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Chapter 15 / Management of Patients with Colorectal Liver Metastases 181
3. Vascular inow and outow and biliary outow to the remaining liver
segments must be spared.
4. e FLR must be of adequate volume to account for any underlying
hepatic dysfunction.
With expanded criteria of resectability for CRLM, a number of strate-
gies for improving resectability have emerged, with the goal of increasing
the number of patients eligible for hepatic resection for CRLM. ese strat-
egies fall into three broad categories: increasing hepatic reserve, decreasing
tumor size, and using combined modality local therapy.
Portal vein embolization (PVE) has been used to increase hepatic
reserve in patients undergoing hepatectomy for CRLM (Fig. 15.1). In
patients with normal hepatic function, an FLR of 20% to 30% is required
to ensure adequate hepatic regeneration and function following resection.
Patients with underlying hepatic dysfunction require a larger FLR: Patients
Embolized
Right Portal Vein
Hypertrophied
Left Liver
FIGURE 15.1 CT scan of the liver following PVE of the right portal vein; note the hypertro-
phy of the left liver.
Old New
Number of metastases < 4 Any number, provided an R0
resection can be achieved
Distribution of
metastases
Unilobar Two contiguous segments of
liver must be preserved
Size of metastases < 5cm Any size, provided an
adequate FLR is preserved
Presence of
extrahepaticdisease
None Allowed, provided all disease
can be resected with an
R0 resection
Changing Denition of Resectability for Colorectal Liver
Metastases
TABLE
15.1
Section II / Liver182
with steatosis or steatohepatitis require an FLR of 30% to 40%, and patients
with cirrhosis require a 40% to 50% FLR. FLR can accurately be measured
on CT or MRI using volumetric assessment. is is the most commonly
used method for measuring FLR in Western centers and is used to iden-
tify patients who may benet from preoperative PVE. Indocyanine green
retention at 15 minutes has also been demonstrated to predict postopera-
tive liver failure and mortality; however, the availability of this technique in
Western centers is limited. Preoperative PVE is a technique that involves
embolization of the portal vein with cyanoacrylate, gelatin microspheres,
polyvinyl alcohol, or coils. Embolization of the tumor-bearing liver induces
hypertrophy of the contralateral liver and thus increases the FLR volume.
PVE is well tolerated with a low complication rate (< 5%) and normally
results in an absolute increase in FLR of approximately 8% to 16% depend-
ing on the degree of underlying hepatic dysfunction. e timing and degree
of hypertrophy in response to PVE may help guide patient selection for
operation.
A two-stage hepatectomy is a surgical approach that may be used in
patients with extensive disease involving both sides of the liver (Fig. 15.2).
In a subset of patients, clearance of all disease is often not possible in one
operation due to concerns of an inadequate FLR. When the CRLM are bilat-
eral, PVE is often not ideal as embolization of the entire tumor- bearing liver
is not feasible. In these circumstances, a two-stage approach may be pos-
sible. With the two-stage approach, the disease in one hemiliver is cleared
and the contralateral portal vein is occluded either by portal vein ligation
during this rst operation or by PVE performed postoperatively. e rem-
nant portion of the liver that has been “cleared” is then allowed to hyper-
trophy, and then the patient is brought back to the operating room 4 to
6weeks later to resect the remaining disease in the liver. When performing
a two-stage hepatectomy, most surgeons advocate initial resection of minor
1s
t
2nd
FIGURE 15.2 Depiction of a two-stage hepatectomy. The rst stage was a segmentectomy
of the left lateral bisector; following PVE, the patient was brought back to the operating
room 6 weeks later for the second stage, which was a right hepatectomy.
Chapter 15 / Management of Patients with Colorectal Liver Metastases 183
disease (threeor fewer segments) followed by resection of major disease
(greater than three segments) at the second operation. Doing the minor
liver resection rst will spare a subset of patients the morbidity of a major
hepatic resection, as 20% to 30% of patients will never undergo the second
stage due to disease progression or worsening performance status. Of note,
patients undergoing a two-stage approach can safely be treated with che-
motherapy between stages without impairing hypertrophy of the FLR.
Improvements in chemotherapy for patients with CRC have substan-
tially improved tumor response rates in patients with CRLM (Fig. 15.3).
Indeed, 12% to 33% of patients with initially unresectable disease can be
downsized after receiving “conversion chemotherapy” to a point where
curative intent resection is feasible. Average 5-year survival for these
patients is 30% to 35%, which is signicantly better than patients receiv-
ing chemotherapy alone (approximately 10%). In this subset of patients,
multidisciplinary involvement including close collaboration between the
medical oncologist and the surgeon is essential. Chemotherapy should be
continued until the patient is resectable, not until maximal response is
achieved. Prolonged chemotherapy beyond the point of resectability may
increase rates of chemotherapy-associated hepatotoxicity and contribute
to increased patient morbidity after hepatic resection. While the care of
each patient must be individualized, in general, preoperative cytotoxic che-
motherapy (e.g., FOLFOX or FOLFIRI) should be stopped about 4 to 6 weeks
prior to surgery, while bevacizumab (Avastin) should generally be stopped
6 to 8 weeks prior to surgery.
Ablation can involve either radiofrequency ablation (RFA) or micro-
wave ablation. Ablation either alone or in combination with resection
can increase the number of patients eligible for liver-directed therapy for
colorectal metastases. Ablation should not be viewed as a substitute for
hepatic resection but as a complementary therapy in patients in whom
complete resection is not possible. Often in patients with extensive disease,
FIGURE 15.3 CT scan of a patient pre- and postreceipt of preoperative chemotherapy.
Note the cytoreduction of the tumor and the decrease in the size of the masses following
chemotherapy.
Section II / Liver184
larger lesions can be resected, while smaller lesions are ablated. Ablation
can be performed percutaneously, laparoscopically, or during laparotomy
and can be used to successfully ablate tumors of up to 3 to 4cm in diameter
with a single application. Generally, a 1-cm “margin” of thermal necrosis is
desired around the lesions. e ecacy of RFA in lesions adjacent to large
blood vessels decreases due to a heat-sink eect, which is associated with
higher local recurrence rates; microwave ablation may be less susceptible
to this “heat-sink” eect. Ablation should generally be avoided with lesions
near the hilum of the liver, as ablation may damage biliary structures and
lead to subsequent stricturing. e combination of ablation with hepatic
resection results in morbidity and mortality rates similar to those seen with
resection alone. It is dicult to compare survival of patients undergoing
ablation to those undergoing resection because patients who undergo abla-
tion often have more extensive disease and medical comorbidities than
those undergoing resection. Nonetheless, ablation can have an important
role in the management of patients with hepatic metastases as an adjunct
to the treatment plan in patients with unresectable disease.
Operative Strategy
At the time of hepatectomy, a thorough assessment for the extent of disease
including full liver mobilization, vi sual inspection, palpation, and intraopera-
tive ultrasound (IOUS) should be performed in all patients. IOUS is an impor-
tant tool to identify lesions intraoperatively and to dene the relationship of
hepatic lesions to vascular structures. In several studies, IOUS has been dem-
onstrated to be superior to intraoperative inspection and palpation for iden-
tication of hepatic neoplasms. A systematic approach should be used to
perform IOUS in order to identify all hyper-, iso-, and hypoechoic lesions. All
suspicious lesions should be scanned in the transverse and sagittal planes to
dene size and anatomic relationships. e IOUS characteristics of hepatic
metastases tend to be similar within patients (as compared to between
patients), and the echogenic appearance of the index lesion can be used to
predict the appearance of additional lesions in the same patient, facilitating
intraoperative identication of lesions. IOUS has been demonstrated in the
literature to change the operative plan in up to 67% of patients undergoing
hepatectomy. In addition, in 10% to 12% of patients, IOUS identies at least
one lesion not seen on preoperative imaging when routinely employed. IOUS
should therefore be used in all patients undergoing surgery for CRLM to facil-
itate identication of all lesions and complete clearance of the liver.
Complete resection of CRLM with a microscopic negative margin
should be the goal when undertaking hepatectomy for CRLM. Numerous
studies have documented both a higher risk of recurrence and decreased
overall survival in patients with positive resection margins. Historically, a
1-cm resection margin was considered mandatory based on data from a
1999 study by Cady et al., which demonstrated improved overall survival in
patients with a 1-cm margin. A number of studies have subsequently dem-
onstrated no dierence in local recurrence or overall survival in patients
with a subcentimeter R0 resection compared with those with margins
greater than 1cm. In a 2008 study, de Hass et al. demonstrated that while
patients undergoing an R1 resection had increased risk of local recurrence,
there was no dierence in overall survival when compared with patients
undergoing R0 resection. e authors attribute this change in outcome
after R1 resection for CRLM to increasingly eective chemotherapeutic
regimens. us, while the goal of surgery for CRLM remains an R0 resection
and the surgeon should strive for at least a 1-cm margin, resection should
be considered in patients where less than a 1-cm margin is obtainable as
long as all macroscopic disease can be resected.
Chapter 15 / Management of Patients with Colorectal Liver Metastases 185
OUTCOMES/FOLLOW-UP
e 5-year survival after curative intent hepatic resection for CRLM ranges
from 40% to 58% (Table 15.2). e NCCN currently recommends surveil-
lance with history, physical exam, CEA, and CT chest/abdomen/pelvis
every 3 to 6 months for 2 years and then every 6 months for years 3 to 5.
Over 60% of patients with resected hepatic disease will recur at some point
during their disease course. If patients do recur with liver-only disease,
repeat hepatectomy may be considered in a select group of patients. Several
studies have demonstrated perioperative morbidity and mortality of repeat
resection for CRLM similar to that for patients undergoing initial surgery.
Five-year overall survival for patients undergoing hepatectomy range from
29% to 42%; thus, an aggressive approach to repeat resection is warranted
in well-selected patients, as it may be the only chance for long-term cure.
CONCLUSION
Signicant improvements in chemotherapeutic regimens, surgical tech-
nique, and patient selection have resulted in improved survival for patients
undergoing hepatic resection for CRLM. Many patients with disease that
was once considered unresectable are now able to enjoy the survival ben-
ets of resection for CRLM due to expanded indications for hepatectomy,
use of conversion chemotherapy, utilization of techniques to increase the
FLR, and liver-directed therapies. Careful preoperative planning and mul-
tidisciplinary collaboration are essential to ensure optimal outcomes for
these patients.
Suggested Readings
Adam R, Avisar E, Ariche A, et al. Five-year survival following hepatic resec-
tion after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol
2001;8:347–353.
Asiyananbola B, Chang D, Gleisner AL, et al. Operative mortality after hepatic
resection: are literature-based rates broadly applicable? J Gastrointest Surg
2008;12:842–851.
Charnsangavej C, Clary B, Fong Y, et al. Selection of patients for resection of
hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol
2006;13:1261–1268.
de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by necessity for colorectal liver
metastases: is it still a contraindication to surgery? Ann Surg 2008;248:626–637.
Author Year
Number of
Patients
Number of Patients
with R0 Resection
5-Year
Overall
Survival
Fong 1999 1,001 895 37%
Choti 2002 133 NS 58%
Abdalla 2004 190 NS 58%
Fernandez 2004 100 100 58%
Wei 2006 423 407 47%
Rees 2008 929 833 36%
de Jong 2009 1,669 1,391 47%
Morris 2010 3,116 NS 44.2%
NS, not specied.
Outcomes Following Resection for Colorectal Liver
Metastases
TABLE
15.2
Section II / Liver186
Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic
resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann
Surg 1999;230:309–318.
Mayo S, Pawlik T. Current management of colorectal hepatic metastases. Expert Rev
Gastroenterol Hepatol 2009;3:131–144.
Pawlik TM, Abdalla EK, Ellis LM, et al. Debunking dogma: surgery for four or more
colorectal liver metastases is justied. J Gastrointest Surg 2006;10:240–248.
187
NEUROENDOCRINE LIVER METASTASES
Introduction
Arguably, one of the greatest advances in solid tumor oncology in the
early twentieth century has been the evolving treatment of liver metasta-
ses. Improvements in modern imaging modalities, renement in surgical
indications and techniques, more eective systemic therapies, and advanc-
ing technology in locoregional nonresectional strategies led to an increas-
ing number of treatment options for patients with hepatic metastases.
Although typically regarded as slow-growing neoplasms, neuroendocrine
tumors vary widely in their clinical behavior and biologic activity, and the
liver is the most common site of distant metastases. Various classication
systems and nomenclature exist for the clinical staging and management
of patients with primary neuroendocrine carcinoma (NEC). Herein, we will
overview the management of hepatic metastases from well-dierentiated
NEC from various sites and summarize management options to provide
an algorithm and overall treatment strategy to approach these complex
patients. Importantly, although cure is rare, treatment typically leads to
prolonged survival, signicant palliation of symptoms, and improved qual-
ity of life (QOL) for patients with metastatic NEC.
After colorectal cancer, NEC is the second most common indication
for liver-directed therapies in patients with metastatic disease. e relatively
indolent growth of these lesions compared to hepatic metastases from other
sites allows for a planned aggressive approach incorporating resection as a
major component of treatment. Surgical treatment must balance the signi-
cant risk of treatment-related morbidity particularly if major hepatic or mul-
tivisceral resections are performed concomitantly. Although the operative
morbidity and mortality of such resections may be signicant, specically
with combined procedures, operation generally provides durable oncologic
or symptomatic benets and rarely precludes medical therapy.
NECs of the gastrointestinal tract and pancreas are rare and comprise
less than 1% of all malignant disease. Recent prospective national tumor
database studies suggest a linearly increasing overall incidence of NEC, with
the second highest prevalence of all gastrointestinal cancers. Overall progno-
sis is dependent on the primary tumor type, site of origin, stage, and various
pathologic features such as size, histologic dierentiation, and prolifera-
tive activity. No single system of nomenclature and grading for all NECs has
been universally accepted. Importantly, poorly dierentiated or high-grade
NECs are more frequently associated with distant metastases (liver and bone
approximately 50% of cases) at initial diagnosis, and overall survival is poor
regardless of therapy. us, these patients are rarely candidates for hepatic
resection because of biologic aggressiveness. Overall, the therapeutic modali-
ties for management of patients with hepatic metastases from NEC include
Neuroendocrine and
Noncolorectal Liver
Metastases
Mark J. Truty and David M. Nagorney
16
Section II / Liver188
surgical, chemo-/biotherapy, ablative, and nuclear medicine strategies. Given
the heterogeneity of NEC, variable disease extent, and biologic behavior, the
recommendations for therapy are based on the results of retrospective out-
comes with sparse prospective high-level evidence.
Hepatic metastases from NEC are diagnosed either at the time of pri-
mary disease diagnosis (synchronous) or with disease progression (meta-
chronous). In general, the primary and regional extent of the NEC should
be resected before addressing hepatic metastases. Concomitant resection
of the primary NEC and the hepatic metastases should be undertaken only
after multidisciplinary assessment of the patient’s disease stage. Staged
resection of the primary NEC with subsequent hepatic resection of the
metastases is performed typically, although data from referral centers
suggest that concomitant resection can be performed safely in selected
patients. Most frequently, concomitant resections are undertaken in
patients requiring minor hepatic resections. In patients with clinical endo-
crinopathies, preoperative control is recommended. Preoperative octreo-
tide therapy is essential in patients with the carcinoid syndrome to prevent
intraoperative carcinoid crises (Fig. 16.1). Patients with carcinoid heart
disease occasionally require cardiac surgery to address valvular right heart
failure prior to hepatic resection (Fig. 16.2). Additionally, interval hepatic
arterial embolization in selected patients with bulky functioning NEC
metastases may be required in preparation for hepatic resection either to
address residual endocrinopathies after resection of the primary NEC or to
downsize intrahepatic metastases. Patients with pancreatic NEC generally
should undergo staged resections of the primary and hepatic metastases to
avoid excess morbidity from combined hepatic and pancreatic resection.
Diagnostic Evaluation
A comprehensive evaluation of patients with neuroendocrine liver metas-
tases includes identication of the anatomic site of origin (whether in
situ or previously resected), clinical and biochemical functional status,
FIGURE 16.1 Frequency of various symptoms in patients with the carcinoid syndrome.
Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 189
tumor histopathology and grade, and evaluation of extent and distribu-
tion of
metastatic disease for resectability. Tumor site of origin is usually
determined by endoscopy, contrast-enhanced enterography, radiolabeled
scintigraphy, or cross-sectional imaging computed tomography (CT) or
magnetic resonance imaging (MRI). NECs are termed functional if asso-
ciated with a discrete clinical syndrome. e syndrome is conrmed bio-
chemically through serum assays of respective neuroendocrine peptides.
e clinical neuroendocrine syndrome is specic to the dominant func-
tioning peptide. Not infrequently, multiple peptide levels are elevated
but rarely do patients present with a combined clinical endocrinopathy.
Nearly all NECs secrete chromogranin A; baseline concentration of this
marker should be obtained regardless of clinical syndrome. Other secretory
FIGURE 16.2 A. Contrast-enhanced CT with large right hepatic ileal carcinoid metas-
tasis. The inferior vena cava is dilated, and the liver has a heterogenous appearance
due to preexisting severe tricuspid valve regurgitation. B. Gross specimen of resected
tumor—the patient underwent tricuspid/pulmonary valve replacement prior to liver
resection.
(Continued )
Section II / Liver190
peptides should be evaluated as clinically indicated. Pathologic conrma-
tion of NEC by ne needle aspiration or core biopsy (either metastases
or primary tumor) is essential for clinical management. Grade of NEC is
dened by proliferative activity via the Ki-67 index and mitotic rate. ese
key features of grading are critically important for clinical management.
Indeed, pathologic ndings correlate, in part, with the malignant behavior
of NEC. In general, patients with well-dierentiated grade 1 NEC benet the
most from aggressive therapy because of typically indolent growth. Patients
FIGURE 16.2 (Continued) C. Contrast-enhanced CT with low-density jejunal carcinoid
metastasis in left lateral sector. D. Gross specimen of resected liver tumor.