial improvement in OS,
which now approaches 40%-45% at 5 years in recent series.6
A retrospective analysis of a large national Swedish cancer registry provides insight into the
different patterns of metastasis observed in colon cancer versus rectal cancer.7 In a study of 49,096
patients, 30% were found to have synchronous metastases at presentation or subsequently
developed metachronous metastatic disease. Among all patients with metastatic disease, the 2 most
common sites of metastasis were liver (70% of patients with colon or rectal cancer primary tumors)
and lung (32% for patients with colon and 47% for patients with rectal). Mucinous and signet ring
cancers metastasized more commonly to the peritoneum (odds ratio [OR] ¼ 3.8 for colon and OR ¼
3.2 for rectum) and less frequently to the liver (OR ¼ 0.5 for colon and OR ¼ 0.6 for rectum).
Increasingly, advances in our understanding of tumor genomics are helping to define the natural
history of colorectal cancer based on the tumor’s molecular signature. For example, patients with
KRAS mutations are more likely to develop lung metastases whereas those with BRAF mutations are
more likely to develop peritoneal metastases.8,9
556 J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602
Definitions and management strategies
Defining resectable disease—An evolving paradigm
The definition of resectability has undergone several revisions since Ekberg and colleagues10
initially proposed in 1986 that resection of CRLM was only indicated if all of the following criteria
were met: the presence of less than 4 liver tumors, no evidence of EHD, and the possibility of
obtaining resection margins ≥10 mm. Although these recommendations have evolved over the past
3 decades, there remains variability in the definition of “resectable CRLM” among studies and even
among self-identified hepatobiliary surgeons.11,12 Patients with CRLM who undergo hepatic
resection demonstrate significantly improved 5-year OS compared to patients treated with
chemotherapy and nonsurgical modalities.13-17 Thus, determination of resectability and candidacy
for metastasectomy has significant prognostic implications. Therefore, defining which patients are
candidates for surgery, as well as employing efforts at safely expanding the indications for resection,
are critical for extending the benefits of surgery to the most patients.
van Dam and colleagues18 expanded historical CRLM resection criteria to include patients with
4 or more liver metastases that could be present in a bilobar distribution, patients with centrally
located metastases, and patients with resectable EHD. Although patients with “extended” indications
in their series of 169 patients demonstrated a shorter median 5-year OS compared to patients
meeting traditional criteria (41 vs 69 months, P o 0.001), the overall outcomes appeared to justify
the extended indications for resection of CRLM.18 Although the extended criteria initially did not
include an assessment of residual liver function or volume preoperatively, the determination of
resectability has now evolved to include a focus on the volume of the future liver remnant (FLR).19
As outlined in a 2012 HPB Expert Consensus Statement, the determination of CRLM resectability
should include 2 considerations: oncologic and technical.20 The oncologic evaluation of resectability
emphasizes the selection of patients most likely to benefit from major liver resection based on their
underlying tumor biology and should take into account the burden of liver metastases, the presence
of EHD, and the response to neoadjuvant therapy, when administered. Progression of disease burden
during neoadjuvant therapy, for example, has been associated with decreased survival and may be a
relative contraindication to surgical intervention.21,22 Increasingly, given its prognostic importance,
tumor mutation status may influence decision-making regarding CRLM’s oncologic resectability.23
Technical resectability refers to the feasibility of achieving a margin-negative resection while
preserving an appropriate FLR with adequate vascular inflow and outflow as well as biliary
drainage.20 This evaluation involves a multidisciplinary team consisting of hepatobiliary surgeons,
radiologists, hepatologists, and pathologists, to evaluate the liver anatomy, histology, and behavior.20
Recently, new data have shifted the focus to preoperative analysis of the volume and quality of liver
that will remain after resection to minimize the risk of postoperative hepatic insufficiency (PHI).
Patients with normal underlying liver parenchyma and hepatic function can safely tolerate resection
of up to 80% of their total liver volume; that is, a FLR size of 420% should be physiologically
sufficient. Among patients who have received chemotherapy for more than 12 weeks, a FLR 430% is
advised, as any smaller remnant size is associated with a significant increase in the observed
incidence of PHI.24 For patients with frank fibrosis or cirrhosis, a FLR 4 40% of total liver volume is
necessary to minimize the risk of PHI.24 In cases of insufficient liver remnant volume, several FLR
augmentation strategies have been developed that are effective at optimizing patients for liver
resection.25,26
The optimal margin width at the time of liver resection to optimize patient outcomes remains
controversial. Historically, the goal of CRLM resection had been to obtain ≥10 mm margins. Pawlik
and colleagues found that R1 margin status (defined as margin width o 1 mm) was associated with
worse OS following liver resection, but that greater margin widths (1-4, 5-9 mm, or ≥1 cm) were not
associated with improved OS, recurrence risk, or site of recurrence.27 Similarly, Sadot and
colleagues28 demonstrated no increased benefit to margins greater than 1 mm and reported that
even submillimeter margin widths were associated with improved OS compared to cases with
tumor cells at the transected margin (ie, 0 mm). Several observations suggest that the effect of
margin status on patient outcomes represents a biological effect rather than the absolute result of
surgical technique. First, patients with RAS mutations are more likely to have positive margins.29
Second, the influence of R1 (o1 mm) resection on survival of patients undergoing liver resection is
mitigated among patients with a significant radiographic or pathologic response to preoperative
chemotherapy.30 Finally, conversion of an R1 margin to R0 via intraoperative reresection was not
associated with an improvement in recurrence or survival.31 Although microscopically negative
margins ≥1 mm remains the goal for CRLM resection, the direct impact of margin status on patient
outcomes is probably less significant than other biological factors.
Table 1 summarizes current recommendations in comparison to those initially postulated more
than 30 years ago. The definition of resectability will likely continue to evolve as systemic and liver-
directed therapies continue to improve, our understanding of tumor biology leads to the
development of new targeted therapies, and combination multimodality strategies are established
for advanced bilobar disease. Ultimately, these advances may help extend the benefits of surgical
resection to patients with CRLM once deemed unresectable.
Management of EHD
The management of CRLM in the setting of EHD remains controversial. Historically, resection of
CRLM in the presence of EHD was relatively contraindicated given the poor prognosis associated
with intrahepatic and extrahepatic metastases.10,32 More recent data suggest that the definitive
exclusion of liver resection for those with CRLM and EHD is not justified, and that resection of all
disease, including extrahepatic sites, should be strongly considered. For example, resection of CRLM
and colorectal pulmonary metastases, whether in a synchronous or staged fashion, is associated
with improvements in survival.33 Furthermore, since most colorectal pulmonary metastases are
relatively indolent, even resection of CRLM in the setting of unresectable lung metastases may be
warranted.34
Conversely, there may be groups of patients with EHD who should not undergo curative-intent
liver resection. In a retrospective review of 219 patients who underwent resection of CRLM and EHD,
the 3-, 5-, and 10-year OS were 49%, 28%, and 10%, respectively.35 Disease recurred in 90% of patients,
at a median time of 8-months postresection. The disease-free survival rates at 5 and 10 years were
6.6% and 3.2%, respectively; and portal or retroperitoneal lymph nodes were the disease site
associated with the worst prognosis (5-year OS of 14%). Indeed, portal lymph node involvement has
long been recognized as a strong negative prognostic factor and clearance of this basin is not
associated with improved survival.36 In addition, Adam and colleagues37 reported on 840 patients
who underwent resection of CRLM and found the presence of EHD was associated with decreased
5-year survival (28% vs 55%). Poor prognostic factors identified included nonpulmonary-EHD, EHD
concomitant to CRLM recurrence, carcinoembryonic antigen (CEA) level ≥10 ng/mL, ≥6 CRLM lesions,
and right colon primary tumor location; among patients with more than 3 of these adverse features,
there were no 5-year survivors. These data suggested that resection was warranted for patients with
pulmonary EHD and low-volume liver disease. A risk score based on size of largest CRLM, number of
Table 1
Historical vs current criteria for resectability of liver metastases in colorectal cancer.
Characteristics Historical criteria Current criteria
Tumor number o4 Lesions Any

Distribution Unilateral Bilateral or unilateral
Extrahepatic disease None Low volume: stable or resectable (excluding portal lymphadenopathy)
Functional liver 4 20% of total liver Same
remnant volume
Venous involvement Contraindication Amenable to venous resection or reconstruction
Margins 4 10 mm ≥1 mm (no tumor cells present at the margin permissible in some
situations)
CRLM lesions, and site of EHD was generated; patients with the lowest risk scores demonstrated
5-year OS of 43%, whereas among patients with the highest risk scores, there were no 5-year
survivors. Although this scoring tool has not been externally validated, these findings suggest that
those in the highest scoring group may not benefit from CRLM resection. Future studies are needed
to fully examine this prognostic scoring tool and whether it could be used in the preoperative setting
to accurately predict the progression of disease.
In summary, although resection of hepatic and EHD has a low chance of true definitive cure,
patients with CRLM and resectable lung-only EHD without portal or retroperitoneal lymph node
disease may benefit from a multimodality treatment strategy that includes surgical resection of all
disease. Although recurrence is expected in this patient population, this does not preclude salvage
therapies that can potentially further prolong survival.
Management of synchronous disease
A generalized approach to the treatment of nonemergent synchronous disease was proposed by

the Expert Group on OncoSurgery management of Liver Metastases (EGOSLIM) consensus meeting,
with synchronous CRLM defined as liver metastases detected at or before the diagnosis of the
primary tumor.38 Nevertheless, controversy remains surrounding the optimal timing and order of
management of the primary colorectal cancer, metastatic disease, and chemotherapy.
Asymptomatic primary colorectal cancer and resectable CRLM can be managed in 1 of 3 ways.
Adam and colleagues38 evaluated data from the LiverMetSurvey and noted that 1-stage resection of
primary and metastases was associated with decreased 5-year survival (40%) vs 2-stage resection of
the primary tumor first (44%) or liver metastases first (47%). These findings have not been replicated,
however, as other data have suggested simultaneous colon and liver resection may be associated
with a lower complication rate, shorter length of stay, less blood loss, less morbidity, and similar
mortality compared to patients who underwent a 2-stage resection.39,40 On the other hand,
simultaneous surgery was shown to be an independent risk factor for the development of an
anastomotic leak, particularly when rectal resection is combined with major hepatectomy for CRLM.
Panel members from the EGOSLIM Group recommended neoadjuvant chemotherapy with or
without radiotherapy before a 1-stage procedure for those with limited hepatic disease and primary
tumors easily amenable to resection. This recommendation, though, does not address the definition
of “limited hepatic disease,” thus leaving it up to the decision-making of the surgical team.
Management of symptomatic colorectal cancer and nonresectable synchronous liver metastases
is much clearer. The EGOSLIM group suggested that in the latter, systemic chemotherapy should be
the priority with the goal to convert the synchronous liver metastases to resectability. If and when
the liver metastases become resectable, the EGOSLIM group recommended metastasectomy before
resection of the primary. Review of the LiverMetSurvey data for these parameters found no
significant difference in 5-year survival rates of the traditional (colorectal first), reverse (liver first),
or 1-stage approach.
Use of systemic perioperative chemotherapy
Perioperative chemotherapy options and rationalization for use
The advent of modern chemotherapy regimens in combination with biologic agents has been
associated with significant improvement in the survival of patients with metastatic disease. First line
treatment regimens with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), fluorouracil, leucovorin,
and irinotecan (FOLFIRI), and capecitabine plus oxaliplatin (XELOX), as well as the triplet
fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI), have been studied in clinical trials
for metastatic disease.41 Advances in systemic chemotherapy have increased the median survival
impressively from 12-30 months among all patients with metastatic disease.42 Figure 2 shows the
most commonly used first-line regimens in a treatment algorithm.
Fig. 2. Treatment algorithm for first-line metastatic colorectal cancer on the basis of RAS/BRAF status. (A) Fluorouracil,
leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) with or without bevacizumab is favored for downstaging for
resection. (B) Bevacizumab should be avoided in patients with high risk of perforation or acute thrombotic events.
(C) Infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI) with
antiendothelial growth factor receptor (EGFR) therapy is favored for downstaging to resection. (A-C) Patient and
physician discussions regarding possible toxicities (alopecia, skin toxicity, neuropathy, acute thrombotic event risk, and
perforation risk) should have a major influence on treatment selection. MT, mutation; WT, wild type. (Reprinted with
permission from Fakih42.)
The use and timing of perioperative chemotherapy in patients with resectable CRLM remains
somewhat controversial (Fig 3). A landmark randomized controlled trial (European Organization for
Research and Treatment of Cancer [EORTC] Intergroup trial 40983) investigated the role of
perioperative folinic acid, 5-floururacil, oxaliplatin (FOLFOX) and surgery vs surgery alone in patients
with initially resectable CRLM.43 In this trial, 364 patients with resectable CRLM were randomized to
receive either 12 cycles of perioperative chemotherapy (6 cycles before resection of liver metastases
and 6 cycles after resection) or to undergo surgery alone. Trial eligibility was limited to patients with
4 or fewer metastatic lesions and no evidence of EHD, and patients in whom the primary tumor had
Fig. 3. Management diagram for colorectal liver metastasis. (Reprinted with permission from Kopetz S and Vauthey JN.
Perioperative chemotherapy for resectable metastases. Lancet. 2008; 371(9617):963-965.) PVE, portal vein embolization.
either previously been completely resected (R0) or was felt to be completely resectable in the case of
synchronous disease. The primary trial endpoint was progression-free survival (PFS). Interval trial
results were reported with a median follow-up of 3.9 years. Among patients for whom complete
resection was achieved the hazard ratio (HR) for PFS with the addition of perioperative FOLFOX4 was
0.73 (95% CI: 0.55-0.97, P ¼ 0.025), which equated to a 9.2% absolute increase in 3-year PFS from
33.2% in surgery alone compared to 42.4% when preoperative and postoperative chemotherapy were
added to the treatment regimen. Similar to the previously reported response rates to chemotherapy
with FOLFOX, approximately 40% of patients had complete or partial response in the liver following
preoperative chemotherapy. Additionally, operative mortality was only 1% in both groups,
suggesting that pretreatment with FOLFOX did not increase the mortality associated with major
liver resection. Although perioperative morbidity was higher in the group that had received
chemotherapy, the morbidity rates were not beyond the expected range for all patients undergoing
major liver resection. Overall, these results from an adjusted early endpoint demonstrated a modest
but statistically significant benefit to perioperative chemotherapy with FOLFOX without significant
added morbidity or mortality associated with dual modality therapy administered in this design.
Follow-up long-term results of this EORTC trial were published 5 years later, with a focus on their
OS data.43,44 At a median follow-up of 8.5 years there was no statistically significant difference in OS.
Additional analyses, including competing risk analysis and cancer specific survival did show a trend
toward improved survival in the group receiving chemotherapy, however these results also failed to
reach statistical significance. Similar to the results published 5 years earlier, median PFS was slightly
improved in patients receiving both chemotherapy and surgery compared to patients treated with
surgery alone (20.9 months vs 12.5 months). This difference, which was the primary endpoint in the
initial study design, did reach statistical significance.
The recent development of targeted therapies has increased the number of treatment options for
patients with metastatic colorectal cancer. For example, cetuximab is an EGFR inhibitor found to be
useful in patients that are wild-type for the KRAS gene. In the COIN trial, which demonstrated a
survival benefit associated with cetuximab among patients with unresectable disease.45 As a rational
extension to these findings, treatment with cetuximab was studied among patients with resected
CRLMs in combination with traditional chemotherapy.46 The eloxatin perioperative chemotherapy
(EPOC) trial randomized patients with resectable CRLM (and resected or resectable primaries) to
perioperative systemic chemotherapy with or without cetuximab. With an overall median follow-up
of 20.7 months, patients who received cetuximab experienced worse PFS (14.1 months compared to
20.5 months; HR ¼ 1.48, 95% CI: 1.04-2.12, P ¼ 0.03). The results of this study were unexpected and it
was theorized that possible molecular modifications in the KRAS pathway rendered the tumor
resistant to therapy or negative interaction between the chemotherapy regimens and cetuximab.
The addition of EGFR-inhibitor therapy does not appear beneficial in patients with resectable liver-
only disease, and cetuximab should not be added to standard perioperative chemotherapy regimens
for patients with resectable CRLM.
One theoretical benefit of perioperative chemotherapy is that early systemic treatment of
microscopic disease will lead to improved survival outcomes. Based on the improvements observed
in PFS in the EORTC trial, perioperative chemotherapy is considered to be equivalent with resection-
first strategies in the National Comprehensive Cancer Network (NCCN) guidelines for CRLM.47 Two
ongoing German clinical trials (CHARTA: NCT01321957, PERIMAX: NCT01540435) aim to clarify
perioperative chemotherapy strategies for resectable and unresectable CRLM.48 The perioperative
treatment of resectable liver metastases (PERIMAX) trial will compare resection and adjuvant
FOLFOX to perioperative FOLFOXIRI þ bevacizumab and resection for resectable CRLM. The CHARTA
trial will evaluate the effect of FOLFOX þ bevacizumab ± irinotecan on PFS in patients with
unresectable CRLM.
Rate of progression on chemotherapy
One consideration in the use of perioperative chemotherapy in patients with resectable CRLM is
the risk that their disease will progress through the best chemotherapeutic agents available and
become unresectable or require a more aggressive surgical approach. In large clinical trials, however,
this rate has remained low, at 5%-7%.44,49 Furthermore, even among patients who did progress while
on therapy in these trials, typically patients were still able to undergo CRLM resection. Treatment of
all patients with perioperative chemotherapy before CRLM resection would therefore only select out
a very small percentage of patients with aggressive biology who likely would progress rapidly
despite any therapy offered.
Chemotherapy-associated liver injury
A potential disadvantage of perioperative chemotherapy for CRLM is the associated liver injury
that can occur with commonly used regimens. Three different histologic entities of liver injury have
been described: steatosis, steatohepatitis, and sinusoidal obstruction syndrome.50 Oxaliplatin has
been associated with sinusoidal obstruction syndrome (“blue liver”) in up to 38% of patients, and
irinotecan is associated with steatohepatitis (“yellow liver”) in 9.3% of patients.51 Chemotherapy-
associated steatohepatitis (CASH) may be an even more adverse entity, as it is associated with
increased 90-day mortality after liver surgery for CRLM.52 The EORTC intergroup trial showed
increased morbidity in the patients who received preoperative FOLFOX, however this was not
confirmed to be as a result of chemotherapy-associated liver injury (CALI). A meta-analysis
confirmed this association of regimen-specific pattern of hepatocyte injury and also confirmed a
protective effect of bevacizumab on sinusoidal injury induced by FOLFOX regimens.53 Finally, recent
evidence has demonstrated that extensive preoperative chemotherapy leads to hepatic atrophy
which is independently associated with PHI.54
CALI is a clinical entity that must be recognized preoperatively and considered during
multidisciplinary decision-making. The influence of preoperative chemotherapy on adverse
postoperative outcomes depends on a number of factors, including the time interval between
chemotherapy and surgery.55 One study demonstrated that complication rates were inversely
proportional to the length of time between cessation of chemotherapy and surgery.56 The authors
found significantly increased risk of postoperative complications were associated with an interval
between stopping perioperative chemotherapy and undergoing surgery of less than 4 weeks (11%),
compared to 5-8 weeks (5.5%) or 9-12 (2.6%) weeks (P ¼ 0.009). The number of cycles of
chemotherapy is also important, as 49 cycles was not associated with improvement in pathologic
response rates but was associated with increased risk of sinusoidal injury up to 42% and increased
risk of postoperative liver insufficiency up to 11%.57
In summary, the use of preoperative FOLFOX ± Bevacizumab has shown efficacy in improving PFS
in patients with resectable CRLM. This regimen is safe, generally well tolerated, and is associated
with a low risk of progression on therapy. In considering the role for preoperative chemotherapy for
CRLM, however, the benefit of improved PFS must be weighed against the potential risks of CALI.
Limiting the duration of preoperative chemotherapy to ≤6 cycles and ensuring adequate FLR volume
and function before surgery will maintain the safety of liver resection. In the future, a greater
understanding of the molecular mechanisms of CALI may allow us to use liver protective strategies
and understand which patients are at increased risk for toxicity without deriving benefit.
Mechanisms to identify which patients would benefit from chemotherapy first vs a resection first
strategy will help define individual treatment strategies. Chemotherapy should be a part of the
treatment plan for most patients with CRLM, as 70% will recur after resection, however the optimal
timing in relation to surgical resection remains unclear.
Preoperative evaluation and optimization
Imaging studies
Computed tomography (CT) scan remains the most common modality for initial diagnosis of
CRLM and is usually adequate for treatment planning. Staging of the patient with CRC includes a CT
scan of the chest, abdomen, and pelvis to evaluate for metastatic disease, as the most metastases are
clinically silent. NCCN guidelines recommend CT as the modality of choice to survey patients for
evidence of recurrence.47 CRLM typically appear as hypodense lesions on the portal-venous phase.
The PROMETEO-01 study sought to define the accuracy of CT imaging for CRLM; this study found
that magnetic resonance imaging (MRI) was more sensitive than CT scan (91% vs 82%), and that after
neoadjuvant therapy, the sensitivity of CT for detection of CRLM dropped to 71%.58 Although not the
most sensitive imaging modality, CT appears to be adequate for determining the resectability of
CRLM for the most patients.
MRI provides increased sensitivity, which may be useful when additional small metastases are
suspected. CRLM are generally hypointense on T1-weighted images, slightly hyperintense on T2
images, and show restricted diffusion. After gadolinium contrast injection, metastases display a
hypovascular enhancement pattern with internal enhancement on portal venous or late venous
phase images.20 A randomized controlled trial of contrast-enhanced MRI compared to conventional
MRI or CT found that contrast-enhanced MRI was superior, with 98% diagnostic confidence
compared to 65% with CT.59 On further studies, preoperative chemotherapy was found to decrease
the sensitivity of CT (69.9%) and positron emission tomography (PET) (54.5%) but not contrast
enhanced MRI (85.7%).60
PET-CT has been adopted as a staging tool by some due in part to early studies, which showed
some improvements in detecting occult metastases.61 The use of PET-CT was evaluated in a
randomized controlled trial compared to intraoperative surgical decision-making.62 PET-CT changed
management for 8% of patients in this cohort, including 2.7% who did not undergo surgery because
of imaging findings. Ultimately similar percentages of patients underwent liver resection (91% vs
92%) and no difference in survival was observed between the 2 groups. This trial suggested that the
addition of PET-CT does not significantly influence decision-making in patients with resectable
CRLM. PET-CT may, however, have a role in the detection of occult EHD, which in 1 series was found
to be as high as 20%.63 Nevertheless, PET-CT is not currently recommended for routine surveillance
of CRLM, in preoperative planning, or for monitoring response to chemotherapy.
Comparison of these imaging modalities was performed in a meta-analysis of 3391 patients
across 39 articles. Compared to pathologic findings after resection, the study found increased
sensitivity of MRI (80.3%) and PET-CT (81.4%), compared to CT (74.4%) per individual lesion.64 When
available, contrast-enhanced MRI is more sensitive, particularly for those lesions smaller than 1 cm
and in patients with chemotherapy associated liver steatosis. PET-CT was less effective for the
detection of small liver metastasis and was more effective for detecting EHD.
Evaluation of the FLR
The risk of postoperative morbidity and mortality is directly linked to the volume and function of
the remnant liver after resection.65 Major complication rates rise to 47%, with a 20% rate of hepatic
failure and a 13% mortality rate if the FLR is less than 20% of the total volume.66 Clinically significant
anatomical variations in hepatic volumes exist among patients, with the right hepatic lobe
comprising 475% of volume in 10% of patients and the left lateral sector comprising o20% of
hepatic volume in 75% of patients.67 This anatomical variability argues for the routine use of
volumetric analysis before major hepatectomy, as the incidence of PHI would approach 10% after
right hepatectomy and 75% after extended right hepatectomy without compensatory preoperative
hypertrophy. Preoperative evaluation of liver volume is available using technology such as Scout
Liver Software (Pathfinder), which is accurate in predicting actual postoperative liver volume (r ¼
0.953, P o 0.001) and has been shown to be superior to estimation using standard equations.68,69
Hepatic steatosis, either due to pre-existing liver disease or systemic chemotherapy, requires a
greater volume of FLR: from 20% with normal hepatic function to 30% volume in patients with severe
injury and 40% in those with frank cirrhosis.70 Liver volume regeneration is negatively affected by
preoperative chemotherapy (83% vs 91% in no chemotherapy) and a linear correlation has been
observed between longer time interval and increased volume regeneration.71 Interestingly, this
effect was not seen in patients treated with FOLOX and bevacizumab.72 In 1 series of patients
undergoing extended right hepatectomy who had received prior chemotherapy, 16% developed PHI,
and the mortality rate among patients undergoing 412 weeks of chemotherapy was 2.3%.24 A FLR of
30% reduces the rate of PHI and mortality in this heavily pretreated population. A potentially
valuable indicator of liver function appears to be 99mTc-Mebrofenin Hepatobiliary Scintigraphy,
using a compound similar to indocyanine green (ICG).73 Its main advantage over traditional
measurements of galactose elimination and ICG clearance are an estimation of the function of the
FLR as opposed to the total liver.
Patient optimization
As patient outcomes become an increasingly relevant quality metric, the importance of

preoperative patient optimization continues to increase. Optimization may come in the form of
assessment and intervention for nutritional status, degree of obesity, or severity of sarcopenia. There
are emerging data on the effect of diet on outcomes after hepatectomy. A randomized controlled
trial of branch chain amino acids supplementation found improved liver regeneration 6 months after
portal vein embolization (PVE).74 A clinical trial of treatment with probiotics 6 days preoperatively
and 10 days postoperatively was found to decrease infectious complications after hepatectomy.75
Simple adjuncts to preoperative regimens may help improve outcomes after hepatectomy.
Poor nutritional status, measured by decreased levels of serum albumin, has long been
considered an adverse prognostic factor associated with poor outcomes. Newer measurements of
frailty and sarcopenia have also been linked to poor outcomes in patients undergoing hepatectomy
for CRLM. Total musculature volume and total psoas volume can be measured based on preoperative
CT scan using volumetric software. Decreased muscle volume as a surrogate for sarcopenia was
found to predict increased major complication rates (OR ¼ 3.3), prolong hospital stay (6.6 vs
5.4 days), and increase the likelihood of intensive care unit stay.76 Sarcopenia, however, was not
independently associated with decreased PFS or OS.77 Neoadjuvant chemotherapy was found to
decrease muscle mass by 5.5% on average and patients with 45% loss were less likely to go on to
receive intended adjuvant therapies (68% vs 85%, P ¼ 0.048).78 Further studies are needed to
determine if any preoperative intervention could increase muscle mass before an operation and if
sarcopenia is truly a modifiable risk factor.
Prognostic factors
Patients with CRLM demonstrate wide heterogeneity in clinical outcomes. Systems that aim to
determine patient prognosis based on individual tumor and personal characteristics have been
developed in an attempt to understand who would derive the most benefit from hepatic resection.
Such a strategy also helps in tailoring an individualized treatment strategy that focuses on delivering
appropriate, timely, and personalized therapy. In addition, in the era of modern effective
chemotherapy and multidisciplinary management, traditional measures of tumor and patient
characteristics may have less effect on survival. Recent research has focused on using genetic
biomarkers and molecular signatures to identify subgroups of patients most likely to derive benefit
from a given therapy and using better estimates of survival to guide individualized patient treatment
plans.
Patient demographics and primary tumor
Analysis of patient demographics and primary tumor pathologic features has demonstrated that
advanced T stage, positive nodal status, larger tumor size, multiple tumors, a disease-free interval of
o12 months, an elevated CEA level, the presence of EHD, and margin width (o1 cm) were negative
prognostic factors.79 Recently, CRLM from right sided colonic primary tumors80 as well as midgut
(compared to hindgut) primary tumors81 were found to be associated with worse outcomes
following liver resection.80
Resection of the primary tumor appears to have a modest survival benefit in the face of
metastatic disease. A meta-analysis of 21 studies found resection of the primary tumor in the setting
of metastatic disease was associated with improved survival compared with chemotherapy alone.82
Patients who had unresectable metastatic disease who underwent resection of the primary tumor
demonstrated a 6.4 months longer survival than those with the primary tumor left in situ. Additional
pathologic features may have varying prognostic value. Mucinous pathology is present in 10%-15% of
CRC and appears to be associated with a worse overall prognosis after resection of CRLM; in a case-
control matched analysis with nonmucinous adenocarcinoma, mucinous CRLM was associated with
significantly decreased 5-year OS (33% vs 55%) and disease-free survival (DFS) (32 vs 49%).83 Among
patients with mucinous pathology, recurrence patterns were more often peritoneal (20% vs 6%) and
at multiple sites (47.5% vs 21%), with low rates of resectable recurrence.
Early recurrence within 6 months of resection was found to occur in 10.6% of a large study of
6025 patients who underwent resection of CRLM.84 Early recurrence was most often intrahepatic
(59%), with independent risk factors for early recurrence including: T3-4 primary tumor,
synchronous CRLM, 43 CRLM lesions, 0-mm margin liver resection, and associated intraoperative
radiofrequency ablation. Overall, 36% of patients with early recurrence underwent repeat resection,
however these patients still demonstrated worse 5-year OS than patients without recurrence (27% vs
49%). Early recurrence is clearly an adverse prognostic factor and may relate to poor preoperative
disease control, inadequate surgical treatment, or aggressive tumor biology.
Clinical risk scoring systems
The use of easily measurable clinical factors to predict long-term outcome has been rigorously
studied. Several scoring systems have been developed using retrospectively collected data on large
patient cohorts. The Fong clinical risk score (CRS) is arguably the most well-known algorithm, and
assigns a single point for each of the following variables: a positive margin, EHD, node-positive
primary, disease-free interval from primary to metastases, number of hepatic tumors 41, largest
hepatic tumor 45 cm, and CEA level 4200 ng/mL.85 Based on this algorithm, patients were
effectively stratified into those with a low risk, who demonstrated a 5-year OS of 47%, versus
patients with a high risk, who demonstrated a 5-year OS of 24%. This scoring system in combination
with early scoring systems from Nordlinger and colleagues, Nagashima and colleagues, and Iwatsuki
and colleagues paved the way for later studies.86–88
The most recent scoring systems developed in the last 10 years (Table 2), show the refinements
on the initial scoring systems developed. A study comparing 8 recognized scoring systems found
that the Rees and Nordlinger system performed the best at 1, 3, 5, and 10-year time points.89 The
Rees system was the only one with a concordance index of greater than 0.7 for DSS at 1 and 3 years,
leading the authors to question the clinical utility of all such scoring systems.
The use of scoring systems as clinically relevant models has been challenged, as they appear to
function relatively well in predicting survival outcomes but have not been validated for guiding
treatment or surveillance decisions. Conditional survival – the future survival probability given
survival time accumulated – was hypothesized to be a better measurement for known scoring
systems.6 In a large multi-institutional analysis of patients who underwent resection of CRLM, the
scoring systems had moderate to poor concordance (c-statistic of 0.56–0.58), whereas conditional
survival provided more accurate prognostic information. This analysis demonstrated that the
probability of surviving an additional 5 years after already surviving 1, 3, or 5 years after CRLM
resection, was 41%, 40%, or 50%, respectively; in this large cohort, conditional survival was superior
to all other scoring systems at clarifying the prognosis of those patients initially predicted to have
poor survival. In the future, incorporation of better markers of tumor biology, such as molecular
features or previous response to therapy, will improve the clinical accuracy and value of these
scoring systems.
Table 2
Select prognostic clinical scoring systems for colorectal liver metastasis (CRLM).
Scoring system Predictive factors Survival estimates
Basingstoke predictive index • Preoperative and postoperative factors Low score: 5 y, 66%
(BPI) • Number of hepatic metastases 4 3 High score: 5 y, 2%
Rees and colleagues247
• Node positive primary
• Poorly differentiated primary
• Extrahepatic disease
• Tumor diameter ≥ 5 cm
• CEA level 460 ng/mL
• Positive resection margin
MSKCC nomogram • Nodal status of the primary tumor Low score: 96-mo OS,
Kattan and colleagues248 • Disease-free interval 40%
High score: 96-mo OS,
• Size of the largest metastatic tumor 10%
• Preoperative CEA
• Bilateral resection
• Extensive resection (lobectomy or more)
• Gender
• Number of hepatic tumors
• Primary cancer site (colon vs rectum)
• Age
Japanese Classification System • Five or more hepatic metastases Low score: 3-y OS, 63%
(Yamaguchi249 2008) • Size 4 5 cm High score: 3 yr OS, 17%
• Nodal status (N2)

• Presence of extrahepatic disease
Damm and colleagues 250
• Clinical factors for survival after Y90 Low score: OS, 10 mo
radioembolization High score: OS, 5 mo
• Tumor load 4 20%
• CEA 4 130 ng/mL
• CA19-9 4 200 U/mL
• Karnofsky index o 80%
Hill and colleagues 251
• Risk of recurrence after hepatectomy: Low score: OS 50 mo
• CEA 4 200 High score: OS 22 mo
• 41 CRLM
• Nonmajor hepatectomy
Tumor Burden Score 252
• Number of liver metastases Low score: 5-y OS, 69%
Sasaki 2016 • Diameter of largest liver metastasis High score: 5-y OS, 26%
Modified clinical score23 • Primary tumor lymph node status Not reported
Brudvik 2017 • Diameter of largest liver metastasis
• RAS mutation status
CEA, carcinoembryonic antigen.
Response to Chemotherapy
Many patients with resectable CRLM are treated with perioperative chemotherapy which results
in an improved PFS of 9 months.43 Other potential advantages of perioperative chemotherapy
include the ability to downstage tumors to make surgery easier or convert unresectable to resectable
disease, and to give patients at high risk of systemic progression the time to declare further
metastatic disease which may preclude curative resection. Indeed, in the EORTC trial, the rate of
non-therapeutic laparotomy (due to unsuspected findings of advanced or unresectable disease) was
lower among patients who received preoperative chemotherapy. Finally, with the tumor in place the
radiologic and pathologic response to chemotherapy can be judged, which in turn helps in
understanding prognosis. Those who received neoadjuvant chemotherapy had high rates of
pathologic response (57%) and fibrosis (21%), which correlated independently with disease specific
survival.90
Pathologic response to therapy carries important prognostic information in many gastrointestinal
cancers including CRLM. A retrospective review of 305 patients found that after CRLM resection,
survival was independently predicted by only tumor margin and response to chemotherapy.91
Complete pathologic response to irinotecan and oxaliplatin based therapies (9% of cohort)
demonstrated the highest 5-year OS of 75%, while major response (36%) and minor response
(55%) were associated with 56% and 33% OS, respectively. Bevacizumab-containing regimens were
found to have an impact on CT morphologic measurements of response and ultimately survival.92,93
Patients with “optimal morphologic response,” defined as evolvement of heterogeneous masses with
ill-defined margins to more homogenous masses with sharp margins, demonstrated improved
median OS of 31 months compared to 19 months among patients with no radiographic response.
Similarly, markers of pathologic response have also been found to be independently predictive of
DFS.94
Although Response Evaluation Criteria in Solid Tumors (RECIST) criteria are used to objectively
measure response to treatment for most solid tumors, these criteria have been found to be poor
predictors of pathologic response to treatments in CRLM. The modified RECIST (mRECIST) criteria
seemed to fare better than RECIST, but neither was predictive of residual viable tumor cells in
resected specimens.95 Metabolic response to chemotherapy may be a more predictive model of final
pathological diagnosis and hence prognosis. Maximum standardized update value on PET correlated
with survival, with 86% 3-year survival in those with metabolic response versus 38% in those with no
response.96
Disappearing liver metastasis
A subset of patients who receive preoperative chemotherapy for any indication will have a
complete radiographic response. The incidence of disappearing liver metastases ranges from 5%-
38%, depending on the completeness and quality of preoperative imaging, the response to therapy,
and the pretreatment size of the metastasis.20 The intraoperative ability to detect lesions which have
disappeared on preoperative imaging is modest, reported at 45% in 1 series.97 This detection rate is
increased with hepatocyte specific contrast agents (Gd-EOB-DTPA) and does not appear impacted by
contrast enhanced ultrasound.98 Even the most sensitive detection methods such as Eovist MRI
found that 38% of CRLM were disappearing, of which 55% of lesions still harbored viable tumor cells
upon resection.99 Management of this patient population is particularly challenging as there are
conflicting data on the natural history of these metastases.100
One question is whether this imaging response correlates with pathologic response and whether
the responses are durable. A study of 435 patients who received preoperative chemotherapy found
that 10% had disappearing liver metastases, of which 64% were “true”: complete responses (CRs)
such that there was either a pathologic CR on resection or a clinically durable response with no
reappearance of lesions on imaging.101 On the other hand, a systematic review found that 25%-45%
of disappearing liver metastases contained residual macroscopic disease at the time of resection.100
Nevertheless, whether resection of disappearing liver metastases results in an improvement in OS is
unknown.97 In the absence of better evidence, current recommendations are to resect all
disappearing liver metastases when feasible.102 Some authors recommend placement of fiducial
markers prior to initiation of systemic chemotherapy for “high risk” lesions (ie, small and
nonperipheral lesions) to aid in their identification at the time of surgery.103
Molecular markers as prognostic indicators
KRAS mutation is present in approximately 15%-36% of patients with CRLM,104 and mutational
status has been found to be a predictor of response to chemotherapy and to have an association with
survival. In patients treated with FOLFOX-Bevacizumab, radiographic and pathologic response rates
were superior in wild type (32.9% and 58.9%) compared to KRAS mutants (10.5% and 36.8%).105 KRAS
mutation was also found to be an independent predictor of decreased OS (OR ¼ 2.0), with a 5-year
survival of 23% compared to wild type at 61%.
The BRAF gene is also implicated in the pathogenesis of colorectal cancer, as is it involved in the
MAPK pathway, similar to KRAS. The most common mutation, V600E, was found in 9% of patients
with CRC and 2%-4% of patients with CRLM who underwent curative surgery.106-108 BRAF mutations
in primary tumors as well as CRLM have been associated with poor survival. Recurrence free survival
was only 5.7 months among patients with BRAF mutants, compared to 11 months for those with
KRAS mutants and 14.7 months for those wild-type for both BRAF and KRAS.108 Conversely, BRAF
mutations are commonly associated with high-level microsatellite instability (30%), which
traditionally carries a good prognosis.109 Despite the association, these patients have the worst
prognosis (10-month median OS) and typically demonstrate poor response to all lines of
chemotherapy, including Cetuximab.110,111 The outcomes of patients undergoing resection of
BRAF-mutant CRLM have traditionally been poor.112
Emerging evidence is elucidating the prognostic significance of other CRLM tumor mutations.
For example, SMAD4 encodes for a protein involved in the transforming growth factor (TGF)-β
signaling pathway and loss of SMAD4 expression from sporadic tumor mutations is associated
with worse prognosis after CRLM resection. Interestingly, other genetic mutations appear to
interact in a synergistic fashion. For example, concomitant RAS and TP53 mutations are
independently associated with worse outcomes following resection of CRLM.113 In addition,
coexistence of APC and PIK3CA mutations have been associated with worse outcomes for patients
with CRLM who undergo resection or are treated with chemotherapy alone.114 Although these genes
are independently prognostic, their clinical use remains unclear at this point (Table 3). One goal has
been to build a prognostic model using gene expression levels from next generation sequencing
platforms that could provide superior prognostication and perhaps even guide individualized
treatment. Similar to a prognostic CRS, a molecular risk score was generated by researchers at
Memorial Sloan Kettering. Two molecular signatures were generated which predicted both disease-
specific survival (DCC) and liver recurrence rates.115 Using both CRS and molecular risk score,
patients were able to be reliably separated into a low risk cohort (3-year DSS ¼ 90%) vs a high-risk
cohort (3-year DSS 42%).
It may also be possible to detect these mutations in circulating tumor cells (CTCs) before
resection and provide targeted therapies even before resection of the tumor.116 In 1 study, CTCs were
detected in the blood of 43% of patients undergoing liver resection for CRLM and 16% had a high
number (43/7.5 mL of blood).117 However, the presence of CTC did not influence the 1-year
recurrence rate (48%) nor did it accurately identify patients at high risk for recurrence. In another
study that included patients with more extensive disease undergoing 2-stage resection, 38% were
found to have detectable CTCs and these predicted increased risk of recurrence and shorter OS.118
Additional studies are needed to determine the predictive ability of CTCs in patients with CRLM and
their utility in influencing treatment decisions.
Technical aspects of resection
After meeting criteria for resectability, the technical aspects of liver resection are similar to the
management of primary hepatic malignancies. One notable difference is the emphasis on
parenchymal-sparing approaches for CRLM, often achieved via non-anatomic resections, which
allow for preservation of liver volume and function and have been associated with improved
outcomes.119 Compared to major hepatectomy, parenchymal-sparing hepatectomy (PSH) has been
associated with lower rates of overall complications (34% vs 25%), lower risk of liver failure (7% vs
Table 3
Select genetic prognostic markers associated with colorectal liver metastases (CRLM).
Molecular profile Clinical predictor in CRLM
KRAS mutation • Decreased radiographic and pathologic response rates to FOLFOX-

Bevacizumab regimen105
• Decreased 5-y survival (23%-30%)105,253,254
• No difference in liver recurrence rate (3 y 50% RFS)255,256
• Earlier lung recurrence256
• Decreased survival after recurrence (HR ¼ 1.9)253,255
• Different patterns of recurrence: bone, brain, and lung254
• Location of mutation impacts survival—G12V and G12S are worse
prognostic factors on overall survival and survival after recurrence255
• Associated with increased CIP2A expression and worse survival257
BRAF V600E mutation • Associated with high level microsatellite instability109
• Decreased overall survival—8 mo258
• High risk of recurrence HR ¼ 2.3 and poor RFS of 5.7 mo108
• Response to systemic chemotherapy is low and does not alter
progression free survival significantly at 2-6 mo110
EGFR family • HER-3 overexpression associated with improved overall survival259
• HER-1 associated with poor prognosis, HR ¼ 1.5260
261
Metastasis associated in colon cancer 1 • Increased risk of recurrence after liver resection, HR ¼ 5.2
(MACC1) overexpression
2%), and less usage of intensive care unit resources.120 PSH appears oncologically equivalent to
formal anatomical resections of CRLM, with no negative impact on OS, RFS, liver-only RFS, or rate of
margin positivity.121,122 Liver-only recurrence rates were 14% in PSH compared to 17% in all other
resection types among patients with low volume disease and 43% vs 50% among patients with
extensive bilobar disease. Furthermore, patients who are managed with PSH are more likely to be
candidates for repeat resection in the event of intrahepatic recurrence. Parenchymal-sparing
techniques should be considered the first-line surgical approach for CRLM unless the anatomy or the
extent of disease preclude such an approach.123
Intraoperative identification of metastases
Preoperative cross-sectional imaging, with either MRI or CT, is imperative for evaluating the
extent and distribution of CRLM as well guiding the extent of surgery required. However, the
sensitivity of these modalities for detecting all metastases is not 100% and therefore intraoperative
ultrasound (IOUS) can be a useful adjunct in identifying CRLMs. Use of standard IOUS to augment
preoperative imaging found additional lesions not seen on MRI or CT in 8% of patients, which in turn
required a change in surgical strategy in 1.4%.124 Although not routinely used in the United States,
contrast-enhanced ultrasound has been shown to improve detection and successful resection of
CRLM in patients with multiple tumors and isoechoic tumors.125 Regardless, IOUS is a mandatory
tool for any hepatobiliary surgeon and should be used routinely to clarify the anatomic relation of
tumors to major vascular and biliary pedicles as well as guide the appropriate parenchymal
transection.
Use of a near-infrared fluorescent dye, ICG, with fluorescent imaging and ultrasound to guide
resection has also been shown to be an effective adjunct. ICG accumulates in the rim of compressed
liver tissue around the tumor, creating a fluorescent halo that accentuates the ability to identify very
small tumors (Fig 4).126 In a small series of 25 patients, 77 tumors were identified by ICG fluoroscopy
with ultrasound, of which only 71% were identified by ultrasound alone, and only 58% by
preoperative imaging alone.127 ICG-guided resection was most useful in identifying lesions smaller
than 3 mm; because this technology suffers from poor tissue penetration for deeper lesions,
however, ICG may remain complementary to standard IUS for the identification of small lesions.
Two-stage resection with PVE
Patients with extensive bilobar liver metastases represent a unique challenge. Use of neoadjuvant
chemotherapy to decrease tumor burden combined with PVE and 2-stage resection can afford
prolonged survival similar to initially resectable patients, with 5-year OS of 40%-50% reported.128
Dropout due to tumor progression after the first stage occurs in approximately 20% of cases and is
associated with worse OS.129,130 On the other hand, tumor progression after PVE that does not
preclude second stage resection did not affect OS, although this was associated with earlier tumor
recurrence. A borderline response to neoadjuvant chemotherapy may predict tumor progression
after PVE.131 Nevertheless, this strategy is now well established in patients with advanced bilobar
CRLM who are initially unresectable because of an insufficient FLR.
PVE is the primary FLR augmentation strategy and has been shown to permit resection in 63% of
patients who initially had an inadequate sized FLR.132 It may also serve as a preoperative test of
hepatic function by evaluating the regenerative capacity of the FLR in response to PVE. PVE should be
performed in an ipsilateral transhepatic approach (to avoid injury to the FLR) and the degree of
hypertrophy (DH) is optimized when PVE is performed using microspheres and coils. Measured 4-6
weeks following PVE, a DH of the FLR by 5% has been associated with reduced rates of PHI.133 In
addition, the kinetic growth rate (KGR), calculated as the DH divided by the number of weeks since
PVE, has been shown to be one of the strongest indicators of posthepatectomy outcomes.134 In a
large single-institution series of patients undergoing PVE before extended hepatectomy, the best
predictor of outcome was a KGR of 42%, with none of these patients experiencing PHI or mortality,
compared to 21% PHI and 8% mortality in those patients with KGR o 2%.135 Extension of the PVE to
segment 4 can help achieve an improved hypertrophic response when extended right hepatectomy
is anticipated.136 Identification of strategies to maximize the DH and KGR after PVE will potentially
improve outcomes in patients undergoing extended and 2-stage resections.
Associating liver partitioning and portal vein occlusion for staged hepatectomy
A novel accelerated 2-stage technique using in situ portal vein ligation, associating liver
partitioning and portal vein occlusion for staged hepatectomy (ALPPS) was first performed in 2007
and then reported in 2012.137 The first stage of ALPPS involves clearing tumor from the FLR, splitting
the liver along a planned transection line, and performing contralateral portal vein ligation. This
results in rapid hypertrophy of the FLR, which permits completion hemihepatectomy at a second
stage operation 7-14 days later.138 This technique has generated significant interest and controversy,
as initial data reported a high rate of morbidity (28% major complication rate) and mortality (12% 90-
day mortality).139 Technical causes surrounding adaptation of a new procedure and poor patient
selection may have initially accounted for these poor outcomes; more recent series reported
improved, albeit still elevated 90-day mortality rates of 8.8%, with the predominant cause being liver
failure in 75% of these patients.140
The consensus remains mixed regarding the benefits of ALPPS as compared to a 2-stage
approach. In a meta-analysis comparison of ALPPS to the planned 2-stage approach, ALPPS was
associated with more rapid and greater increase in the size of the FLR, and a greater proportion of
patients made it to the second stage of resection than with the 2-stage approach.138 These benefits of
the ALPPS were offset, however, by increased morbidity and mortality (up to 73% and 12%,
respectively). One study found similar gain in FLR volume (47% vs 41%) but found increased rates of
major complications after the second stage of ALPPS (41.7% vs 17.6% in the 2-stage group).141 OS was
decreased in the ALPPS group (42% vs 77% OS at 2 years) and recurrence rates within the liver were
higher in the ALPPS group, with fewer patients able to be salvaged by repeat hepatectomy.142 As
Fig. 4. Near-infrared (NIR) fluorescence imaging of colorectal liver metastases is shown. A colorectal liver metastasis
(arrow) is clearly identified by a rim around the tumor in vivo (top row), 24 hours after injection of 10 mg indocyanine
green. Normal liver tissue (arrowhead) shows minimal background uptake of indocyanine green. In 5 patients, small,
superficial, otherwise occult metastases (middle row, arrow) were identified by NIR fluorescence imaging. Benign
lesions (bottom row, dashed arrow) could be differentiated from malignant lesions by a lack of a fluorescent rim around
the lesion. (Reprinted with permission from van der Vorst and colleagues.126)
with any new procedure, it remains critical to define the optimal selection criteria for this procedure,
with special scrutiny for patients that are candidates for other curative-intent treatments.
Combined resection and ablation
Use of combined strategies may turn a 2-stage resection into 1 stage with ablation and allow for
preservation of hepatic parenchyma. These 2 strategies were previously compared in 156 matched
patients, including those who dropped out after the first stage, with analysis revealing similar OS
(37.2 vs 34.5 months) and DFS (9.4 vs 7.5) months.143 Several other series have shown similar
outcomes with low complication rates and mortality.144 These comparisons are difficult, however, as
the patient populations being compared are inherently different; patients within the resection and
ablation cohort often have poor prognostic factors which confound any comparisons. Because
recurrence is common among both resected and ablated patients, the optimal criteria for combined
resection and ablation strategies remains undefined. Nevertheless, the use of intraoperative or
percutaneous ablation should be considered as part of a comprehensive multidisciplinary strategy to
manage patients with advanced bilobar CRLM.145
Minimally invasive techniques
Laparoscopic liver resection (LLR) was first described in the early 1990s, as surgeons sought to
extend the benefits of minimally invasive surgery to patients undergoing liver resection. This
technique has gained some popularity in particular for patients with small (o5 cm) lesions that are
located in peripheral (ie, favorable) locations within the liver. Patients with benign lesions requiring
nonanatomical resections were good candidates for the early phase of LLR. As experience in LLR has
grown, more complex resections including major hepatectomies and living donor hepatectomies are
currently being performed in highly specialized centers. Several inherent challenges to the wider
adoption of LLR remain, including the lack of necessary laparoscopic skills, concern regarding the
difficulty of controlling potential massive hemorrhage, concerns about gas embolism, difficulty in
accessing certain lesions, and the inability to palpate the liver and provide tactile feedback. The use
of hand assistance or laparoscopic assistance (hybrid laparoscopic-open procedures), where the liver
is mobilized laparoscopically but the parenchymal transection is performed via a small open
incision, have helped overcome some of these challenges and allowed for wider adoption of
minimally invasive techniques. Given unique challenges of LLR and the rapidly increasing interest in
the platform, an international conference convened in 2008 and established guidelines and
recommendations for the use of LLR.146
Excellent outcomes of laparoscopic major hepatectomies in highly specialized centers are being
achieved. Dhager and colleagues147 retrospectively evaluated the outcomes of 210 laparoscopic
major hepatectomies performed at 6 centers in Europe, Australia, and the United States, including
136 right and 74 left hepatectomies. Mean operative time was 250 minutes, operative blood loss was
300 mL, and 14% of patients received a blood transfusion. The conversion rate to open hepatectomy
was 12%, and the Pringle maneuver was performed 11% of the time. Median tumor size was 5.4 cm
with a surgical margin of 10.5 mm. Two patients died from pulmonary embolism and urosepsis,
while the liver-specific complication rate was 8% and overall complication rate was 14%. Hospital
length of stay was 6 days.147
Although prospective randomized controlled trials comparing laparoscopic and open liver
resections are lacking, numerous retrospective case controlled studies comparing both approaches
have been reported (Tables 4 and 5). A systematic review of 31 retrospective studies comparing
laparoscopic and open liver resection encompassing a total of 2473 patients was reported by Nguyen
and colleagues.135 In case-cohort matched patients, LLR was associated with less intraoperative
blood loss, earlier resumption of oral diet, less opioid analgesic use, and a shorter hospital stay. The
complication rate was similar between the 2 groups. The higher operative cost of laparoscopic
resections was offset by the cost savings due to the shorter hospital stay.148
Initial concerns about margin status and oncologic outcomes also served as deterrents to the
widespread usage of LLR for malignant lesions. Beppu and colleagues149 evaluated the long-term
oncologic outcomes of LLR for CRLM in a retrospective case-control study using propensity score
matching to compare 342 patients who underwent open hepatectomy and 171 patients who underwent
laparoscopic hepatectomy. Estimated blood loss and hospital stay were reduced in the laparoscopic
group, perioperative morbidity and mortality were similar between the 2 groups, and 5-year OS, RFS,
and DFS rates were similar between the 2 groups. R0 resection rates were similar, with equal median
pathological surgical margins of 5 mm achieved in both groups. No studies have reported port site
metastases following laparoscopic hepatectomy for malignant lesions. In addition, LLR has been
associated with a decrease in the time interval between surgical resection and the administration of
adjuvant chemotherapy, likely due to more rapid recovery and lower rates of wound complications.150
Laparoscopic resection requires extensive knowledge of liver anatomy including potential
anatomical variants, experience in open liver resection, and advanced laparoscopic skills. There may
be a significant learning curve associated with the technical steps required for LLR; in 1 large study this
learning curve was shown to be approximately 60 hepatectomies.151 Over an 8-year period of
laparoscopic hepatectomy experience, average operative time decreased from 210-150 minutes, the
conversion rate to open resection decreased from 15.5%-3.4%, and morbidity decreased from 17.2%-3.4%.
During LLR the liver is accessed from a caudal direction, which makes lesions in the anterolateral
hepatic segments (segments II, III, IVb, V, and VI) more favorable to a laparoscopic approach while
those in the posterosuperior hepatic segments (segments I, IVa, VII, and VIII) are more challenging
(Fig 5).152 Laparoscopic resection of central hepatic lesions, bilobar metastases, and tumors close to
the roots of the hepatic veins and the inferior vena cava have been reported, however LLS appears
most suitable for smaller lesions located in the periphery of the liver. Some surgeons advocate
changing the patient’s position from the traditional supine approach to lateral decubitus or even
prone positioning to facilitate access to difficult lesions. In addition, some have suggested placing
trocars at the intercostal spaces through the pleural space and the diaphragm to better approach the
posterosuperior segments.153 The liver hanging maneuver can also be performed laparoscopically to
reduce blood loss during major hepatectomies. Finally, newer technologies, including the use of ICG
and near-infrared red light, have the potential to improve laparoscopic localization of the lesions,
572
Table 4
Select studies comparing short-term outcomes of laparoscopic liver resection (LLR) and open liver resection (OLR).
Study Hepatectomy number Follow-up (mo) Conversion rate (%) Blood loss (mL) R0 resection (%) Morbidity (%) Hospital stay (d)
LLR OLR LLR OLR LLR OLR LLR OLR LLR OLR
Martinez-Cecilia and colleagues262 4 40 400* 39* 8*
J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

287 488 7.5 250 88 88 22 5
Zeng and Tian263 385 385 43 NR 250 351* 100 100 14 19 10 13*
Untereiner and colleagues264 18 101 5.4 5.6 30 200 94 94 17 44 6.0 7.5
Cipriani and colleagues265 176 191 LLR ¼ 30 9.8 400 500* 93 87 31 53* 4 7*
OLR 23
Lewin and colleagues266 146 138 36 NR 300 570* 91 82* 23 29 5 7.8*
Alard and colleagues267 176 2444 29 1.7 NR NR 85 74* 33 19* 11.1 13.9*
Nachmany and colleagues268 42 132 LLR ¼ 21 11.6 251 422 89 90 26 41 6.8 8.4*
OLR ¼ 42
Langella and colleagues269 37 37 LLR ¼ 35.7 NR 100 85 89 92 14 38* 5 6.6*
OLR ¼ 47.9
Beppu and colleagues149 171 342 LLR ¼ 42 NR 163 405* 90 92 14 13 12 14*
OLR ¼ 49
Hasegawa and colleagues270 100 68 LLR ¼ 29 1 127 620* 93 91 9 17* 9 16*
OLR ¼ 36
Lin and colleagues271 36 36 43 0 278 382* 100 100 25 31 7.4 9*
de’Angelis and colleagues272 52 52 LLR ¼ 59 5.8 200 300* 83 89 9 11 6 9*
OLR ¼ 54
Qiu and colleagues273 24 25 LLR ¼ 31 NR 210 380* 92 100 25 48* 7 11*
OLR ¼ 32
Montali and colleagues274 57 57 LLR ¼ 41 16 454 691* 87 91 16 32* 7 9*
OLR ¼ 54
Iwahashi and colleagues275 21 21 NR NR 198 326* NR NR 10 24 18 27
Inoue and colleagues276 23 24 NR 4.3 99 397* NR NR 9 21 11 14
Doughtie and colleagues277 8 76 23 0 225 400* 100 90 13 61* 3.5 7*
Qiu and colleagues278 30 30 NR 6.6 215 385* NR NR NR NR 8 12*
Cheung and colleagues279 20 40 NR NR vs 0 200 310* NR NR NR NR 4.5 7*
Guerron and colleagues280 40 40 16 5 376 753* NR NR 15 20 4 7*
NR ¼ not recorded.
⁎
P o 0.05.
Table 5
Overall, disease free, and recurrence free survival of laparoscopic liver resection (LLR) and open liver resection (OLR).
Study OS (%) RFS (%) DFS (%) Survival measure
LLR OLR LLR OLR LLS OLR
Martinez-Cecilia and colleagues262 51 45 33 27 NR NR Median

Zeng and Tian263 51 51 NR NR 42 42 5y
Untereiner and colleagues264 100 83 NR NR 89 78 3y
Cipriani and colleagues265 64 63 23.7 24 34 53 5y
Lewin and colleagues266 54 63 36 38 NR NR 5y
Alard and colleagues267 78 75 NR NR 32 36 5y
Nachmany and colleagues268 64 73 NR NR NR NR 3y
Langella and colleagues269 92 75 NR NR 69 66 3y
Beppu and colleagues149 70 68 53 51 73 70 5y
Hasegawa and colleagues270 57 49 40 29 NR NR 5y
Lin and colleagues271 51 55 NR NR 38 27 5y
de’Angelis and colleagues272 73 63 NR NR 21 21 5y
Qiu and colleagues273 24 30 NR NR 30 35 3y
Montali and colleagues274 60 65 NR NR 29 38 5y
Iwahashi and colleagues275 42 51 NR NR 14 25 5y
Doughtie and colleagues277 NR 22 NR NR 14 13 Median
Cheung and colleagues279 69 42 10 11 NR NR Median
Guerron and colleagues280 89 81 35 30 NR NR 5y
NR, not recorded.
ensure adequate resection margins, and allow detection of smaller lesions that were missed on
preoperative imaging but require further investigation.
Ultimately as these techniques continue to evolve, their use may become more commonplace.
There are strong data that in appropriately selected patients, LLR is safe and oncologically equivalent
to open hepatectomy. How widely LLR is incorporated into current practice will depend on the
benefits of decreased length of stay and apparent decreased complication rates versus the technical
expertise required.
Postoperative outcomes
Morbidity and mortality in modern series
Operative mortality for resection of CRLM has steadily decreased in the last few decades.
Improvements in surgical technique and anesthesia and critical care have contributed to improved
outcomes, including for major hepatectomies. Modern studies have shown that high volume centers
have achieved perioperative mortality rates of 1%-5%, with several centers reaching rates less than
3% (Table 6). As an example, a 2-decade review of more than 4000 consecutive liver resections
performed at Memorial Sloan Kettering found postoperative complication rates decreased from
53%-20% while 90-day mortality decreased from 5.0%-1.6%.154
Contemporary series have estimated that approximately 20% of patients undergoing hepatic
resection will develop a major postoperative morbidity (Table 7). The most common significant
complications after liver resection are infectious in nature. Sepsis, organ space infection, and septic
shock have relatively high prevalence, at 6.7%, 6.0%, and 3.7%, respectively. Biliary fistula, a major
concern of hepatobiliary surgeons, is a primary contributor to these rates. In addition, the higher
rates of pulmonary-related complications may be a result of large upper abdominal incisions, with
ventilator dependence greater than 48 hours, pneumonia, and unplanned intubation rates reported
at 4.4%, 4.0%, and 3.7%, respectively.
Fig. 5. Favorable and unfavorable liver segments for minimally invasive hepatectomy. (Reprinted with permission from
Guro and colleagues.152)
Early recovery after surgery protocols
Enhanced recovery after surgery (early recovery after surgery [ERAS]) protocols have been
applied to all types of surgery, including hepatectomy for CRLM. These protocols incorporate a
variety of factors in the preoperative, intraoperative, and postoperative periods that are intended to
reduce the overall physiologic stress of surgery and expedite recovery, which in turn theoretically
reduces postoperative complications and overall length-of-stay in the hospital.
The components of ERAS protocols vary by study and institution but most share similar themes.
In the preoperative period, the patient may be allowed nutrient-rich fluids for carbohydrate loading
up to 2 hours before the operation. No oral bowel preparation is typically used, and an epidural is
often placed as the preferred source of analgesia. Intraoperatively, temperatures are regulated to
avoid hypothermia, with tighter control of postoperative nausea or vomiting. Unless clinically
indicated, routine placement of abdominal drains and nasogastric tubes is avoided. Postoperatively,
care is taken to expedite recovery with the early removal of urinary catheters and resumption of
normal diet on the first postoperative day. Intravenous fluids are titrated to urine output and
euvolemia and are stopped after tolerance of a diet.
A systemic review evaluating the outcomes of patients undergoing hepatic resection who were
placed on ERAS protocols found that the protocols are feasible.155 Overall length of stay was
reduced from 11 days using traditional surgery protocols to 4 days using the ERAS protocol. This
was achieved without a significant increase of patient morbidity, surgical complications, or
readmission rates. Based on this systemic review and anecdotal institutional evidence, ERAS
protocols appear safe and effective for implementation in patients undergoing hepatic resection of
CRLM.
Quality improvement initiatives
With increasing focus on surgical outcomes, a joint collaborative between the American Hepato-
Pancreato-Biliary Association (AHPBA) and the American College of Surgeons (ACS) National Surgical
Quality Improvement Program (NSQIP) was initiated to formulate new randomized controlled trials
to reduce the morbidity and mortality associated with hepatic resections. A review of the NSQIP
database of hepatectomies shows the current benchmark for 30-day mortality rate for all
hepatectomy patients is roughly 2.5%, with specific 30-day mortality of partial, left, right, and
extended hepatectomies to be 1.8%, 0.9%, 3.7%, and 5.2%, respectively, correlating to the extent of
resection. With improvement of surgical technique and modern parenchymal sparing resections,
overall morbidity and mortality of hepatectomies has improved. Furthermore, multiple studies have
correlated perioperative outcomes with surgical volumes for hepatectomy.
Table 6
Survival outcomes after resection of colorectal liver metastasis (CRLM) in select large reported series.
Study Patients (n) Operative mortality (%) Overall survival (%)
1y 3y 5y Median (mo)
Fong and colleagues85 1001 2.8 89 57 36 42

Choti and colleagues13 226 1 93 57 40 46
Pawlik and colleagues27 557 0.9 97 74 58 49.6
Cummings and colleagues14 833 4.3 – – 32.8 –
Wang and colleagues281 923 – – – 22 –
Niu and colleagues282 415 3.1 85 45 29 32
Blazer and colleagues91 305 – – – 42.7 51
Malik and colleagues283 700 – – – 45 –
Reissfelder and colleagues284 281 – 94.6 61.8 33.7 48.6
de Jong and colleagues2 1669 – – – 47.3 36
Robertson and colleagues285 3957 8.2 – – 25.5 –
House et al (2010)16 1600 2.3 88 61.2 41.9 50.4
Hwang and colleagues286 3481 0-4.2 – 42.4 28 30.5
Leung and colleagues22 219 – – 49 28 34.4
Adjuvant therapies following hepatectomy
Indications and use of chemotherapy
In the early era of resection for CRLM, several landmark trials and analyses demonstrated modest
benefit to adjuvant chemotherapy. Following complete resection of CRLM, the majority of
recurrences are hepatic or pulmonary metastases, suggesting that the addition of systemic therapy
to surgical resection may be integral for controlling subsequent recurrences. An early multi-center
randomized control trial conducted by the French Federation of Digestive Cancers (FFCD)
Table 7
Incidence of major complications based on type of hepatic resection. (Reprinted with permission from Aloia and
colleagues.287)
All Partial Left Right Extended

hepatectomy, hepatectomy, hepatectomy, hepatectomy, hepatectomy,
n (%) n (%) n (%) n (%) n (%)
Total 2313 (100) 1344 (58) 230 (10) 510 (22) 229 (10)
Sepsis 154 (6.7) 77 (5.7) 12 (5.2) 43 (8.4) 22 (9.6)
Organ space infection 138 (6.0) 61 (4.5) 12 (5.2) 40 (7.8) 25 (10.9)
Return to the operating 112 (4.8) 46 (3.4) 11 (4.8) 37 (7.3) 18 (7.9)
room
Ventilator requirement 101 (4.4) 43 (3.2) 7 (3.0) 34 (6.7) 17 (7.4)
4 48 h
Pneumonia 93 (4.0) 41 (3.1) 8 (3.5) 28 (5.5) 16 (7.0)
Septic shock 86 (3.7) 36 (2.7) 5 (2.2) 26 (5.1) 19 (8.3)
Unplanned intubation 85 (3.7) 39 (2.9) 6 (2.6) 24 (4.7) 16 (7.0)
Deep venous thrombosis 47 (2.0) 17 (1.3) 4 (1.7) 14 (2.7) 12 (5.2)
Pulmonary embolism 38 (1.6) 16 (1.2) 1 (0.4) 13 (2.5) 8 (3.5)
Acute renal failure 35 (1.5) 13 (1.0) 1 (0.4) 16 (3.1) 5 (2.2)
Cardiac arrest 25 (1.1) 10 (0.7) 1 (0.4) 10 (2.0) 4 (1.7)
Progressive renal 15 (0.6) 5 (0.4) 1 (0.4) 7 (1.4) 2 (0.9)
insufficiency
Cerebrovascular accident 11 (0.5) 4 (0.3) 1 (0.4) 3 (0.6) 3 (1.3)
Myocardial infarction 8 (0.3) 5 (0.4) 0 (0) 2 (0.4) 1 (0.4)
Coma 6 (0.3) 4 (0.3) 0 (0) 1 (0.2) 1 (0.4)
randomized 173 patients who underwent complete R0 resection of CRLM to either surveillance or to
receive 6 months of adjuvant 5-FU plus leucovorin, to assess whether the addition of adjuvant
chemotherapy improved outcomes following CRLM resection.156 Exclusion criteria included
presentation with recurrence of primary tumor or more than 1 metastatic site, receipt of any other
chemotherapy within 1 year or radiotherapy within 1 month of resection, or a long delay between
surgery and initiation of chemotherapy. The study ultimately closed after a slow patient accrual rate
over a 10-year period. With a median follow-up of 87.4 months across the study population, 2-year
and 5-year DFS rates for the adjuvant chemotherapy cohort were 50.4% and 33.1%, respectively, vs
38.1% and 27.6% for the resection-only cohort (OR for recurrence or death ¼ 0.66, 95% CI: 0.46-0.96).
Overall survival was evaluated as a secondary endpoint, with a modest benefit observed for patients
treated with adjuvant chemotherapy (OR ¼ 0.73, 95% CI: 0.48-1.10), although this did not reach
statistical significance (5-year OS ¼ 51.1% vs 41.1%). Short tumor-free interval (less than 12 months),
postoperative complications, and an elevated preoperative CEA level were all associated with worse
DFS.
Similarly, the EORTC Trial 40923 randomized 129 patients with colorectal metastases to either
liver or lung who underwent complete R0 resection to either observation or adjuvant chemotherapy,
using a similar regimen as in the FFCD trial.157 The primary outcome measure was OS, with DFS
considered a secondary endpoint in this analysis. Just as in the FFCD trial, enrollment was stopped
prematurely due to slow accrual rates, which precluded adequate power for the intended analysis.
Therefore, data were pooled with results from the FFCD trial.157 In the pooled analysis, the median
PFS was 27.9 months in the group receiving adjuvant chemotherapy compared to 18.8 months in the
patients receiving resection alone. Median OS was 62.2 months in the chemotherapy arm compared
to 47.3 months in the resection-only arm. Although the survival curves failed to differ significantly,
these results suggested that chemotherapy provided a clinically relevant benefit in select patients. In
multivariate analysis, the presence of more than 1 metastatic lesion (HR ¼ 1.43, CI: 1.05-1.95) and
treatment with surgery alone (HR ¼ 1.39, CI: 1.04-1.85) were independently associated with shorter
PFS; a similar association was observed for OS.
As first-line adjuvant chemotherapy regimens for colorectal primaries have evolved to include
oxaliplatin- (FOLFOX) and irinotecan- (FOLFIRI) based regimens, there was obvious interest in
evaluating these regimens in stage IV disease for patients with CRLM, both in the neoadjuvant and
adjuvant settings. As previously mentioned, the EORTC Intergroup trial 40983 evaluated the effect of
FOLFOX-4 (folinic acid, 5-floururacil, oxaliplatin) in the perioperative setting and found an absolute
increase in PFS of 9.2% at 3 years (42.4% vs 33.2%) associated with the use of perioperative
chemotherapy versus surgery alone.43 An update to the results of this trial published with 8.5 years
of follow-up found no significant difference in median OS (61 months in the perioperative
chemotherapy group vs 54 months in the surgery-only group); based on the previously observed
benefit in PFS, however, perioperative FOLFOX, or by extrapolation of these data, adjuvant FOLFOX,
are mainstays of treatment in this patient population.44
Other studies have investigated the efficacy of adjuvant FOLFIRI. A phase III trial randomized 321
patients to either adjuvant FOLFIRI or 5-FU and folinic acid following resection of CRLM and found
similar DFS between the 2 groups (median ¼ 24.7 months vs 21.6 months).158 Factors associated
with improved DFS on multivariate regression included longer disease free interval from primary
tumor diagnosis and the presence of only 1 liver metastasis, whereas chemotherapy regimen was
not significant. Median OS was not reached in this study, but the 3-year OS was 71.6% in the 5-FU/
leucovorin group compared to 72.7% in the FOLFIRI group. For treatment tolerance, more patients in
the FOLFIRI arm required dose reductions due to hematologic suppression and only 75% of patients
completed all 12 cycles of therapy compared to 82% among the group treated without irinotecan.
Based on these data, adjuvant FOLFIRI is not routinely given following resection of CRLM.
In light of the clear, albeit modest, benefit demonstrated in these original studies the NCCN
recommends that most patients undergoing complete resection of either lung or liver metastases
should undergo 6 months of perioperative chemotherapy.47 Pooled analysis of the previously
presented data suggests a modest benefit in PFS and DFS, although no difference in OS. The panel
does not specify choice of regimen, suggesting that choice of regimen should be individualized and
is dependent on prior chemotherapy received, comorbidities, and functional status of the patient.
Additionally, they do not make precise recommendations about the timing of therapy and leave to
the discretion of providers whether neoadjuvant chemotherapy is offered in the setting of clearly
resectable lesions or whether surgery is undertaken first and followed with chemotherapy in the
adjuvant setting.
Hepatic arterial infusion therapy in the adjuvant setting
Hepatic arterial infusion (HAI) therapy uses an implantable subcutaneous pump connected to a
catheter that has been surgically placed into the hepatic artery via the gastroduodenal artery to
allow for isolated hepatic infusion. An implanted catheter for delivery of chemotherapy directly to
the liver was first reported by Sullivan and colleagues159 in 1964. The most widely used
chemotherapeutic agent for HAI is FUDR, which functions via inhibition of thymidylate
synthetase.160 High extraction of FUDR, followed by rapid clearance has been demonstrated with
systemic infusion of FUDR.161 Although a number of agents have been studied, both individually and
in multi-drug combination, 5-fluoro 2-deoxyuridine (FUDR), a derivative of 5-flurouracil, is the most
widely studied and used. Purported advantages to this treatment strategy include the ability to
provide direct hepatic infusion, with tumor levels reaching up to 400 times that which may be
delivered systemically.162 Tumoral levels of FUDR have also been demonstrated to be significantly
higher with infusion via the hepatic artery in comparison to portal vein infusion.163 An implantable
pump was first reported by Buchwald and colleagues164 in 1980 and the device appeared to be well
tolerated by patients. Fully implantable HAI pumps (HAIPs) are typically placed with an open
operation and have low rates of complications; a recent review reported a total of 237 complications
in 1502 operations (15.8%), in comparison to 34% for surgical catheter implantation and 36.1% for
radiological catheter implantation.165 Laparoscopic HAI pump (HAIP) placement has also been
demonstrated to be technically feasible and safe, with a 13% pump complication rate.166 Recent
studies have also shown the safety and feasibility of robotic HAIP placement.167,168 No randomized
comparisons between open, laparoscopic, and robotic pump insertion have been reported.
Indications for HAIP placement are not clearly defined, but considerations include: less than
70% liver tumor burden, preserved hepatic function with bilirubin less than 1.5 mg/dL, no evidence
of portal hypertension or portal vein thrombosis, and good performance status. The catheter is
inserted into the gastroduodenal artery, thus careful preoperative evaluation of hepatic arterial
anatomy is mandatory.160 A description of the procedure for pump placement is beyond the scope of
this article.
HAI therapy has been studied in the adjuvant setting and found to be feasible and safe. In 1999,
Kemeny and colleagues169 published the results of a clinical trial in which 156 patients undergoing
resection of CRLM were randomized to IV 5FU/leucovorin with or without HAI FUDR/
dexamethasone systemic. In patients who received dual therapy, median OS was 72.2 months
compared with 59.3 months in the systemic therapy alone group, with a 2-year OS of 86% vs 74%,
respectively (P ¼ 0.03). Although RFS was significantly different between groups, favoring the HAI
group, DFS was not statistically significant (57% vs 42%, P ¼ 0.07). In 2005, long-term results of this
trial were published. The combined therapy group of HAI þ IV 5-FU/leucovorin demonstrated a DFS
of 31.3 months vs 17.2 months in the monotherapy group (P ¼ 0.02), and 10-year OS rates were 41.1%
vs 27.2%.170 A subsequent cooperative group study published in 2002 found similar results,
demonstrating that patients treated with HAI/FUDR/dexamethasone þ IV 5-FU compared with
resection alone had superior 4-year RFS for the combination group of 46% vs 25% (P ¼ 0.04).171 HAI
therapy has been evaluated in this context of modern chemotherapy as well. Notably, there have
been 2 phase I/II trials to assess HAI FUDR/Dexamethasone þ FOLFOX as well as HAI FUDR/Dex þ
Irinotecan.172,173 A recent 20-year follow-up of the original study by Kemeny and colleagues study
from 1999 evaluated 4 different posthepatic resection treatment groups based on the systemic
chemotherapeutic agent used alongside of HAI/FUDR. Patients were categorized by date entering the
protocol, either before 2003 or after. Overall median follow-up was 11 years, with a median OS for
patients treated before 2003 of 71 months, and not reached for those treated after 2003 (p ≤ 0.01),
with 5-year and 10-year survivals for the entire cohort of 66% and 48%, respectively.174
Few direct comparisons of HAI þ systemic therapy versus systemic therapy alone for patients
who undergo hepatic resection are available. A retrospective review of 125 patients who underwent
hepatic resection followed by adjuvant chemotherapy with or without HAI with FUDR/
dexamethasone demonstrated that HAI-FUDR was independently associated with improved hepatic
RFS (HR ¼ 0.34, P ≤ 0.01), and overall RFS (HR ¼ 0.65, P ¼ 0.01) on multivariate analysis.175 Goere and
colleagues176 evaluated patients who received adjuvant HAI þ systemic 5-FU or FOLFOX/FOLFIRI vs
systemic therapy alone. Although 3-year DFS was significantly higher with HAI therapy compared to
systemic therapy alone (33% vs 5%, P o 0.0001), improved 3-year OS in the HAI group did not reach
statistical significance.
In well-selected patients, there is evidence to support the utilization of HAI therapy in the
adjuvant setting for patients with resected hepatic CRM. However, it is only available at select
institutions in the United States and patient compliance is critical to the success of this therapy.
Further prospective, randomized studies are needed to better validate this treatment option.
Repeat resection of recurrence
The role of repeat hepatectomy for CRLM recurrence following resection has not been studied in
a prospective fashion but has been reviewed in retrospective series. In many ways, the efficacy of
repeat resection mirrors that of the initial metastasectomy and should be considered in the
appropriate clinical setting. At least 14 different series, ranging from 26-288 patients, have evaluated
survival outcomes following repeat resection.177 Study design and inclusion criteria for these
retrospective analyses were heterogeneous, but estimates of survival ranged from approximately
25-40 months, which is similar to the results following initial CRLM resection. These survival data
likely reflect some degree of selection bias given the relatively stability and favorable biology of the
tumors chosen for reresection. In light of these results, most providers would offer repeat resection
if the same oncologic and technical resectability requirements are met as discussed earlier.
Multidisciplinary management of unresectable disease
Chemotherapy to downstage disease
Chemotherapy can be used in patients with unresectable CRLM as definitive therapy to improve
survival duration and quality or in an effort to convert borderline or unresectable CRLM into
resectable liver disease. Common chemotherapeutic regimens include FOLFIRI,178 with or without
targeted therapy agents such as the anti-EGFR agents cetuximab and panitumumab. KRAS mutation
status remains an important predictor of response to these therapies as well as a prognostic factor
for recurrence and survival.179,180 The use of EGFR inhibitors in combination with chemotherapy has
been shown to be effective in downstaging CRLM in patients with wild-type KRAS expression.181,182
The BOXER trial investigated capecitabine and oxaliplatin (CAPOX) plus bevacizumab in patients
with high risk CRLM: more than 4 metastases, diameter 45 cm, R0 resection unlikely, inadequate
viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or
synchronous colorectal primary presentation.183 The overall response rate for the regimen was 78%,
with 40% converted to resectable disease. In a randomized phase 2 trial comparison of mFOLFOX6
with panitumumab vs bevacizumab in patients with wild-type KRAS exon 2 tumors, PFS was similar
and OS was improved for patients treated with chemotherapy and panitumumab.184
Radiofrequency ablation
In addition to chemotherapeutic options, a variety of locoregional approaches for the treatment

of unresectable CRLM are available. Radiofrequency ablation (RFA) is effective in local destruction of
tumor tissue and therefore indicated in patients whose tumors are not resectable due to number of
lesions or their distribution. RFA is typically performed percutaneously with ultrasound or CT image
guidance, but can be performed through a laparoscopic or open surgical approach as well. One or
more electrodes are inserted into the tumor and an alternating current is used to generate a radio
wave. Single or multiple electrodes may be used depending on the diameter of the tumor. RFA has
been shown to be most effective when the tumor is ≥1 cm deep to Glisson’s capsule and ≥2 cm from
the nearest large intrahepatic vessel.185
A recent Cochrane Database systematic review on RFA in the treatment of CRLM found 10
observational studies, 7 clinical controlled trials, and 1 randomized controlled trial and demonstrated
that PFS was significantly higher in the group that underwent RFA in comparison to the group that
underwent chemotherapy alone, but that information on OS was not available.185 A recent systematic
review and meta-analysis compared RFA to liver resection in patients with CRLM and concluded that
liver resection was associated with improved OS and PFS, but RFA had lower rates of morbidity.186
Although prospective studies and the recent Cochrane review have failed to demonstrate a benefit in
OS with RFA, a recent phase II study demonstrated that aggressive multimodality treatment with
systemic chemotherapy, RFA with or without surgery can improve OS in patients with unresectable
liver metastases compared to chemotherapy alone. Totally, 3-, 5-, and 8-year OS in the group
undergoing chemotherapy and RFA combined were 56.9%, 43.1%, and 35.9%, respectively, in
comparison to 55.2%, 30.3%, and 8.9%, respectively, in the systemic treatment-alone group.187
Microwave ablation (MWA) has been similarly shown to improve local control in patients with
unresectable liver metastases. MWA causes oscillation of water molecules leading to coagulation
necrosis and can be applied percutaneously using image guidance with ultrasound, CT or MRI, or
under IOUS guidance via laparoscopy or laparotomy. MWA is thought to overcome some limitations
of RFA and can be used in patients with lesions located closer to major vessels.188 MWA has also
been combined with resection in patients whose CRLMs were otherwise thought to be
unresectable.189
Stereotactic body radiotherapy
Technical innovations have led to the ability to deliver a concentrated dose of radiation to a
specific portion of the liver, while sparing normal parenchyma. Stereotactic body radiotherapy
(SBRT) is effective at achieving local control and may improve survival rates in patients with
unresectable CRLM not amenable to RFA or MVA. The mechanism of action is primarily due to
radiation-induced DNA damage or breaks leading to apoptosis, but other theories have been
proposed, including indirect cell death caused by vascular damage.190,191
Patients eligible for SBRT are those with unresectable liver metastases and adequate hepatic
function. The presence of unresected primary disease or widespread EHD may be considered a
relative exclusion criteria, while patients with limited EHD may be included.192 Criteria based on
number of tumors, size of tumors, volume of unaffected liver, tissue and proximity to adjacent
organs have also been applied. In general the goal is to ensure that sufficient functional liver volume
remains after SBRT.192 Many authors recommend limiting SBRT to patients with 1-5 liver
metastases.193,194 Additionally, a Karnosfky Performance Score ≥ 60-70 and ECOG ≤ 2 are often
recommended.191
Preprocedure planning is an important component of SBRT delivery. To localize the target, define
gross tumor volume, and estimate the clinical target volume, a multiphase contrast-enhanced CT
scan is obtained. Fiducial placement allows for the option of real-time tumor motion tracking.192 In
both retrospective studies and randomized controlled trials, SBRT has been associated with excellent
local control, with 2-year rates ranging from 86%-100%.193-198 The effective dose of SBRT, and the
number of fractions in which it is delivered, varies among studies, but ranges from 34-75 Gy
delivered in 3-6 fractions.193-199 Potential complications of SBRT include nausea, loss of appetite,
vomiting, fever, chills, ascites, increased liver function tests, gastritis, and asthenia and skin toxicity.
Additionally, radiation induced liver disease is a potentially serious complication of SBRT that has
been reported in rare instances.200 SBRT using proton-beam techniques may permit greater ablative
doses of radiation while sparing more uninvolved liver.201 Details of clinical trials and select
retrospective studies are summarized in Table 8.
Yttrium-90 selective internal radiotherapy
Malignant tumors of the liver are preferentially supplied by the hepatic arteries, whereas normal
hepatic tissue is preferentially supplied by the portal vein. By delivering radiation therapy intra-
arterially, high-dose radiation can specifically target tumors, whereas sparing the normal liver
parenchyma. Ytrrium-90 (Y-90), a high energy β emitter with a half-life of 64.2 hours, can be used to
label glass or resin microspheres.202 When these are delivered intra-arterially, the dose ranges from
100-3000 Gy.203 As a reference, the dose of external radiation that can typically be delivered to the
liver is limited to 30-70 Gy. Y-90 microspheres trapped in the vasculature have an average
penetration range of 2.5 mm and a maximum range of 11 mm in tissue, limiting damage to
surrounding parenchymal tissue.204 Selective internal radiation therapy (SIRT) with Y-90 is a safe
and effective treatment for unresectable CRLMs, with 2 commercial products available: Thera-
Spheres, glass microspheres from Sirtex Medical, Sydney, Australia and SIR-Spheres, resin
microspheres from MDS Nordion, Ottawa, Ontario, Canada.
Y-90 therapy is typically considered in patients who are not amenable to resection. Patients
with EHD may still be eligible if their disease burden is minimal and well-controlled on
systemic chemotherapy. This locoregional therapy is typically used in combination with first-,
second-, or third-line chemotherapy. Y-90 can also be used as salvage therapy for patients with
chemotherapy-resistant CRLM. Careful evaluation of liver function is an important part of patient
selection for SIRT. Although criteria for Y-90 therapy have not been clearly defined, some authors
suggest that patients with total bilirubin 42 g/dL or with transaminases greater than 5 times the
upper limit of normal be excluded.202 Evaluation of tumor burden, biliary and vascular invasion, and
anatomic localization should be performed with high-quality MRI or CT. Patients who have been
determined to be eligible for SIRT should then undergo hepatic angiography and hepatic arterial
perfusion scintography with Tc-99m-labeled macroaggregated albumin to carefully delineate
hepatic arterial anatomy and determine predicted biodistribution of microspheres and presence of
gastrointestinal shunts.202
Postprocedurally patients are usually observed for several hours or overnight. Follow-up
laboratory studies are usually performed while the patient is in the hospital and once per week for
4 weeks. Common side effects from Y-90 treatment include lethargy, nausea, vomiting, abdominal
pain, and fever.204 More severe complications that have been reported include transient intrahepatic
bile duct obstruction and radiation induced liver disease, a rare and progressive type of radiation-
induced liver failure. Postembolic syndrome is rarely encountered.202 SIRT has been associated with
improved response rate, longer time to liver progression, and stable OS compared to standard
chemotherapy alone. Details of early phase clinical trials examining outcomes in patients
undergoing SIRT with Y-90 are listed in Table 9.205-208
Several recently reported and ongoing clinical trials may help resolve critical questions about
the role of Y-90 in the treatment of unresectable colorectal liver metastases (CRLM). The SIRFLOX
study randomized patients with treatment-naïve CRLMs to either FOLFOX (with or without
bevacizumab) with or without SIRT. Although patients who underwent SIRT had better in-liver
control, there was no difference in objective response rates, PFS, or OS between the 2 groups.209 The
EPOCH trial, an international phase III trial examining PFS in patients who have had progression on
first-line chemotherapy and are eligible to receive second-line chemotherapy, is currently recruiting
patients. In this trial patients are randomized to receive standard second-line chemotherapy and
TheraSphere Y-90 labeled glass microspheres versus second line chemotherapy alone. A protocol for
combining the results of 3 clinical trials (SIRFLOX, FOXFIRE, FOXFIREGlobal) designed to examine the
use of SIR-spheres Y-90 labeled resin microspheres on PFS was also recently proposed.210 The
SIRFLOX and FOXFIRE trials are completed, and the FOXFIREGlobal trial is ongoing, but has
completed recruitment. A selection of recently completed and ongoing phase III clinical trials
examining the use of Y-90 labeled microspheres is outlined in Table 10. Small series have also
demonstrated that, although liver resection after Y-90 selective internal radiotherapy is technically
challenging, hepatectomy may be able to provide additional DFS or OS benefit in properly selected
patients.211
Table 8
Studies examining outcomes of stereotactic body radiotherapy (SBRT) for unresectable colorectal liver metastases.
Study Phase/study type Treatment Patients Outcome Toxicity
Goodman and Retrospective Median dose 5400 cGy in 81 patients, 106 lesions, Local control ≥Grade 3 rate ¼ 4.9%
colleagues198 3-5 fractions 67% with colorectal • 1 y: 96%

primaries
• 3 y: 91%
• 4 y: 91%
OS:
• 1-y OS: 90%,
• 3-y OS: 44%
• 4-y OS: 28%
Scorsetti and II 75 Gy in 3 fractions 42 patients and 52 lesions • 2-y local control rate No patients experienced
colleagues195 91% RILD or grade
• 2-y OS 65% ≥ 3 toxicity
• 2-y PFS rate 35%

Rule and colleagues194 I 30 Gy in 3 fractions, 50 Gy 27 pts, 37 lesions and • 24-mo local control No grade 4 or 5 toxicity,
in 5 fractions, and 60 Gy 44.4% colorectal rates: no treatment-related
in 5 fractions primaries • 30-Gy: 56% grade 3 toxicity
• 50-Gy 89%
• 60-Gy 100%
(P ¼ 0.009)
Vautravers-Dewas and Retrospective 40 Gy in 4 fractions/45 Gy 42 patients and 62 lesions • Local control Grade 3 (n ¼ 1)
colleagues197 in 3 fractions • 1 y: 90%
• 2 y: 86%
• 1 y OS 94%,
• 2 y OS 48%
581
• Grade 3 ¼ 9% (n ¼ 6)
582
Lee and colleagues199 I 6 fractions, median dose 68 patients, 40 with 1-y local control rate 71%,
¼ 41.8 Gy (range: colorectal primaries median OS ¼ 17.6 mo • Grade 4 ¼ 1% (n ¼ 1)
27.7-60)
Rusthoven and I/II Phase I 36-60 Gy, N ¼ 47 patients and Actuarial in-field local ≥Grade 3 toxicity ¼ 2%
colleagues193 3 fractionated doses, N ¼ 63 lesions, control rates at 1 and
phase II dose 60 Gy 2 y 95% and 92%, among
lesions with max
diameter of 3 cm, 2-y
local control was 100%,

median survival ¼
20.5 mo
Hoyer and colleagues196 II 15 Gy × 3 within 5-8 days N ¼ 64 patients and 2 y actuarial local control 1 hepatic failure and
N ¼ 141 liver lesions was 86% in tumor and 1 colonic perforation
63% in patient-based
analysis; 19% were
without local or distant
progression after 2 y
and OS was 67, 38, 22,
13, 13% after 1-5 y,
respectively
RILD, radiation induced liver disease; KM, Kaplan-Meier.

Table 9
Trials examining outcomes of Y-90 therapy for unresectable colorectal liver metastases (CRLM).
Study Phase Treatment Patients Outcome Toxicity
205
Van Hazel and colleagues II (Randomized) Systemic fluorouracil/ N ¼ 21, untreated advanced Response rate better for Chemo-only group one
leucovorin versus systemic CRLM, with or without SIR-Spheres group (P o death from
fluorouracil/leucovorin and extrahepatic metastases 0.001), TTP greater for neutropenic sepsis,
SIR-Spheres SIR-Spheres patients more grade 3 and
(29.4 vs 12.8 mo, P ¼ 4 toxicity events in

0.02), no difference QoL combination
Hendlisz and colleagues206 III Fluorouracil protracted IV FU N ¼ 46 unresectable, Median TTLP 2.1 vs 5.5 mo, Grade 3 or 4 toxicity in
infusion versus chemo-refractory liver- P ¼ 0.003; median TTP 6 patients after FU
radioembolization and IV FU limited metastatic CRC 2.1 vs 4.5 mo, P ¼ 0.03; monotherapy, one
12/44 patients further patient after FU plus
treatment after radioembolization (P ¼
progression, including 10 0.1)
in arm A who underwent
radioembolization,
median OS ¼ 7.3 mo vs
10.0 mo,
P ¼ 0.8
Cosimelli and colleagues288 II Radioembolization with Y-90 N ¼ 50, unresectable CRLM, 1 (2%) CR, 11 (22%) PR, 12 WHO G1-2 adverse
resin microspheres, whole failed previous (24%) stable disease, 22 events (mostly fever,
liver procedure oxaliplatin/irinotecan (44%) progressive, pain) 16% and 22% of
based chemotherapy median OS 12.6 mo (95% patients, 2 died (renal
CI: 7.0-18.3); 2-y survival failure, 40 days), 2 died
was 19.6% (liver failure, 60 days)
Gray and colleagues207 III SIR-Spheres and regional HAC N ¼ 74, bilobar PR þ CR ¼ 44% vs 17.6%, P No increase in grade 3/4
versus HAC-alone nonresectable CRLM ¼ 0.01, tumor volumes treatment related
50% vs 24%, P ¼ 0.03, CEA toxicity and no loss of
¼ 72% vs 47%, P ¼ 0.004; quality of life for
median TTP longer for patients receiving SIR-
SIR-Spheres tumor area Spheres
15.9 vs 9.7 mo, P ¼ 0.001,
tumor volumes 12.0 vs
7.6 mo, P ¼ 0.04 or CEA
6.7 vs 5.7 mo, P ¼ 0.06;
1-3, 5-y- survival 72%,
39%, 17%, and 3.5% vs 68%,
29%, 6.5%, and 0%
583
584
Gulec and colleagues204 II (Randomized) In vivo comparison right and N ¼ 20, patients with CRLM Decrease in total lesion
left lobes, systemic glucose on
chemotherapy to both lobes, fludeoxyglucose PET-CT
SIRT administered selectively in 19/20 patients, mean
to target liver lobe decrease in TLG values in
tumors receiving chemo
SIRT and chemo-only was
significant at 4 weeks (P
o 0.01), 2-4 mo (P ¼
0.01) and 6-8 mo

(P o 0.01)
Cohen and colleagues208 I 3 þ 3 design with escalating N ¼ 24, patients with 24 (17 colorectal) enrolled, Transaminitis/alkaline
doses of capecitabine unresectable liver- MTD not reached, partial phosphatase elevation
radioembolization with Y-90 dominant cancer, 17 of response in 4 (16.7%), (9, 37.5%), nausea (9,
resin microspheres these were colorectal stable in 17 (70.8%) and 37.5%), abdominal pain
progression in 3 (12.5%), (7, 29%), fatigue (7, 25%)
median time to and hand-foot
progression and OS of syndrome (7, 29%),
CRLM cohort was 6.4 and 1 gastric antral
8.1 mo perforation
FU, fluorouracil; TTLP, time to liver progression; TTP, time to tumor progression; PR, partial response; HAC, hepatic artery chemotherapy; CRC, colorectal cancer; WHO, World Health
Organization; PET, positron emission tomography; CT, computed tomography; TLG, total lesion glucose.
Table 10
Ongoing clinical trials examining the use of Y-90 for unresectable liver metastases.
Author, Trial title Phase Treatment Patients Outcomes to be measured
Mulcahy, EPOCH III, Recruiting Treatment Group: standard of 18 years or older, not resected Progression free survival
care second-line primary tumor, colorectal (time frame: from date of
chemotherapy plus cancer with unresectable randomization until date
TheraSphere yttrium-90 metastatic disease to the of first documented
microspheres, Control liver with disease progression or date of

Group: standard of care progression on oxaliplatin death from any cause,
second-line chemotherapy or irinotecan based first-line whichever comes first,
with no added therapy chemotherapy, eligible to assessed up to 36 mo)
receive second line
chemotherapy, tumor
replacement o 50%
SIRTEX Medical, FOXFIREGlobal III, Ongoing, but not Treatment Group: systemic 18 years or older, liver Progression free survival
recruiting chemotherapy with metastases not treatable by (time frame: date of
FOLFOX6m plus or minus surgical resection or local randomization for average
bevacizumab plus SIR- ablation, limited of 12 mo), to compare the
Spheres microspheres, extrahepatic metastases in effectiveness of SIRT using
Control Group: systemic lung or lymph nodes SIR-Spheres microspheres
chemotherapy with plus FOLFOX6m vs
FOLFOXm plus or minus FOLFOX6m alone
bevacizumab repeated
every 2 wk until evidence
SIRTEX Medical, SIRFLOX III, Completed Active Comparator A: FOLFOX 18 y or older, CT evidence of Progression free survival
alone, systemic liver metastases which are (time frame: from
chemotherapy consisting of not treatable by surgical randomization until
oxaliplatin þ leucovorin þ resection or local ablation, progressive disease is
5-fluorouracil (FOLFOX); limited extrahepatic confirmed or upon patient
active comparator B FOLFOX metastases in lung and/or death if disease
and SIR-Spheres, a single lymph node, no prior progression has not been
injection of SIR-Spheres into chemotherapy for colorectal evident at that time)
the liver plus systemic cancer
chemotherapy consisting of
oxaliplatin þ leucovorin þ
5-fluorouracil (FOLFOX)
Sharma, FOXFIRE III, Completed Arm A: systemic OxMdG 18 y or older, histologically Primary outcome: overall
chemotherapy: oxaliplatin, confirmed colorectal cancer survival (OS), secondary
folinic acid (FA) and with liver-only or liver- outcome measures:
585
• Progression-free survival
586
5-fluorouracil (5-FU); Arm dominant metastases not
B: SIR-Spheres amenable to curative (R0) • Liver-specific PFS
radioembolization (RE) plus liver surgical resection, CT
systemic OxMdG evidence of liver metastases • Safety and toxicity
chemotherapy: oxaliplatin, which are not treatable by • Health care costs or health
FA, 5-FU resection or ablation, economics
eligible for systemic
• Quality of life, assessed
chemotherapy as first-line with the euroqol EQ-5D
treatment for metastatic questionnaire at baseline,
colorectal cancer, limited or
start of cycle 4, cycle 12,

resectable extrahepatic month 24, and 36, and at
disease progression
• Response rate
• Resection rate
• Percentage of patients
receiving second line
treatment
• Interval from
randomization to start of
second line treatment
Peeters III, Ongoing recruitment Active Comparator A: 18 y or older, histologically Primary end-point: time to
systemic chemotherapy confirmed adenocarcinoma first progression,
LV5FU2 ± bevacizumab or of the colon or rectum, with secondary end-points:
cetuximab or or without primary tumor time to global
panitumumab; Active in situ, CT evidence of liver progression, time-to-
Comparator B: SIR-Spheres metastases which are not second progression, time
þ systemic chemotherapy treatable by surgical to first progression liver
LV5FU2 ± bevacizumab or resection or local ablation only, PFS, OS, safety, R0
cetuximab or panitumumab with curative intent at the resection rate, and quality
time of trial entry, partial of life
response or stable disease
after chemotherapy
induction with oxaliplatin
or irinotecan based
induction chemotherapy ±
targeted therapies during
3-6 months, limited
extrahepatic metastases
FU, fluorouracil; LV5FU2, leucovorin and 5-FU; PFS, progression free survival; CT, computed tomography.
Isolated hepatic perfusion
Isolated hepatic perfusion (IHP) is a viable option for the treatment of unresectable CRLM and,
importantly, it has been shown that isolated organ perfusion does not result in systemic
microembolization of tumor cells.212 IHP allows for a greater total dose of chemotherapy and
greater dose intensity, potentially translating to an increased response rate and improving the
likelihood of a CR.213 IHP is typically performed during the course of open surgery, although a
technique for performing percutaneous hepatic perfusion with melphalan has recently been
described.214 In the percutaneous technique, catheters are placed in the hepatic artery to perform
the perfusion as well as the inferior vena cava to aspirate chemosaturated blood, which is then
filtered and returned to the patient. This procedure must be performed with hemodynamic
monitoring and support.214
This procedure was originally described using tumor necrosis factor and melphalan, which were
demonstrated to have an overall objective radiographic response rate of 60%-76% faring favorably to
previous failed chemotherapy regimens.215-217 Melphalan is an alkylating agent, used systemically
for multiple myeloma and in isolated limb perfusion for melanoma and sarcoma, whose effects are
enhanced by hyperthermia.213 Peak concentrations of melphalan were substantially higher in
perfusate than in systemic circulation, suggesting that isolated hepatic perfusion leads to increased
dose intensity within metastases.215
More recently the use of oxaliplatin IHP has been explored in phase I trials and has been
demonstrated to be safe and feasible with an encouraging response rate.215-220 Oxaliplatin is a
platinum derivate that forms DNA crosslinks thereby blocking DNA transcription and regulation.213
IHP has been demonstrated to increase the dose of oxaliplatin delivered to the liver whereas none
was detected in the plasma.213
Irreversible electroporation
Irreversible electroporation (IRE) is a novel treatment for unresectable CRLM located in close
proximity to vital structures. This technique uses electrical pulses to cause cell death and results in
non-thermal tissue ablation.221,222 The technique can be administered via an open or percutaneous
approach, with electrodes inserted around the tumor.223,224 Given that ablation with IRE is non-
thermal, the heat sink associated with other ablation modalities in the region of large vessels does
not impede IREs efficacy.222 The ability of IRE to successfully ablate CRLM in humans was
demonstrated in patients with resectable CRLM in the COLDFIRE-1 ablate and resect trial. In this trial
lesions were ablated using IRE and then resected one hour later, with demonstration of cell death
within 1 hour of IRE and no significant damage to vascular structures located in the ablation zone.224
IRE has since been used to ablate unresectable CRLM, as reported in recent case reports,
retrospective analyses, and prospective series, summarized in Table 11.221,223,225-227 A single-arm
phase II trial including patients with unresectable CRLM is currently enrolling patients.222
IRE is overall well-tolerated, although rare complications have been reported, including reports
of biliary stent occlusion, cholangitis, acute renal failure, neurogenic bladder, transaminitis, self-
limiting hematomas in the ablation zone, biliary stricture, and thrombosis or narrowing of portal
venous structures.225,228
Drug-eluting beads preloaded with irinotecan
Drug-eluting beads preloaded with irinotecan (DEBIRI) delivered with selective catheterization is
a novel liver-directed treatment for unresectable CRLM. Irinotecan, a topoisomerase inhibitor, is
loaded onto microspheres and typically delivered to the entire right or left hemiliver to allow for
activation by normal liver parenchyma and to treat both known and radiographically occult lesions.
Patients are typically considered to be candidates for DEBIRI if they have CRLM not amenable to
surgical resection or thermal ablation and have liver-only or liver-dominant disease.229 A recent
technical report recommended that unilobar disease be treated with 2 lobar treatments of 100 mg
588
Table 11
Published clinical trials of irreversible electroporation (IRE) for colorectal liver metastases (CRLM).
Study Study Type Treatment Patient(s) Outcomes Complications
Fruhling and Single-center, IRE N ¼ 30 patients, 38 tumors, 23 3 mo ablation success 78.9%, 6 mo Minor complication in 6 (20%),
colleagues228 nonrando- CRLM, not candidates for RFA or ablation success 65.8% major complication in 1 (3.3%),
mized clinical MWA, tumor o 3 cm, 1-2 no 30-d mortality
trial tumors
Schoellham- Case report FOLFOX and A 68-y old female, colon cancer, No evidence of disease at 30 mo None

mer and cetuximab to bilateral unresectable CRLM
colleagues221 convert to
resectability,
resection of
primary and
metastases, IRE
of the margin
Scheffer and Protocol, single- IRE N ¼ 29, (18)F-FDG-PET-avid CRLM
colleagues222 arm Phase II, ≤ 3.5 cm, unresectable,
COLDFIRE-2 unsuitable for thermal ablation
Trial due to proximity to vascular
structures
Niessen and Prospective, IRE N ¼ 39 patients, 79 lesions, N ¼ 20 Local recurrence 6 of 16 (37.5%) Not reported
colleagues227 single-center (41.7%) CRLM CRLM
clinical trial
Cannon and Retrospective, IRE Total N ¼ 44, N ¼ 20 colorectal N ¼ 20 CRLM only, RFS: 3-mo N ¼ 20 CRLM only, 2 (10%) with
colleagues225 multi- liver metastases (80% previous 100%, 6-mo 94.1%, 12-mo 58.8% adverse events
institutional FOLFOX, 10 prior liver directed
Registry therapy), N ¼ 14 HCC, N ¼ 10
other metastases, therapy
Kasivisvana- Case report IRE A 61-y old man, solitary Decrease in tumor volume at 3 mo No early or late complications
than and chemoresistant CRLM, from 5.25-3.16 cm3
colleagues226 unsuitable for RFA due to
proximity to porta hepatis
Kingham and Retrospective Open or N ¼ 28 (21, 75% CRLM), Tumors o 31 procedures to treat 65 tumors, 9/50 (18%) high current, 3/50
colleagues223 percutaneous 2 cm from third-order or larger 3 local recurrences (5.6%) and (6%) failed delivery other
IRE hepatic veins or portal pedicles 1 tumor with persistent disease reasons, 1/50 (2%) arrhythmia,
(1.9%) after IRE for local failure 6/50 (12%) need to reposition
rate 7.5% probes, no occluded hepatic
veins
RFA, radiofrequency ablation; MWA, microwave ablation; PET, positron emission tomography.
irinotecan administered 3-4 weeks apart; for bilobar disease, 4 lobar treatments should be planned,
alternating sides, every 2 weeks, with 100 mg of irinotecan.230
A selection of recent studies and trials examining outcomes of unresectable CRLM treated with
DEBIRI are summarized in Table 12. In the final report of a phase III study comparing DEBIRI vs
systemic FOLFIRI, Fiorentini and colleagues reported significantly improved median OS (22 months
vs 15 months, P ¼ 0.031) and median PFS (7 months vs 4 months, P ¼ 0.006) for patients treated
with DEBIRI.231 All patients in both arms developed extrahepatic progression by the end of the study
(median 13 months vs 9 months, P ¼ 0.064). DEBIRI treatment was also associated with quicker time
to achieve an improved quality of life (9 months vs 3 months) and longer duration of symptom
improvement.231 The safety and efficacy of DEBIRI has also been demonstrated in several other trials.
Martin and colleagues232,233 demonstrated the safety and efficacy of 12 cycles of FOLFOX followed by
2 cycles of DEBIRI in patients with unresectable CRLM who were previously chemotherapy-naïve
with a 100% response rate and 40% conversion to resectability; a follow-up study then demonstrated
the superiority of FOLFOX, bevacizumab, and DEBIRI over FOLFOX and bevacizumab alone.
Additional single-arm studies by Akinwande and colleagues234 examining DEBIRI and capecitabine,
and by Fiorentini and colleagues235 examining DEBIRI and cetuximab, have demonstrated
encouraging PFS and OS results.
Hepatic artery infusion pump therapy for unresectable disease
In addition to its role as an adjuvant therapy, HAI chemotherapy can also be used in the setting of
unresectable CRLMs. Recent phase II and phase III clinical trials examining the use of HAI in patients
with unresectable CRLM are summarized in Table 13. Although some early trials demonstrated
equivocal results for HAI therapy in patients with unresectable CRLMs,236 recent evidence is
suggestive of improved OS and PFS compared to systemic chemotherapy, even among previously
treated patients.237,238 Furthermore, in appropriately selected patients, HAI therapy in combination
with chemotherapy may effectively convert initially unresectable CRLM to a resectable disease
burden.239,240 These studies are summarized in Table 14.
Liver transplant
Historically, 2 of the first 7 liver transplants were performed in patients with CRLMs, but poor
outcomes led to more restrictive indications.241 As outcomes have improved for all patients
undergoing liver transplant, there is renewed interest in the use of this therapy for treatment of
patients with CRLMs.242 The SECA study was a prospective pilot study including 21 colorectal
patients with liver-only metastases after excision of their primary tumors and at least 6 weeks of
chemotherapy who underwent liver transplantation; the OS rates of 95% at 1 year, 68% at 3 years,
and 60% at 5 years were comparable to outcomes achieved with liver transplant for nonmalignant
disease.243 Subgroup analysis of 6 patients in this cohort who had progressive disease on last-line
standard chemotherapy demonstrated 5-year OS of 44%.244 OS, DFS, and PFS were also compared
between this cohort of patients and a cohort of colorectal liver-only metastases patients in the
NORDIC VII first-line chemotherapy study. In this analysis, patients in the SECA study had 5-year OS
of 56%, while those in the NORDIC VII study had 5-year OS of 9%. Both groups had similar DFS or PFS
of 8-10 months. The authors attributed the difference in OS despite similarities in PFS or DFS to the
fact that patients in the SECA study recurred with small, slow growing pulmonary metastases,
whereas those in the chemotherapy trial had progression of their unresectable liver metastases.245
Modifications to the liver transplant procedure, including the use of small partial grafts to address
the ethical questions of donor shortage and graft scarcity in this population, have been suggested.246
A randomized controlled trial (NCT01479608, SECA II) comparing survival and quality of life with
liver transplantation versus surgical resection in selected patients with CRLM is currently enrolling
patients at Oslo University Hospital. Trials are also ongoing that compare liver transplant to
chemotherapy (TRANSMET), 2-stage hepatectomy with transplant (RAPID 2014), as well as possibly
even living donor liver transplant for unresectable CRLM.
590
Table 12
Reported trials of DEBIRI for unresectable colorectal liver metastases (CRLM).
Study Study type Treatment Patients Outcomes Complications
231
Fiorentini and colleagues Randomized 2 Groups Total N ¼ 74, no previous OS DEBIRI group better than Less neutropenia (P o 0.0001),
controlled trial • DEBIRI irinotecan, N ¼ 36 DEBIRI, FOLFIRI (median ¼ 22 vs 15 mo, mucositis (P ¼ 0.00002) in DEBIRI
N ¼ 38 FOLFIRI, all had P ¼ 0.031); PFS also better DEBIRI group
• FOLFIRI (NO
received 2-3 previous lines group (median ¼ 7 vs 4 mo,
cetuximab)
of chemo P ¼ 0.006); improved QoL in

DEBIRI group (1 mo P ¼ 0.038,
3 mo P ¼ 0.025, 8 mo P ¼ 0.025)
Martin and colleagues232 Phase I 12 cycles FOLFOX, at N ¼ 10, unresectable CRLM in Minimal detectable irinotecan and One grade 3 hypertensive event
least 2 DEBIRI chemo-naïve patients SN-38 after first, second, and
treatments third DEBIRI treatment; 9 and
12 mo response rate 100% (2 CR,
8 PR); 4 (40%) downstaged to
resection or ablation median
OS ¼ 15.2 mo
Akinwande and Prospective study 2 Groups 149 DEBIRI, 22 DEBIRI þ Disease control rate similar in both No difference between groups in
colleagues234 capecitabine, patients with groups at 3 and 6 mo, at 12-mo adverse events (P ¼ 0.56)
unresectable metastatic evaluation disease control was
• DEBIRI, colorectal cancer after better in DEBIRI þ capecitabine
• 2 – DEBIRI þ c multiple therapies group (P ¼ 0.03), median survival
13 months in DEBIRI group and
• apecitabine 22 mo in DEBIRI þ capecitabine
group (P ¼ 0.217)
Martin and colleagues233 Phase II 2 Groups N ¼ 70, first-line treatment Overall response rate FOLFOX-
for unresesctable CRLM DEBIRI group higher at 2 mo (78%
vs 54%, P ¼ 0.03), 4 mo (95% vs
• DEBIRI þ mFOLFOX6
70%, P ¼ 0.03), 6 mo (76% vs 60%,
þ bevacizumab
P ¼ 0.05); more downsizing to
• mFOLFOX6 þ resection 35% vs 16%, P ¼ 0.05;
bevacizumab improved median PFS (15.3 vs
7.6 mo)
Fiorentini and colleagues235 Prospective trial DEBIRI and cetuximab N ¼ 40 PFS ¼ 9.8 mo and OS ¼ 20.4 mo 10 adverse events: acne-like rash,
fissuring, dryness, hypersensitivity,
30% postembolization syndrome
FOLFOX, leucovorin, 5-fluorouracil, oxaliplatin; DEBIRI, drug-eluting beads preloaded with irinotecan.
Table 13
Clinical trials of hepatic arterial infusion (HAI) therapy for unresectable colorectal liver metastases (CRLM) published after 2000.
Study Phase Treatment Patients Outcomes Toxicities

238
Kemeny and colleagues II One Group: FUDR, Dex, high Total n ¼ 63, unresectable Chemo-naïve response 73%, median 7.9% liver biloma, 22% elevated
dose Mit-C liver metastases, chemo- survival 23 mo; previously treated bilirubin, 9.5% biliary sclerosis,
naïve n ¼ 26, previously response 70%, median survival ¼ hematologic o2%, and
treated n ¼ 37 20 mo gastrointestinal o2%
Kemeny and colleagues289 III Two Groups: HAI vs systemic Total n ¼ 135, unresectable OS HAI vs systemic median 24.4 vs Grade ≥3 neutropenia 2% vs 45%, P o
bolus 5-FU and LV liver metastases 20 mo, P ¼ 0.0034, response rates 0.01, stomatitis 0% vs 24% P o 0.01,
47% vs 24%, P ¼ 0.012, time to hepatic bilirubin elevation 18.6% vs 0%, P o
progression ¼ 9.8 vs 7.3 mo, P ¼ 0.01 in HAI and systemic group,
0.034, improved QoL in HAI group respectively
Kerr and colleagues236 III Two Groups: HAI fluorouracil Total n ¼ 290, unresectable OS ¼ 14.7 mo HAI, 14.8 mo systemic, 50 (37%) patients allocated to HAI did
and folinic avid vs IV liver-only metastases P ¼ 0.79; no difference PFS not start, 39 (29%) had to stop
fluorouracil and folinic acid because of catheter failure, grade
3 and 4 toxicities uncommon in
both groups
Lorenz and colleagues237 III Three Groups: Total n ¼ 168, unresectable Median to disease progression: Most common adverse events:
• 5-FU/LV via HAI liver metastases o75% • 9.2 mo stomatitis, nausea and vomiting,
liver volume skin irritation, diarrhea, elevated
• 5-FU/LV IV • 6.6 mo
serum liver enzymes; severe
• FUDR HAI • 5.9 mo adverse events: biliary sclerosis,
median OS: chemical hepatitis
• 18.7 mo
• 17.6 mo
• 12.7 mo
QoL, quality of life; FUDR, floxuridine; Dex, dexamethasone; Mit-C, mitomycin C; 5-FU, fluorouracil; LV, leucovorin.
591
592
Table 14
Clinical trials of hepatic arterial infusion (HAI) therapy for unresectable colorectal liver metastases (CRLM), conversion to resectability.
Study Phase Treatment Patients Outcome Toxicity

239
Levi and colleagues II One Group: irinotecan, oxaliplatin, Total n ¼ 64, Median 6 courses deliver, R0-R1 42.6% grade 3-4 neutropenia, 26.2%
5-FU delivered via implanted unresectable liver hepatectomy of 19 of 64 previously abdominal pain, 18% fatigue, and
HAIP, combined with IV metastases from treated patients, objective response 16.4% diarrhea
cetuximab q14 days wild-type KRAS rate 40.6%, median PFS ¼ 9.3 mo,
colorectal cancer, median OS ¼ 25.5 mo, those with R0-
exclusion: R1 resection had median OS of 35.2 mo
advanced non- with 37.4% alive at 4 y
hepatic disease,
prior HAI, grade
3 neuropathy
D’Angelica and II One Group: HAI plus systemic N ¼ 49, unresectable Overall response 76%, 23 (47%) achieved High biliary toxicity rate in first 24
colleagues290 chemo including bevacizumab colorectal liver conversion to resection at a median of patients and remaining 25 treated
metastases 6 mo, median OS ¼ 38 mo, median PFS without bevacizumab
¼ 13 mo, conversion associated with
prolonged OS/PFS, patients who
underwent resection had longer OS
than no resection (3 y: 80% vs 26%), 10
of 49 (20%) have NED at median f/u
39 mo
Kemeny and I One Group: HAI with floxuridine N ¼ 49, unresectable 92% of patients had complete (9%) or Grade 3 or 4 tox first 2 cycles: 14%
colleagues240 and dexamethasone plus liver metastases partial (84%) response, 23 (47%) were diarrhea, 23% neutropenia, after
systemic oxaliplatin and from colorectal able to undergo resection, for chemo- second 2 cycles: 18% neutropenia,
irinotecan (CPT-11) cancer naïve and previously treated patients, 23% neurotoxicity, 5% bili 4
median survival was 50.8 and 35 mo, 3 mg/mL
female sex was associated with higher
resection rate
HAP, hepatic arterial in fusion pump.

Conclusions
CRLMS pose a significant clinical challenge, one to which a large amount of research has been
dedicated in recent decades. With modern systemic chemotherapy regimens and improvements in
surgical technique, more patients with CRLM are now candidates for curative-intent liver resection
than ever before, and the prognosis for all patients with CRLM has improved from a dismal 5-year
survival rate of 5% historically to 40%-50% in more recent series. Using appropriate selection criteria,
careful evaluation of FLR volume and function, modern parenchymal transection techniques, and
meticulous perioperative care, liver resection can be performed safely with low morbidity.
Moreover, advances in minimally invasive approaches are rapidly developing and evidence appears
to suggest equivalent oncologic outcomes to open approaches. Among the most significant advances
over the past 2 decades has been the rapid increase in treatment options available for patients with
CRLM, even those who present with initially unresectable disease. Recognition that patients with
CRLM comprise a clinically and biologically diverse group has helped to tailor more personalized
treatment options and provide more accurate prognostic data. Given the complexity of treatment
options available for patients with CRLM and the rapid advances in systemic and locoregional
therapies, these patients are best served in tertiary centers where expert multidisciplinary care can
be offered. The development of targeted therapeutics and continued refinement of operative
strategies should only continue to improve the outcomes of these patients.
References
1. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of
hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–3683.
2. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal
liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440–448.
3. American Cancer Society. Cancer Facts & Figures 2017. Atlanta, Ga: American Cancer Society; 2017.
4. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable
liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23(9):2038–2048.
5. Mohammad WM, Balaa FK. Surgical management of colorectal liver metastases. Clin Colon Rectal Surg. 2009;22(4):
225–232.
6. Nathan H, de Jong MC, Pulitano C, et al. Conditional survival after surgical resection of colorectal liver metastasis: an
international multi-institutional analysis of 949 patients. J Am Coll Surg. 2010;210(5):755–764. [764-6].
7. Riihimaki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Cancer. 2016;15(6):
29765.
8. Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected
colorectal cancer. Clin Cancer Res. 2011;17(5):1122–1130.
9. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread
and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–4632.
10. Ekberg H, Tranberg KG, Andersson R, et al. Determinants of survival in liver resection for colorectal secondaries. Br J
Surg. 1986;73(9):727–731.
11. Mohammad WM, Martel G, Mimeault R, Fairfull-Smith RJ, Auer RC, Balaa FK. Evaluating agreement regarding the
resectability of colorectal liver metastases: a national case-based survey of hepatic surgeons. HPB (Oxford). 2012;14(5):
291–297.
12. Jones RP, Hamann S, Malik HZ, Fenwick SW, Poston GJ, Folprecht G. Defined criteria for resectability improves rates of
secondary resection after systemic therapy for liver limited metastatic colorectal cancer. Eur J Cancer. 2014;50(9):
1590–1601.
13. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal
metastases. Ann Surg. 2002;235(6):759–766.
14. Cummings LC, Payes JD, Cooper GS. Survival after hepatic resection in metastatic colorectal cancer: a population-based
study. Cancer. 2007;109(4):718–726.
15. Kavlakoglu B, Ustun I, Oksuz O, Pekcici R, Ergocen S, Oral S. Surgical treatment of liver metastases from colorectal
cancer: experience of a single institution. Arch Iran Med. 2011;14(2):120–125.
16. House MG, Ito H, Gönen M, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for
1600 patients during two decades at a single institution. J Am Coll Surg. 2010;210(5):744–752. [752-5].
17. Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg.
2006;141(5):460–466. [discussion 466-7].
18. van Dam RM, Lodewick TM, van den Broek MA, et al. Outcomes of extended versus limited indications for patients
undergoing a liver resection for colorectal cancer liver metastases. HPB (Oxford). 2014;16(6):550–559.
19. Pulitano C, Crawford M, Joseph D, Aldrighetti L, Sandroussi C. Preoperative assessment of postoperative liver function:
the importance of residual liver volume. J Surg Oncol. 2014;110(4):445–450.
20. Adams RB, Aloia TA, Loyer E, Pawlik TM, Taouli B, Vauthey JN. Selection for hepatic resection of colorectal liver
metastases: expert consensus statement. HPB (Oxford). 2013;15(2):91–103.
21. Allen PJ, Kemeny N, Jarnagin W, DeMatteo R, Blumgart L, Fong Y. Importance of response to neoadjuvant chemotherapy
in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg. 2003;7(1):
109–115. [discussion 116-7].
22. Leung U, Gönen M, Allen PJ, et al. Colorectal cancer liver metastases and concurrent extrahepatic disease treated with
resection. Ann Surg. 2017;265(1):158–165.
23. Brudvik KW, Jones RP, Giuliante F, et al. RAS mutation clinical risk score to predict survival after resection of colorectal
liver metastases. Ann Surg. 2017, http://dx.doi.org/10.1097/SLA.0000000000002319 [Epub ahead of print].
24. Shindoh J, Tzeng CW, Aloia TA, et al. Optimal future liver remnant in patients treated with extensive preoperative
chemotherapy for colorectal liver metastases. Ann Surg Oncol. 2013;20(8):2493–2500.
25. Kosuge T, Makuuchi M, Takayama T, et al. Preoperative portal embolization increases safety of hepatectomy. Nihon Geka
Gakkai Zasshi. 1991;92(9):1320–1323.
26. Cieslak KP, Huisman F, Bais T, et al. Future remnant liver function as predictive factor for the hypertrophy response after
portal vein embolization. Surgery. 2017;162(1):37–47.
27. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic
resection for colorectal metastases. Ann Surg. 2005;241(5):715–722. [discussion 722-4].
28. Sadot E, Groot Koerkamp B, Leal JN, et al. Resection margin and survival in 2368 patients undergoing hepatic resection
for metastatic colorectal cancer: surgical technique or biologic surrogate? Ann Surg. 2015;262(3):476–485.
[discussion 483-5].
29. Brudvik KW, Mise Y, Chung MH, et al. RAS mutation predicts positive resection margins and narrower resection
margins in patients undergoing resection of colorectal liver metastases. Ann Surg Oncol. 2016;23(8):2635–2643.
30. Andreou A, Aloia TA, Brouquet A, et al. Margin status remains an important determinant of survival after surgical
resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257(6):1079–1088.
31. Margonis GA, Spolverato G, Kim Y, Ejaz A, Pawlik TM. Intraoperative surgical margin re-resection for colorectal liver
metastasis: is it worth the effort? J Gastrointest Surg. 2015;19(4):699–707.
32. Adson MA, van Heerden JA, Adson MH, Wagner JS, Ilstrup DM. Resection of hepatic metastases from colorectal cancer.
Arch Surg. 1984;119(6):647–651.
33. Brouquet A, Vauthey JN, Contreras CM, et al. Improved survival after resection of liver and lung colorectal metastases
compared with liver-only metastases: a study of 112 patients with limited lung metastatic disease. J Am Coll Surg.
2011;213(1):62–69. [discussion 69-71].
34. Mise Y, Kopetz S, Mehran RJ, et al. Is complete liver resection without resection of synchronous lung metastases
justified? Ann Surg Oncol. 2015;22(5):1585–1592.
35. Leung U, Gonen M, Allen PJ, et al. Colorectal cancer liver metastases and concurrent extrahepatic disease treated with
resection. Ann Surg. 2017;265(1):158–165.
36. Jaeck D, Nakano H, Bachellier P, et al. Significance of hepatic pedicle lymph node involvement in patients with
colorectal liver metastases: a prospective study. Ann Surg Oncol. 2002;9(5):430–438.
37. Adam R, de Haas RJ, Wicherts DA, et al. Concomitant extrahepatic disease in patients with colorectal liver metastases:
when is there a place for surgery? Ann Surg. 2011;253(2):349–359.
38. Adam R, de Gramont A, Figueras J, et al. Managing synchronous liver metastases from colorectal cancer: a
multidisciplinary international consensus. Cancer Treat Rev. 2015;41(9):729–741.
39. Martin R, Paty P, Fong Y, et al. Simultaneous liver and colorectal resections are safe for synchronous colorectal liver
metastasis. J Am Coll Surg. 2003;197(2):233–241. [discussion 241-2].
40. Martin RC, Augenstein V, Reuter NP, Scoggins CR, McMasters KM. Simultaneous versus staged resection for synchronous
colorectal cancer liver metastases. J Am Coll Surg. 2009;208(5):842–850. [discussion 850-2].
41. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan
(FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for
metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670–1676.
42. Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol. 2015;33(16):1809–1824.
43. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone
for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.
Lancet. 2008;371(9617):1007–1016.
44. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for
resectable liver metastases from colorectal cancer (EORTC 40983): long-term esults of a randomised, controlled, phase
3 trial. Lancet Oncol. 2013;14(12):1208–1215.
45. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination
chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet.
2011;377(9783):2103–2114.
46. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable
colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15(6):601–611.
47. Benson 3rd AB, Bekaii-Saab T, Chan E, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN
Guidelines. J Natl Compr Canc Netw. 2013;11(2):141–152. [quiz 152].
48. Stein A, Glockzin G, Wienke A, et al. Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal
cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature. BMC Cancer. 2012;12:356.
49. Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for
patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008;26(11):1830–1835.
50. Schwarz RE, Berlin JD, Lenz HJ, Nordlinger B, Rubbia-Brandt L, Choti MA. Systemic cytotoxic and biological therapies of
colorectal liver metastases: expert consensus statement. HPB (Oxford). 2013;15(2):106–115.
51. Vigano L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases
after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases
on long-term survival. Ann Surg. 2013;258(5):731–740. [discussion 741-2].
52. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day
mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24(13):2065–2072.
53. Robinson SM, Wilson CH, Burt AD, Manas DM, White SA. Chemotherapy-associated liver injury in patients with
colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19(13):4287–4299.
54. Yamashita S, Shindoh J, Mizuno T, et al. Hepatic atrophy following preoperative chemotherapy predicts hepatic
insufficiency after resection of colorectal liver metastases. J Hepatol. 2017;67(1):56–64.
55. White MA, Fong Y, Singh G. Chemotherapy-associated hepatotoxicities. Surg Clin North Am. 2016;96(2):207–217.
56. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection following chemotherapy for colorectal metastases
is a matter of timing. Br J Cancer. 2007;96(7):1037–1042.
57. Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response
and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol.
2010;17(11):2870–2876.
58. Rojas Llimpe FL, Di Fabio F, Ercolani G, et al. Imaging in resectable colorectal liver metastasis patients with or without
preoperative chemotherapy: results of the PROMETEO-01 study. Br J Cancer. 2014;111(4):667–673.
59. Zech CJ, Korpraphong P, Huppertz A, et al. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus
conventional MRI or CT in the staging of colorectal cancer liver metastases. Br J Surg. 2014;101(6):613–621.
60. van Kessel CS, Buckens CF, van den Bosch MA, van Leeuwen MS, van Hillegersberg R, Verkooijen HM. Preoperative
imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis. Ann Surg Oncol. 2012;19(9):
2805–2813.
61. Desai DC, Zervos EE, Arnold MW, Burak Jr. WE, Mantil J, Martin Jr. EW. Positron emission tomography affects surgical
management in recurrent colorectal cancer patients. Ann Surg Oncol. 2003;10(1):59–64.
62. Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal
adenocarcinoma metastases: a randomized clinical trial. J Am Med Assoc. 2014;311(18):1863–1869.
63. Lake ES, Wadhwani S, Subar D, et al. The influence of FDG PET-CT on the detection of extrahepatic disease in patients
being considered for resection of colorectal liver metastasis. Ann R Coll Surg Engl. 2014;96(3):211–215.
64. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG
PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment.
Radiology. 2010;257(3):674–684.
65. Thirunavukarasu P, Aloia TA. Preoperative assessment and optimization of the future liver remnant. Surg Clin North Am.
2016;96(2):197–205.
66. Abdalla EK. Resection of colorectal liver metastases. J Gastrointest Surg. 2011;15(3):416–419.
67. Abdalla EK, Denys A, Chevalier P, Nemr RA, Vauthey JN. Total and segmental liver volume variations: implications for
liver surgery. Surgery. 2004;135(4):404–410.
68. Simpson AL, Geller DA, Hemming AW, et al. Liver planning software accurately predicts postoperative liver volume and
measures early regeneration. J Am Coll Surg. 2014;219(2):199–207.
69. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the future liver remnant prior to extended liver
resection: methodology and clinical associations. Surgery. 2000;127(5):512–519.
70. Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and
surgery for colorectal liver metastases. Br J Surg. 2007;94(3):274–286.
71. Sturesson C, Nilsson J, Eriksson S, Spelt L, Andersson R. Limiting factors for liver regeneration after a major hepatic
resection for colorectal cancer metastases. HPB (Oxford). 2013;15(8):646–652.
72. Millet G, Truant S, Leteurtre E, et al. Volumetric analysis of remnant liver regeneration after major hepatectomy in
bevacizumab-treated patients: a case-matched study in 82 patients. Ann Surg. 2012;256(5):755–761. [discussion 761-2].
73. Hoekstra LT, de Graaf W, Nibourg GA, et al. Physiological and biochemical basis of clinical liver function tests: a review.
Ann Surg. 2013;257(1):27–36.
74. Beppu T, Nitta H, Hayashi H, et al. Effect of branched-chain amino acid supplementation on functional liver regeneration
in patients undergoing portal vein embolization and sequential hepatectomy: a randomized controlled trial.
J Gastroenterol. 2015;50(12):1197–1205.
75. Liu Z, Li C, Huang M, Tong C, et al. Positive regulatory effects of perioperative probiotic treatment on postoperative liver
complications after colorectal liver metastases surgery: a double-center and double-blind randomized clinical trial. BMC
Gastroenterol. 2015;15:34.
76. Peng PD, van Vledder MG, Tsai S, et al. Sarcopenia negatively impacts short-term outcomes in patients undergoing
hepatic resection for colorectal liver metastasis. HPB (Oxford). 2011;13(7):439–446.
77. Lodewick TM, van Nijnatten TJ, van Dam RM, et al. Are sarcopenia, obesity and sarcopenic obesity predictive of outcome
in patients with colorectal liver metastases? HPB (Oxford). 2015;17(5):438–446.
78. Eriksson S, Nilsson JH, Strandberg Holka P, Eberhard J, Keussen I, Sturesson C. The impact of neoadjuvant chemotherapy
on skeletal muscle depletion and preoperative sarcopenia in patients with resectable colorectal liver metastases. HPB
(Oxford). 2017;19(4):331–337.
79. Ribero D, Vigano L, Amisano M, Capussotti L. Prognostic factors after resection of colorectal liver metastases: from
morphology to biology. Future Oncol. 2013;9(1):45–57.
80. Sasaki K, Andreatos N, Margonis GA, et al. The prognostic implications of primary colorectal tumor location on
recurrence and overall survival in patients undergoing resection for colorectal liver metastasis. J Surg Oncol. 2016;114
(7):803–809.
81. Yamashita S, Brudvik KW, Kopetz SE, et al. Embryonic origin of primary colon cancer predicts pathologic response and
survival in patients undergoing resection for colon cancer liver metastases. Ann Surg. 2016, http://dx.doi.org/10.1097/
SLA.0000000000002087 [Epub ahead of print].
82. Clancy C, Burke JP, Barry M, Kalady MF, Calvin Coffey J. A meta-analysis to determine the effect of primary tumor
resection for stage IV colorectal cancer with unresectable metastases on patient survival. Ann Surg Oncol. 2014;21(12):
3900–3908.
83. Vigano L, Russolillo N, Ferrero A, et al. Resection of liver metastases from colorectal mucinous adenocarcinoma: is this a
different disease? Results of a case-control study. Ann Surg. 2014;260(5):878–884. [discussion 884-5].
84. Vigano L, Capussotti L, Lapointe R, et al. Early recurrence after liver resection for colorectal metastases: risk factors,
prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. Ann Surg Oncol. 2014;21(4):1276–1286.
85. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for
metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–318. [discussion 318-21].
86. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver.
A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie.
Cancer. 1996;77(7):1254–1262.
87. Nagashima I, Takada T, Matsuda K, et al. A new scoring system to classify patients with colorectal liver metastases:
proposal of criteria to select candidates for hepatic resection. J Hepatobiliary Pancreat Surg. 2004;11(2):79–83.
88. Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a
prognostic scoring system. J Am Coll Surg. 1999;189(3):291–299.
89. Roberts KJ, White A, Cockbain A, et al. Performance of prognostic scores in predicting long-term outcome following
resection of colorectal liver metastases. Br J Surg. 2014;101(7):856–866.
90. Poultsides GA, Bao F, Servais EL, et al. Pathologic response to preoperative chemotherapy in colorectal liver metastases:
fibrosis, not necrosis, predicts outcome. Ann Surg Oncol. 2012;19(9):2797–2804.
91. Blazer 3rd DG, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point
after resection of hepatic colorectal metastases. J Clin Oncol. 2008;26(33):5344–5351.
92. Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with
pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. J Am Med Assoc.
2009;302(21):2338–2344.
93. Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate
outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30(36):4566–4572.
94. Brouquet A, Zimmitti G, Kopetz S, et al. Multicenter validation study of pathologic response and tumor thickness at the
tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and
surgery for colorectal liver metastases. Cancer. 2013;119(15):2778–2788.
95. Egger ME, Cannon RM, Metzger TL, et al. Assessment of chemotherapy response in colorectal liver metastases in
patients undergoing hepatic resection and the correlation to pathologic residual viable tumor. J Am Coll Surg. 2013;216
(4):845–856. [discussion 856-7].
96. Lau LF, Williams DS, Lee ST. Metabolic response to preoperative chemotherapy predicts prognosis for patients
undergoing surgical resection of colorectal cancer metastatic to the liver. Ann Surg Oncol. 2014;21(7):2420–2428.
97. van Vledder MG, de Jong MC, Pawlik TM, Schulick RD, Diaz LA, Choti MA. Disappearing colorectal liver metastases after
chemotherapy: should we be concerned? J Gastrointest Surg. 2010;14(11):1691–1700.
98. Sturesson C, Nilsson J, Lindell G, Andersson RG, Keussen I. Disappearing liver metastases from colorectal cancer: impact
of modern imaging modalities. HPB (Oxford). 2015;17(11):983–987.
99. Owen JW, Fowler KJ, Doyle MB, Saad NE, Linehan DC, Chapman WC. Colorectal liver metastases: disappearing lesions in
the era of Eovist hepatobiliary magnetic resonance imaging. HPB (Oxford). 2016;18(3):296–303.
100. Bischof DA, Clary BM, Maithel SK, Pawlik TM. Surgical management of disappearing colorectal liver metastases. Br J Surg.
2013;100(11):1414–1420.
101. Auer RC, White RR, Kemeny NE, et al. Predictors of a true complete response among disappearing liver metastases from
colorectal cancer after chemotherapy. Cancer. 2010;116(6):1502–1509.
102. Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean
cure? J Clin Oncol. 2006;24(24):3939–3945.
103. Passot G, Odisio BC, Zorzi D, et al. Eradication of missing liver metastases after fiducial placement. J Gastrointest Surg.
2016;20(6):1173–1178.
104. Brudvik KW, Kopetz SE, Li L, Conrad C, Aloia TA, Vauthey JN. Meta-analysis of KRAS mutations and survival after
resection of colorectal liver metastases. Br J Surg. 2015;102(10):1175–1183.
105. Mise Y, Zimmitti G, Shindoh J, et al. RAS mutations predict radiologic and pathologic response in patients treated with
chemotherapy before resection of colorectal liver metastases. Ann Surg Oncol. 2015;22(3):834–842.
106. Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated
with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin
Oncol. 2009;27(35):5931–5937.
107. Karagkounis G, Torbenson MS, Daniel HD, Azad NS, Diaz LA, Donehower RC, et al. Incidence and Prognostic Impact of
KRAS and BRAF Mutation in Patients Undergoing Liver Surgery for Colorectal Metastases. Cancer. 2013;119(23):
4137–4144.
108. Schirripa M, Bergamo F, Cremolini C, et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer
patients undergoing liver resection. Br J Cancer. 2015;112(12):1921–1928.
109. Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level
microsatellite instability (MSI-H). Ann Oncol. 2014;25(5):1032–1038.
110. Morris V, Overman MJ, Jiang ZQ, et al. Progression-free survival remains poor over sequential lines of systemic therapy
in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer. 2014;13(3):164–171.
111. Kaczirek K, Ciuleanu TE, Vrbanec D, et al. FOLFOX4 plus cetuximab for patients with previously untreated metastatic
colorectal cancer according to tumor RAS and BRAF mutation status: updated analysis of the CECOG/CORE 1.2.002 study.
Clin Colorectal Cancer. 2015;14(2):91–98.
112. Yaeger R, Cercek A, Chou JF, et al. BRAF mutation predicts for poor outcomes after metastasectomy in patients with
metastatic colorectal cancer. Cancer. 2014;120(15):2316–2324.
113. Chun YS, Passot G, Yamashita S, et al. Deleterious effect of RAS and evolutionary high-risk TP53 double mutation in
colorectal liver metastases. Ann Surg. 2017, http://dx.doi.org/10.1097/SLA.0000000000002450 [Epub ahead of print].
114. Yamashita S, Chun YS, Kopetz SE, et al. APC and PIK3CA mutational cooperativity predicts pathologic response and
survival in patients undergoing resection for colorectal liver metastases. Ann Surg. 2017, http://dx.doi.org/10.1097/
SLA.0000000000002245 [Epub ahead of print].
115. Ito H, Mo Q, Qin LX, et al. Gene expression profiles accurately predict outcome following liver resection in patients with
metastatic colorectal cancer. PLoS One. 2013;8(12):e81680.
116. Mostert B, Jiang Y, Sieuwerts AM, et al. KRAS and BRAF mutation status in circulating colorectal tumor cells and their
correlation with primary and metastatic tumor tissue. Int J Cancer. 2013;133(1):130–141.
117. Lalmahomed ZS, Mostert B, Onstenk W, et al. Prognostic value of circulating tumour cells for early recurrence after
resection of colorectal liver metastases. Br J Cancer. 2015;112(3):556–561.
118. Brudvik KW, Seeberg LT, Hugenschmidt H, et al. Detection of circulating tumor cells at surgery and at follow-up
assessment to predict survival after two-stage liver resection of colorectal liver metastases. Ann Surg Oncol. 2015;22(12):
4029–4037.
119. Gold JS, Are C, Kornprat P, et al. Increased use of parenchymal-sparing surgery for bilateral liver metastases from
colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over
time in 440 patients. Ann Surg. 2008;247(1):109–117.
120. Memeo R, de Blasi V, Adam R, et al. Parenchymal-sparing hepatectomies (PSH) for bilobar colorectal liver metastases are
associated with a lower morbidity and similar oncological results: a propensity score matching analysis. HPB (Oxford).
2016;18(9):781–790.
121. Mise Y, Aloia TA, Brudvik KW, Schwarz L, Vauthey JN, Conrad C. Parenchymal-sparing hepatectomy in colorectal liver
metastasis improves salvageability and survival. Ann Surg. 2016;263(1):146–152.
122. Matsumura M, Mise Y, Saiura A, et al. Parenchymal-sparing hepatectomy does not increase intrahepatic recurrence in
patients with advanced colorectal liver metastases. Ann Surg Oncol. 2016;23(11):3718–3726.
123. Moris D, Ronnekleiv-Kelly S, Rahnemai-Azar AA, et al. Parenchymal-sparing versus anatomic liver resection for
colorectal liver metastases: a systematic review. J Gastrointest Surg. 2017;21(6):1076–1085.
124. Hoch G, Croise-Laurent V, Germain A, Brunaud L, Bresler L, Ayav A. Is intraoperative ultrasound still useful for the
detection of colorectal cancer liver metastases? HPB (Oxford). 2015;17(6):514–519.
125. Torzilli G, Botea F, Donadon M, et al. Criteria for the selective use of contrast-enhanced intra-operative ultrasound
during surgery for colorectal liver metastases. HPB (Oxford). 2014;16(11):994–1001.
126. van der Vorst JR, Schaafsma BE, Hutteman M, et al. Near-infrared fluorescence-guided resection of colorectal liver
metastases. Cancer. 2013;119(18):3411–3418.
127. Peloso A, Franchi E, Canepa MC, et al. Combined use of intraoperative ultrasound and indocyanine green fluorescence
imaging to detect liver metastases from colorectal cancer. HPB (Oxford). 2013;15(12):928–934.
128. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-stage resection of advanced colorectal liver
metastases: response-based selection and complete resection define outcome. J Clin Oncol. 2011;29(8):1083–1090.
129. Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver
metastases. J Surg Oncol. 2013;107(2):211–216.
130. Tsai S, Marques HP, de Jong MC, et al. Two-stage strategy for patients with extensive bilateral colorectal liver metastases.
HPB (Oxford). 2010;12(4):262–269.
131. Simoneau E, Hassanain M, Shaheen M, et al. Portal vein embolization and its effect on tumour progression for colorectal
cancer liver metastases. Br J Surg. 2015;102(10):1240–1249.
132. Shindoh J, Tzeng CW, Aloia TA, et al. Portal vein embolization improves rate of resection of extensive colorectal liver
metastases without worsening survival. Br J Surg. 2013;100(13):1777–1783.
133. Ribero D, Abdalla EK, Madoff DC, Donadon M, Loyer EM, Vauthey JN. Portal vein embolization before major hepatectomy
and its effects on regeneration, resectability and outcome. Br J Surg. 2007;94(11):1386–1394.
134. Leung U, Simpson AL, Araujo RL, et al. Remnant growth rate after portal vein embolization is a good early predictor of
post-hepatectomy liver failure. J Am Coll Surg. 2014;219(4):620–630.
135. Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts posthepatectomy
outcomes: toward zero liver-related mortality in patients with colorectal liver metastases and small future liver
remnant. J Am Coll Surg. 2013;216(2):201–209.
136. Mise Y, Aloia TA, Conrad C, Huang SY, Wallace MJ, Vauthey JN. Volume regeneration of segments 2 and 3 after right
portal vein embolization in patients undergoing two-stage hepatectomy. J Gastrointest Surg. 2015;19(1):
133–141. [discussion 141].
137. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid
left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg.
2012;255(3):405–414.
138. Eshmuminov D, Raptis DA, Linecker M, Wirsching A, Lesurtel M, Clavien PA. Meta-analysis of associating liver partition
with portal vein ligation and portal vein occlusion for two-stage hepatectomy. Br J Surg. 2016;103(13):1768–1782.
139. Bertens KA, Hawel J, Lung K, Buac S, Pineda-Solis K, Hernandez-Alejandro R. ALPPS: challenging the concept of
unresectability—a systematic review. Int J Surg. 2015;13:280–287.
140. Schadde E, Raptis DA, Schnitzbauer AA, et al. Prediction of mortality after ALPPS stage-1: an analysis of 320 patients
from the International ALPPS Registry. Ann Surg. 2015;262(5):780–785. [discussion 785-6].
141. Ratti F, Schadde E, Masetti M, et al. Strategies to increase the resectability of patients with colorectal liver metastases: a
multi-center case-match analysis of ALPPS and conventional two-stage hepatectomy. Ann Surg Oncol. 2015;22(6):
1933–1942.
142. Adam R, Imai K, Castro Benitez C, et al. Outcome after associating liver partition and portal vein ligation for staged
hepatectomy and conventional two-stage hepatectomy for colorectal liver metastases. Br J Surg. 2016;103(11):
1521–1529.
143. Faitot F, Faron M, Adam R, et al. Two-stage hepatectomy versus 1-stage resection combined with radiofrequency for
bilobar colorectal metastases: a case-matched analysis of surgical and oncological outcomes. Ann Surg. 2014;260(5):
822–827. [discussion 827-8].
144. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection and radiofrequency ablation for advanced hepatic
malignancies: results in 172 patients. Ann Surg Oncol. 2003;10(9):1059–1069.
145. de Jong MC, van Vledder MG, Ribero D, et al. Therapeutic efficacy of combined intraoperative ablation and resection for
colorectal liver metastases: an international, multi-institutional analysis. J Gastrointest Surg. 2011;15(2):336–344.
146. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery: the Louisville Statement,
2008. Ann Surg. 2009;250(5):825–830.
147. Dagher I, O’Rourke N, Geller DA, et al. Laparoscopic major hepatectomy: an evolution in standard of care. Ann Surg.
2009;250(5):856–860.
148. Nguyen KT, Marsh JW, Tsung A, Steel JJ, Gamblin TC, Geller DA. Comparative benefits of laparoscopic vs open hepatic
resection: a critical appraisal. Arch Surg. 2011;146(3):348–356.
149. Beppu T, Wakabayashi G, Hasegawa K, et al. Long-term and perioperative outcomes of laparoscopic versus open liver
resection for colorectal liver metastases with propensity score matching: a multi-institutional Japanese study.
J Hepatobiliary Pancreat Sci. 2015;22(10):711–720.
150. Mbah N, Agle SC, Philips P, et al. Laparoscopic hepatectomy significantly shortens the time to postoperative
chemotherapy in patients undergoing major hepatectomies. Am J Surg. 2017;213(6):1060–1064.
151. Vigano L, Laurent A, Tayar C, Tomatis M, Ponti A, Cherqui D. The learning curve in laparoscopic liver resection: improved
feasibility and reproducibility. Ann Surg. 2009;250(5):772–782.
152. Guro H, Cho JY, Han HS, Yoon YS, Choi Y, Periyasamy M. Current status of laparoscopic liver resection for hepatocellular
carcinoma. Clin Mol Hepatol. 2016;22(2):212–218.
153. Cloyd JM, Visser BC. Video-assisted thoracoscopic transdiaphragmatic liver resection for hepatocellular carcinoma. Surg
Endosc. 2012;26(6):1772–1776.
154. Kingham TP, Correa-Gallego C, D’Angelica MI, et al. Hepatic parenchymal preservation surgery: decreasing morbidity
and mortality rates in 4152 resections for malignancy. J Am Coll Surg. 2015;220(4):471–479.
155. Coolsen MM, Wong-Lun-Hing EM, van Dam RM, et al. A systematic review of outcomes in patients undergoing liver
surgery in an enhanced recovery after surgery pathways. HPB (Oxford). 2013;15(4):245–251.
156. Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with
surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24(31):
4976–4982.
157. Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from
colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008;26(30):4906–4911.
158. Ychou M, Hohenberger W, Thezenas S, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic
acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol.
2009;20(12):1964–1970.
159. Sullivan RD, Norcross JW, Watkins E. Chemotherapy of metastatic liver cancer by prolonged hepatic-artery infusion.
N Engl J Med. 1964:270321–270327.
160. Lewis HL, Bloomston M. Hepatic artery infusional chemotherapy. Surg Clin North Am. 2016;96(2):341–355.
161. Ensminger WD, Rosowsky A, Raso V, et al. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-
2′-deoxyuridine and 5-fluorouracil. Cancer Res. 1978;38(11 Pt 1):3784–3792.
162. Dizon DS, Schwartz J, Kemeny N. Regional chemotherapy: a focus on hepatic artery infusion for colorectal cancer liver
metastases. Surg Oncol Clin N Am. 2008;17(4):759–771. [viii].
163. Sigurdson ER, Ridge JA, Kemeny N, Daly JM. Tumor and liver drug uptake following hepatic artery and portal vein
infusion. J Clin Oncol. 1987;5(11):1836–1840.
164. Buchwald H, Grage TB, Vassilopoulos PP, Rohde TD, Varco RL, Blackshear PJ. Intraarterial infusion chemotherapy for
hepatic carcinoma using a totally implantable infusion pump. Cancer. 1980;45(5):866–869.
165. Bacchetti S, Pasqual E, Crozzolo E, Pellarin A, Cagol PP. Intra-arterial hepatic chemotherapy for unresectable colorectal
liver metastases: a review of medical devices complications in 3172 patients. Med Devices (Auckl). 2009:231–240.
166. Cheng J, Hong D, Zhu G, Swanstrom LL, Hansen PD. Laparoscopic placement of hepatic artery infusion pumps: technical
considerations and early results. Ann Surg Oncol. 2004;11(6):589–597.
167. Qadan M, D’Angelica MI, Kemeny NE, Cercek A, Kingham TP. Robotic hepatic arterial infusion pump placement. HPB
(Oxford). 2017;19(5):429–435.
168. Dhir M, Zenati MS, Padussis JC, et al. Robotic assisted placement of hepatic artery infusion pump is a safe and feasible
approach. J Surg Oncol. 2016;114(3):342–347.
169. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases
from colorectal cancer. New Engl J Med. 1999;341(27):2039–2048.
170. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. New Engl J Med. 2005;352(7):734–735.
171. Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the
liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—an intergroup
study. J Clin Oncol. 2002;20(6):1499–1505.
172. Kemeny N, Jarnagin W, Gonen M, et al. Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone
in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal
cancer. J Clin Oncol. 2003;21(17):3303–3309.
173. Kemeny N, Capanu M, D’Angelica M, et al. Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine
(FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver
metastases from colorectal cancer. Ann Oncol. 2009;20(7):1236–1241.
174. Kemeny NE, Chou JF, Boucher TM, et al. Updated long-term survival for patients with metastatic colorectal cancer
treated with liver resection followed by hepatic arterial infusion and systemic chemotherapy. J Surg Oncol. 2016;113(5):
477–484.
175. House MG, Kemeny NE, Gonen M, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial
infusional chemotherapy after hepatic resection for metastatic colorectal cancer. Ann Surg. 2011;254(6):851–856.
176. Goere D, Benhaim L, Bonnet S, et al. Adjuvant chemotherapy after resection of colorectal liver metastases in patients at
high risk of hepatic recurrence: a comparative study between hepatic arterial infusion of oxaliplatin and modern
systemic chemotherapy. Ann Surg. 2013;257(1):114–120.
177. Wurster EF, Tenckhoff S, Probst P, et al. A systematic review and meta-analysis of the utility of repeated versus single
hepatic resection for colorectal cancer liver metastases. HPB (Oxford). 2017;19(6):491–497.
178. Passot G, Soubrane O, Giuliante F, et al. Recent advances in chemotherapy and surgery for colorectal liver metastases.
Liver Cancer. 2016;6(1):72–79.
179. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal
cancer. N Engl J Med. 2009;360(14):1408–1417.
180. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic
colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634.
181. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver
metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol.
2010;11(1):38–47.
182. Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type
unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31(16):1931–1938.
183. Wong R, Cunningham D, Barbachano Y, et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as
perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.
Ann Oncol. 2011;22(9):2042–2048.
184. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus
modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with
previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32(21):
2240–2247.
185. Cirocchi R, Trastulli S, Boselli C, et al. Radiofrequency ablation in the treatment of liver metastases from colorectal
cancer. Cochrane Database Syst Rev. 2012;6:CD006317.
186. Han Y, Yan D, Xu F, Li X, Cai JQ. Radiofrequency ablation versus liver resection for colorectal cancer liver metastasis: an
updated systematic review and meta-analysis. Chin Med J (Engl). 2016;129(24):2983–2990.
187. Ruers T, Van Coevorden F, Punt CJ, et al. Local treatment of unresectable colorectal liver metastases: results of a
randomized phase II trial. J Natl Cancer Inst. 2017;109(9).
188. Ierardi AM, Floridi C, Fontana F, et al. Microwave ablation of liver metastases to overcome the limitations of
radiofrequency ablation. Radiol Med. 2013;118(6):949–961.
189. Stättner S, Primavesi F, Yip VS, et al. Evolution of surgical microwave ablation for the treatment of colorectal cancer liver
metastasis: review of the literature and a single centre experience. Surg Today. 2015;45(4):407–415.
190. Song CW, Lee YJ, Griffin RJ, et al. Indirect tumor cell death after high-dose hypofractionated irradiation: implications for
stereotactic body radiation therapy and stereotactic radiation surgery. Int J Radiat Oncol Biol Phys. 2015;93(1):166–172.
191. Méndez Romero A, de Man RA. Stereotactic body radiation therapy for primary and metastatic liver tumors: from
technological evolution to improved patient care. Best Pract Res Clin Gastroenterol. 2016;30(4):603–616.
192. Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer. 2009;45
(17):2947–2959.
193. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy
for liver metastases. J Clin Oncol. 2009;27(10):1572–1578.
194. Rule W, Timmerman R, Tong L, et al. Phase I dose-escalation study of stereotactic body radiotherapy in patients with
hepatic metastases. Ann Surg Oncol. 2011;18(4):1081–1087.
195. Scorsetti M, Comito T, Tozzi A, et al. Final results of a phase II trial for stereotactic body radiation therapy for patients
with inoperable liver metastases from colorectal cancer. J Cancer Res Clin Oncol. 2015;141(3):543–553.
196. Hoyer M, Roed H, Traberg Hansen A, et al. Phase II study on stereotactic body radiotherapy of colorectal metastases. Acta
Oncol. 2006;45(7):823–830.
197. Vautravers-Dewas C, Dewas S, Bonodeau F, et al. Image-guided robotic stereotactic body radiation therapy for liver
metastases: is there a dose response relationship? Int J Radiat Oncol Biol Phys. 2011;81(3):e39–e47.
198. Goodman BD, Mannina EM, Althouse SK, Maluccio MA, Cárdenes HR. Long-term safety and efficacy of stereotactic body
radiation therapy for hepatic oligometastases. Pract Radiat Oncol. 2016;6(2):86–95.
199. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized stereotactic body radiotherapy of liver metastases. J Clin
Oncol. 2009;27(10):1585–1591.
200. Méndez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation therapy for primary and metastatic
liver tumors: A single institution phase I-II study. Acta Oncol. 2006;45(7):831–837.
201. Colbert LE, Cloyd JM, Koay EJ, Crane CH, Vauthey JN. Proton beam radiation as salvage therapy for bilateral colorectal
liver metastases not amenable to second-stage hepatectomy. Surgery. 2017;161(6):1543–1548.
202. Bozkurt MF, Salanci BV, Uğur Ö. Intra-arterial radionuclide therapies for liver tumors. Semin Nucl Med. 2016;46(4):
324–339.
203. Kennedy AS, Nutting C, Coldwell D, Gaiser J, Drachenberg C. Pathologic response and microdosimetry of (90)Y
microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys. 2004;60(5):1552–1563.
204. Gulec SA, Pennington K, Wheeler J, et al. Yttrium-90 microsphere-selective internal radiation therapy with
chemotherapy (chemo-SIRT) for colorectal cancer liver metastases: an in vivo double-arm-controlled phase II trial.
Am J Clin Oncol. 2013;36(5):455–460.
205. Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin
chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004;88
(2):78–85.
206. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion
alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory
to standard chemotherapy. J Clin Oncol. 2010;28(23):3687–3694.
207. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for
treating patients with liver metastases from primary large bowel cancer. Ann Oncol. 2001;12(12):1711–1720.
208. Cohen SJ, Konski AA, Putnam S, et al. Phase I study of capecitabine combined with radioembolization using yttrium-90
resin microspheres (SIR-Spheres) in patients with advanced cancer. Br J Cancer. 2014;111(2):265–271.
209. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus
or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in
patients with metastatic colorectal cancer. J Clin Oncol. 2016;34(15):1723–1731.
210. Virdee PS, Moschandreas J, Gebski V, et al. Protocol for combined analysis of FOXFIRE, SIRFLOX, and FOXFIRE-global
randomized phase III trials of chemotherapy ± selective internal radiation therapy as first-line treatment for patients
with metastatic colorectal cancer. JMIR Res Protoc. 2017;6(3):e43.
211. Wright GP, Marsh JW, Varma MK, Doherty MG, Bartlett DL, Chung MH. Liver resection after selective internal radiation
therapy with yttrium-90 is safe and feasible: a bi-institutional analysis. Ann Surg Oncol. 2017;24(4):906–913.
212. Wu PC, McCart A, Hewitt SM, et al. Isolated organ perfusion does not result in systemic microembolization of tumor
cells. Ann Surg Oncol. 1999;6(7):658–663.
213. Boone BA, Bartlett DL, Zureikat AH. Isolated hepatic perfusion for the treatment of liver metastases. Curr Probl Cancer.
2012;36(2):27–76.
214. de Leede EM, Burgmans MC, Martini CH, et al. Percutaneous hepatic perfusion (PHP) with melphalan as a treatment for
unresectable metastases confined to the liver. J Vis Exp. 2016(113).
215. Bartlett DL, Libutti SK, Figg WD, Fraker DL, Alexander HR. Isolated hepatic perfusion for unresectable hepatic metastases
from colorectal cancer. Surgery. 2001;129(2):176–187.
216. Alexander HR, Libutti SK, Bartlett DL, et al. Hepatic vascular isolation and perfusion for patients with progressive
unresectable liver metastases from colorectal carcinoma refractory to previous systemic and regional chemotherapy.
Cancer. 2002;95(4):730–736.
217. Alexander HR, Libutti SK, Pingpank JF, Bartlett DL, Helsabeck C, Beresneva T. Isolated hepatic perfusion for the treatment
of patients with colorectal cancer liver metastases after irinotecan-based therapy. Ann Surg Oncol. 2005;12(2):138–144.
218. Alexander HR, Bartlett DL, Libutti SK, Fraker DL, Moser T, Rosenberg SA. Isolated hepatic perfusion with tumor necrosis
factor and melphalan for unresectable cancers confined to the liver. J Clin Oncol. 1998;16(4):1479–1489.
219. Magge D, Zureikat AH, Bartlett DL, et al. A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in
patients with unresectable isolated liver metastases from colorectal cancer. Ann Surg Oncol. 2013;20(7):2180–2187.
220. Zeh HJ, Brown CK, Holtzman MP, et al. A phase I study of hyperthermic isolated hepatic perfusion with oxaliplatin in the
treatment of unresectable liver metastases from colorectal cancer. Ann Surg Oncol. 2009;16(2):385–394.
221. Schoellhammer HF, Goldner B, Merchant SJ, Kessler J, Fong Y, Gagandeep S. Colorectal liver metastases: making the
unresectable resectable using irreversible electroporation for microscopic positive margins—a case report. BMC Cancer.
2015;15:271.
222. Scheffer HJ, Vroomen LG, Nielsen K, et al. Colorectal liver metastatic disease: efficacy of irreversible electroporation—a
single-arm phase II clinical trial (COLDFIRE-2 trial). BMC Cancer. 2015;15:772.
223. Kingham TP, Karkar AM, D’Angelica MI, et al. Ablation of perivascular hepatic malignant tumors with irreversible
electroporation. J Am Coll Surg. 2012;215(3):379–387.
224. Scheffer HJ, Nielsen K, van Tilborg AA, et al. Ablation of colorectal liver metastases by irreversible electroporation:
results of the COLDFIRE-I ablate-and-resect study. Eur Radiol. 2014;24(10):2467–2475.
225. Cannon R, Ellis S, Hayes D, Narayanan G, Martin RC. Safety and early efficacy of irreversible electroporation for hepatic
tumors in proximity to vital structures. J Surg Oncol. 2013;107(5):544–549.
226. Kasivisvanathan V, Thapar A, Oskrochi Y, Picard J, Leen EL. Irreversible electroporation for focal ablation at the porta
hepatis. Cardiovasc Intervent Radiol. 2012;35(6):1531–1534.
227. Niessen C, Igl J, Pregler B, et al. Factors associated with short-term local recurrence of liver cancer after percutaneous
ablation using irreversible electroporation: a prospective single-center study. J Vasc Interv Radiol. 2015;26(5):694–702.
228. Frühling P, Nilsson A, Duraj F, Haglund U, Norén A. Single-center nonrandomized clinical trial to assess the safety and
efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: short to mid-term results. Eur J Surg
Oncol. 2017;43(4):751–757.
229. Young S, D’Souza D, Flanagan S, Golzarian J. Review of the clinical evidence for the use of DEBIRI in the treatment of
colorectal metastatic disease. Cardiovasc Intervent Radiol. 2017;40(4):496–501.
230. Lencioni R, Aliberti C, de Baere T, et al. Transarterial treatment of colorectal cancer liver metastases with irinotecan-
loaded drug-eluting beads: technical recommendations. J Vasc Interv Radiol. 2014;25(3):365–369.
231. Fiorentini G, Aliberti C, Tilli M, et al. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus
intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer
Res. 2012;32(4):1387–1395.
232. Martin RC, Scoggins CR, Tomalty D, et al. Irinotecan drug-eluting beads in the treatment of chemo-naive unresectable
colorectal liver metastasis with concomitant systemic fluorouracil and oxaliplatin: results of pharmacokinetics and
phase I trial. J Gastrointest Surg. 2012;16(8):1531–1538.
233. Martin RC, Scoggins CR, Schreeder M, et al. Randomized controlled trial of irinotecan drug-eluting beads with
simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis. Cancer.
2015;121(20):3649–3658.
234. Akinwande O, Miller A, Hayes D, O’Hara R, Tomalty D, Martin RC. Concomitant capecitabine with hepatic delivery of
drug eluting beads in metastatic colorectal cancer. Anticancer Res. 2014;34(12):7239–7245.
235. Fiorentini G, Aliberti C, Sarti D, et al. Locoregional therapy and systemic cetuximab to treat colorectal liver metastases.
World J Gastrointest Oncol. 2015;7(6):47–54.
236. Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for
colorectal cancer liver metastases: a multicentre randomised trial. Lancet. 2003;361(9355):368–373.
237. Lorenz M, Müller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic
arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with
nonresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2000;18(2):243–254.
238. Kemeny N, Eid A, Stockman J, et al. Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose
mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma. J Surg Oncol. 2005;91(2):
97–101.
239. Lévi FA, Boige V, Hebbar M, et al. Conversion to resection of liver metastases from colorectal cancer with hepatic artery
infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV. Ann Oncol. 2016;27(2):
267–274.
240. Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic
chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):
3465–3471.
241. Starzl TE. The saga of liver replacement, with particular reference to the reciprocal influence of liver and kidney
transplantation (1955-1967). J Am Coll Surg. 2002;195(5):587–610.
242. Moris D, Tsilimigras DI, Chakedis J, et al. Liver transplantation for unresectable colorectal liver metastases: a systematic
review. J Surg Oncol. 2017;116(3):288–297.
243. Hagness M, Foss A, Line PD, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann
Surg. 2013;257(5):800–806.
244. Dueland S, Hagness M, Line PD, Guren TK, Tveit KM, Foss A. Is liver transplantation an option in colorectal cancer
patients with nonresectable liver metastases and progression on all lines of standard chemotherapy? Ann Surg Oncol.
2015;22(7):2195–2200.
245. Dueland S, Guren TK, Hagness M, et al. Chemotherapy or liver transplantation for nonresectable liver metastases from
colorectal cancer? Ann Surg. 2015;261(5):956–960.
246. Line PD, Hagness M, Berstad AE, Foss A, Dueland S. A novel concept for partial liver transplantation in nonresectable
colorectal liver metastases: the RAPID concept. Ann Surg. 2015;262(1):e5–e9.
247. Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic
colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247(1):125–135.
248. Kattan MW, Gonen M, Jarnagin WR, et al. A nomogram for predicting disease-specific survival after hepatic resection for
metastatic colorectal cancer. Ann Surg. 2008;247(2):282–287.
249. Yamaguchi T, Mori T, Takahashi K, Matsumoto H, Miyamoto H, Kato T. A new classification system for liver metastases
from colorectal cancer in Japanese multicenter analysis. Hepatogastroenterology. 2008;55(81):173–178.
250. Damm R, Seidensticker R, Ulrich G, et al. Y90 Radioembolization in chemo-refractory metastastic, liver dominant
colorectal cancer patients: outcome assessment applying a predictive scoring system. BMC Cancer. 2016;16:509.
251. Hill CR, Chagpar RB, Callender GG, et al. recurrence following hepatectomy for metastatic colorectal cancer:
development of a model that predicts patterns of recurrence and survival. Ann Surg Oncol. 2012;19(1):139–144.
252. Sasaki K, Morioka D, Conci S, et al. The tumor burden score: a new “Metro-ticket” prognostic tool for colorectal liver
metastases based on tumor size and number of tumors. Ann Surg. 2016 [Epub ahead of print].
253. Margonis GA, Spolverato G, Kim Y, Karagkounis G, Choti MA, Pawlik TM. Effect of KRAS mutation on long-term
outcomes of patients undergoing hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2015;22(13):
4158–4165.
254. Kemeny NE, Chou JF, Capanu M, et al. KRAS mutation influences recurrence patterns in patients undergoing hepatic
resection of colorectal metastases. Cancer. 2014;120(24):3965–3971.
255. Margonis GA, Kim Y, Spolverato G, et al. Association between specific mutations in KRAS codon 12 and colorectal liver
metastasis. JAMA Surg. 2015;150(8):722–729.
256. Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients
undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258(4):619–626. [discussion 626-7].
257. Chen KF, Yen CC, Lin JK, et al. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an independent prognostic
marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy. BMC Cancer. 2015;15:301.
258. Teng HW, Huang YC, Lin JK, et al. BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy. J Surg
Oncol. 2012;106(2):123–129.
259. Styczen H, Nagelmeier I, Beissbarth T, et al. HER-2 and HER-3 expression in liver metastases of patients with colorectal
cancer. Oncotarget. 2015;6(17):15065–15076.
260. Goos JA, Hiemstra AC, Coupe VM, et al. Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide
synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases. Br J Cancer.
2014;111(4):749–755.
261. Isella C, Mellano A, Galimi F, et al. MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer
liver metastases. Ann Surg. 2013;257(6):1089–1095.
262. Martinez-Cecilia D, Cipriani F, Vishal S, et al. Laparoscopic versus open liver resection for colorectal metastases
in elderly and octogenarian patients: a multicenter propensity score based analysis of short- and long-term outcomes.
Ann Surg. 2017;265(6):1192–1200.
263. Zeng Y, Tian M. Laparoscopic versus open hepatectomy for elderly patients with liver metastases from colorectal cancer.
J Buon. 2016;21(5):1146–1152.
264. Untereiner X, Cagniet A, Memeo R, et al. Laparoscopic hepatectomy versus open hepatectomy for colorectal cancer liver
metastases: comparative study with propensity score matching. Hepatobiliary Surg Nutr. 2016;5(4):290–299.
265. Cipriani F, Rawashdeh M, Stanton L, et al. Propensity score-based analysis of outcomes of laparoscopic versus open liver
resection for colorectal metastases. Br J Surg. 2016;103(11):1504–1512.
266. Lewin JW, O’Rourke NA, Chiow AK, et al. Long-term survival in laparoscopic vs open resection for colorectal liver
metastases: inverse probability of treatment weighting using propensity scores. HPB (Oxford). 2016;18(2):183–191.
267. Allard MA, Cunha AS, Gayet B, et al. Early and long-term oncological outcomes after laparoscopic resection for colorectal
liver metastases: a propensity score-based analysis. Ann Surg. 2015;262(5):794–802.
268. Nachmany I, Pencovich N, Zohar N, et al. Laparoscopic versus open liver resection for metastatic colorectal cancer. Eur J
Surg Oncol. 2015;41(12):1615–1620.
269. Langella S, Russolillo N, D’Eletto M, Forchino F, Lo Tesoriere R, Ferrero A. Oncological safety of ultrasound-guided
laparoscopic liver resection for colorectal metastases: a case-control study. Updates Surg. 2015;67(2):147–155.
270. Hasegawa Y, Nitta H, Sasaki A, et al. Long-term outcomes of laparoscopic versus open liver resection for liver metastases
from colorectal cancer: a comparative analysis of 168 consecutive cases at a single center. Surgery. 2015;157(6):
1065–1072.
271. Lin Q, Ye Q, Zhu D, Wei Y, Ren L, Zheng P, et al. Comparison of minimally invasive and open colorectal resections for
patients undergoing simultaneous R0 resection for liver metastases: a propensity score analysis. Int J Colorectal Dis.
2015;30(3):385–395.
272. de’Angelis N, Eshkenazy R, Brunetti F, et al. Laparoscopic versus open resection for colorectal liver metastases: a single-
center study with propensity score analysis. J Laparoendosc Adv Surg Tech A. 2015;25(1):12–20.
273. Qiu J, Chen S, Pankaj P, Wu H. Laparoscopic hepatectomy is associated with considerably less morbidity and a long-term
survival similar to that of the open procedure in patients with hepatic colorectal metastases. Surg Laparosc Endosc
Percutan Tech. 2014;24(6):517–522.
274. Montalti R, Berardi G, Laurent S, et al. Laparoscopic liver resection compared to open approach in patients with
colorectal liver metastases improves further resectability: oncological outcomes of a case-control matched-pairs
analysis. Eur J Surg Oncol. 2014;40(5):536–544.
275. Iwahashi S, Shimada M, Utsunomiya T, et al. Laparoscopic hepatic resection for metastatic liver tumor of colorectal
cancer: comparative analysis of short- and long-term results. Surg Endosc. 2014;28(1):80–84.
276. Inoue Y, Hayashi M, Tanaka R, Komeda K, Hirokawa F, Uchiyama K. Short-term results of laparoscopic versus open liver
resection for liver metastasis from colorectal cancer: a comparative study. Am Surg. 2013;79(5):495–501.
277. Doughtie CA, Egger ME, Cannon RM, Martin RC, McMasters KM, Scoggins CR. Laparoscopic hepatectomy is a safe and
effective approach for resecting large colorectal liver metastases. Am Surg. 2013;79(6):566–571.
278. Qiu J, Chen S, Pankaj P, Wu H. Laparoscopic hepatectomy for hepatic colorectal metastases—a retrospective comparative
cohort analysis and literature review. PLoS One. 2013;8(3):e60153.
279. Cheung TT, Poon RT, Yuen WK, et al. Long-term survival analysis of pure laparoscopic versus open hepatectomy for
hepatocellular carcinoma in patients with cirrhosis: a single-center experience. Ann Surg. 2013;257(3):506–511.
280. Guerron AD, Aliyev S, Agcaoglu O, et al. Laparoscopic versus open resection of colorectal liver metastasis. Surg Endosc.
2013;27(4):1138–1143.
281. Wang X, Hershman DL, Abrams JA, et al. Predictors of survival after hepatic resection among patients with colorectal
liver metastasis. Br J Cancer. 2007;97(12):1606–1612.
282. Niu R, Yan TD, Zhu JC, Black D, Chu F, Morris DL. Recurrence and survival outcomes after hepatic resection with or
without cryotherapy for liver metastases from colorectal carcinoma. Ann Surg Oncol. 2007;14(7):2078–2087.
283. Malik HZ, Prasad KR, Halazun KJ, et al. Preoperative prognostic score for predicting survival after hepatic resection for
colorectal liver metastases. Ann Surg. 2007;246(5):806–814.
284. Reissfelder C, Rahbari NN, Koch M, et al. Validation of prognostic scoring systems for patients undergoing resection of
colorectal cancer liver metastases. Ann Surg Oncol. 2009;16(12):3279–3288.
285. Robertson DJ, Stukel TA, Gottlieb DJ, Sutherland JM, Fisher ES. Survival after hepatic resection of colorectal cancer
metastases: a national experience. Cancer. 2009;115(4):752–759.
286. Hwang M, Jayakrishnan TT, Green DE, et al. Systematic review of outcomes of patients undergoing resection for
colorectal liver metastases in the setting of extra hepatic disease. Eur J Cancer. 2014;50(10):1747–1757.
287. Aloia TA, Fahy BN, Fischer CP, et al. Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in
the NSQIP database. HPB (Oxford). 2009;11(6):510–515.
288. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in
unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer. 2010;103(3):324–331.
289. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases
from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol.
2006;24(9):1395–1403.
290. DʼAngelica MI, Correa-Gallego C, Paty PB, et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for
patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes.
Ann Surg. 2015;261(2):353–360.

Update On Current Problems in Colorectal Liver Metastasis

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Current Problems in Surgery 54 (2017) 554–602

Contents lists available at ScienceDirect

Current Problems in Surgery

journal homepage: www.elsevier.com/locate/cpsurg

Update on current problems in colorectal

Natural history of colorectal liver metastasis

Deﬁnitions and management strategies

Deﬁning resectable disease—An evolving paradigm

Characteristics Historical criteria Current criteria

Tumor number o4 Lesions Any

Management of synchronous disease

A generalized approach to the treatment of nonemergent synchronous disease was proposed by

Use of systemic perioperative chemotherapy

Perioperative chemotherapy options and rationalization for use

Rate of progression on chemotherapy

Chemotherapy-associated liver injury

Preoperative evaluation and optimization

Evaluation of the FLR

As patient outcomes become an increasingly relevant quality metric, the importance of

Patient demographics and primary tumor

Clinical risk scoring systems

Scoring system Predictive factors Survival estimates

• Nodal status (N2)

CEA, carcinoembryonic antigen.

Disappearing liver metastasis

Molecular markers as prognostic indicators

Technical aspects of resection

Molecular proﬁle Clinical predictor in CRLM

KRAS mutation • Decreased radiographic and pathologic response rates to FOLFOX-

Intraoperative identiﬁcation of metastases

Two-stage resection with PVE

Combined resection and ablation

Minimally invasive techniques

Martinez-Cecilia and colleagues262 4 40 400* 39* 8*

J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

Study OS (%) RFS (%) DFS (%) Survival measure

LLR OLR LLR OLR LLS OLR

Martinez-Cecilia and colleagues262 51 45 33 27 NR NR Median

NR, not recorded.

Morbidity and mortality in modern series

Early recovery after surgery protocols

Quality improvement initiatives

Study Patients (n) Operative mortality (%) Overall survival (%)

Fong and colleagues85 1001 2.8 89 57 36 42

Adjuvant therapies following hepatectomy

Indications and use of chemotherapy

All Partial Left Right Extended

Hepatic arterial infusion therapy in the adjuvant setting

Repeat resection of recurrence

Multidisciplinary management of unresectable disease

Chemotherapy to downstage disease

In addition to chemotherapeutic options, a variety of locoregional approaches for the treatment

Stereotactic body radiotherapy

Yttrium-90 selective internal radiotherapy

Study Phase/study type Treatment Patients Outcome Toxicity

J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

• 2-y PFS rate 35%

J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

RILD, radiation induced liver disease; KM, Kaplan-Meier.

Study Phase Treatment Patients Outcome Toxicity

J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

J. Chakedis et al. / Current Problems in Surgery 54 (2017) 554–602

Author, Trial title Phase Treatment Patients Outcomes to be measured