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Chapter19:Neuroendocrine tumor metastases
http://internalmedicinebook.com
Table 19.2 Summary of various systematic therapies
Agent Mechanism Action Response PFS OS
Octreotide Somatostatin receptor antagonist Symptom control, antiproliferative Very low Increased No effect
Lanreotide Somatostatin receptor antagonist Symptom control, antiproliferative Very low Increased No effect
Evirolimus mTOR inhibitor Symptom control, antiproliferative Very low Increased No effect
Sunitinib Tyrosine kinase inhibitor Symptom control, antiproliferative Very low Increased No effect
CapTem Cytotoxic Cytoreduction High Increased Unknown
PRRT Receptor-targeted radioligand Cytoreduction Low Increased Unknown
MIBG Receptor-targeted radioligand Cytoreduction Low Increased Unknown
PFS = progression-free survival; OS = overall survival; PRRT = peptide receptor radiotherapy; MIBG = metaiodobenzylguanidine.
100
80
Kaplan-Meier median PFS
Everolimus: 11.0 months
Placebo: 4.6 months
Hazard ratio = 0.35; 95% Cl (0.27-0.45)
Figure 19.4 Results of the RADIANT-3
trial. Kaplan–Meier estimates are shown
for progression-free survival (PFS).
No difference in overall survival was
seen in this trial (curves not shown).
CI = confidence interval.
P < 0.001
60
40
Percentage Event-Free
20
Censoring times
Everolimus (n/N = 109/207)
0
(debulking) of liver metastases may have an important role.
Retrospective data regarding resection of non-pancreatic primary tumors in patients with metastases suggest a survival
benet.33 e role of resection of pancreatic primaries is less
clear. Similarly, there are limited data for the role of cytoreduction in patients with unresectable metastases. Dened as resection of 90% of the tumor or metastasis, debulking has been
advocated in the surgical literature based on retrospective case
studies; however, the ecacy of modern antisecretory medications in controlling symptoms has been cited as an argument
against cytoreduction.
Based on the slow growth of neuroendocrine hepatic
metastases and the benet of liver resection in their treatment,
liver transplantation has been performed in select cases. While
the reported experience has grown, the role of liver transplantation for the treatment of metastatic neuroendocrine disease
remains unclear.
Placebo (n/N = 165/203)
0246810121416
Time, months
34,35,36
37
18 20 22
24 26 28 30
resection.38 Each technique has its advantages and disadvantages. Percutaneous ablation is less invasive, relatively inexpensive, and allows for direct image guidance, while open or
laparoscopic ablation allows direct visualization of disease
extent, access to locations not conducive to a percutaneous
approach, as well as the ability to resect the primary lesion as
well as additional bulky metastases. In selecting between surgical and percutaneous techniques a multidisciplinary approach
is recommended with careful attention to the above-mentioned
considerations.
Percutaneous ablation is primarily used for palliation of
carcinoid symptoms and management of recurrent disease in
patients with fewer than 4–5 metastatic lesions, each of which
measures less than 3cm in maximal diameter.39 Radiofrequency
ablation (RFA) is the most frequently reported technology for
the treatment of hepatic metastases of NETs, and may be performed using MR, CT, or ultrasound guidance. is technique
produces thermal injury by a high-frequency alternating cur-
Image-guided therapy
Tumor ablation
Ablation has been developed for both percutaneous and surgical approaches, including as an adjunct to liver resection
and for the treatment of patients who are not candidates for
rent passed from an uninsulated electrode into surrounding
tissues, resulting in frictional heating of tissue surrounding the
electrodes leading to cellular injury. Given the demonstrated
release of vasoactive hormones during ablation, patients should
be premedicated with somatostatin analogs prior to ablation in
order to avoid carcinoid crisis.40 Like with chemoembolization,
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Section IV:Liver metastases
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bilioenteric anastomosis is a risk factor for the development of
liver abscess following thermal ablation and liver abscesses have
been reported to occur despite prolonged antibiotic therapy in
4 of 9 patients with a bilioenteric anastomosis 13–62days aer
RFA.41 In the largest reported series of RFA for metastases of
NETs, RFA was performed during laparoscopy in 89 patients
bearing a mean of six metastases, with a mean size of 3.6cm.42
Symptom relief was achieved in 97%. Median overall survival
was 6years. Symptomatic response to RFA is well established
and has been eective for the control of symptoms in patients
unresponsive to hepatic artery embolization.43 More recently,
Karabulut etal. reported decreased morbidity for RFA in comparison to embolization and resection in their multimodality
study of neuroendocrine liver metastases.
44
Additional ablative techniques have been applied for the
treatment of neuroendocrine liver metastases on a more limited basis, including ethanol injection. Rarely eective for
treatment of metastases from other malignancies, Livraghi
etal. reported that ablation using percutaneous, intratumoral
injection of ethanol aected a complete response in all four of
the treated neuroendocrine hepatic metastases.45 Other thermal ablation technologies include microwave, cryoablation,
and laser application systems, all of which can be applied to
NET metastases.
Hepatic arterial therapy
e two primary indications for intra-arterial therapy supported by current National Comprehensive Cancer Network,
North American Neuroendocrine Tumor Society, and
European Neuroendocrine Tumor Society guidelines are palliation for hormone-related symptoms that are uncontrolled
with somatostatin analogs, and progression of unresectable
hepatic metastases that threaten liver function. e most eective timing of the intervention with respect to disease burden
has not been clearly dened and approaches dier considerably
among centers. Liver metastases of NETs are sometimes very
slow-growing and can remain stable for several years. It is generally agreed that, in the case where tumor burden of the liver
is low (< 25% of for liver volume), progression of the tumor
must be documented on sequential imaging studies prior to
starting treatment. Even with documented progressive disease,
some centers will not initiate liver-directed therapy in asymptomatic patients with normal liver function until the tumor
burden reaches 25–50% of the liver volume. e rationale for
this conservative approach is that even progressive disease may
take years before it threatens liver function, and embolization
therapies can only be applied a nite number of times in a
patient’s lifetime; hence they should only be employed when
there is a clinical indicator. Extensive tumor burden within
the liver at the time of diagnosis is an indication for prompt
and aggressive therapy because it is now established in several
studies that extensive liver involvement limits the likelihood of
success and increases the risk of complication of intra-arterial
therapy.46 Intra-arterial therapy is considered to be the rst-line
therapy for unresectable liver-dominant low-grade NETs.47
Extrahepatic disease to the lungs, bones, or lymph nodes does
not constitute a contraindication to intra-arterial therapy
as long as the disease predominates within the liver and the
prognosis is primarily dependent on the natural history of the
hepatic metastases.
e two primary forms of intra-arterial therapy are infusion of chemotherapeutics and embolic occlusion of the
selected artery to induce ischemia. Intra-arterial infusion of
chemotherapeutics alone or in combination with systemic
chemotherapy has proven ineectual in the treatment of neuroendocrine metastases to the liver, with response rates of
21% and 22% to doxorubicin and streptozocin/5-uorouracil,
respectively.48 Given its limited ecacy, the infusion-only
approach has been supplanted by embolic approaches. Initially
achieved through surgical ligation of arteries supplying the
liver with response rates as high as 60% and duration of up to
12months, catheter-based delivery of embolics with or without coincident administration of chemotherapeutics is now the
standard of care for inducing ischemia in metastatic neuroendocrine neoplasms to theliver.
Bland embolization was initially applied in the 1970s with a
variety of embolics, including Gelfoam slurry with49 and without Lipiodol,50 Gelfoam powder,
51,52
polyvinyl alcohol (PVA)
particles52 and tris-acryl particles.
Chemoembolization combining intra-arterial chemotherapy with embolics developed in the 1980s. A variety of
agents have been used for chemoembolization in aqueous or
lipid-based formulations without a signicant dierence in
response rates.53 e two most commonly reported regimens
include doxorubicin alone (50 mg/m2) or a combination of
cisplatin (100 mg), Adriamycin (50 mg), and mitomycin C
(10 mg). e use of streptozocin, known to have some ecacy against NETs aer intravenous delivery, has not demonstrated superiority to other agents and is associated with a poor
side-eect prole, including pain upon injection.
54
Chemoembolization classically involves injection of an
emulsion of the selected agent with iodized oil (Lipiodol,
Guerbet Group, Bloomington, IN) followed by particle embolization until near-stasis is achieved. e selected chemotherapeutic is mixed with iodized oil in order to maximize delivery
based on this agent’s propensity to be selectively taken up and
retained by the tumor-feeding vessels.55 In addition, iodized oil
increases dwell time of the chemotherapeutic within the tumor
due to vascular slackening induced by the agent’s viscosity and
permeation of the abnormal tumor vasculature.
56
More recently, a non-oil-based platform for drug delivery
using drug-eluting embolic microspheres has been translated
for clinical application in patients with metastatic gastrointestinal NETs.57 Drug-eluting microspheres combine arterial embolization with the sustained release of chemotherapy drugs into
adjacent tissue.58 e microspheres range from 100 to 900m
in diameter and are composed of biocompatible polymers such
as PVA hydrogel that have been sulphonated to enable the
binding of chemotherapy and are loadable with up to 100mg
of chemotherapeutic. Once loaded with chemotherapeutic, the
microspheres are mixed with iodinated contrast and injected
intra-arterially to allow visualization of delivery under uoroscopy. If stasis is not reached with administration of up to 4g of
microspheres, then the treatment can be completed with bland
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Chapter19:Neuroendocrine tumor metastases
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microspheres. e systemic pharmacokinetic prole achieved
with drug-eluting beads has been demonstrated to be more
favorable than that seen with conventional chemoembolization,
with decreased serum levels of chemotherapeutic expected to
decrease systemic side eects.59 However, two recent reports
highlight an unexpectedly high rate of liver and biliary necrosis
following drug-eluting bead embolization of neuroendocrine
neoplasm metastases, with a relative risk ratio of 8:1 compared
to oily chemoembolization, indicating the need for caution in
applying this new technology in such patients.
60,61
In evaluating patients with hepatic metastases from NETs
for bland or chemoembolization, patient anatomy as well as
the extent of disease must be assessed. Hepatopetal ow via
the portal vein is of paramount importance as hepatic artery
occlusion in patients with portal vein thrombosis may lead to
liver failure. In order to avoid injury to the gut or pancreas, it
is important to carefully identify non-target branches such as
the right gastric artery, which may arise from the hepatic artery
proper or its le-sided branches, supraduodenal branches of
the right hepatic artery, omental, and falciform arteries, and
typically arises from the le hepatic artery.
Catheterization should try to pass beyond the origin of
the cystic artery in order to lower postembolization pain. Bile
duct dilation is a relative contraindication due to the risk of
biliary necrosis and biloma formation in these patients. Of
greater concern are patients with a bilioenteric anastomosis,
a situation not uncommon in patients with pancreatic islet
cell tumors, who are at high risk for liver abscess following
hepatic artery embolization.62 In such patients, aggressive
antibiotic prophylaxis should be administered. A recommended regimen includes 500mg of oral levooxacin once
daily and 500mg of oral metronidazole twice daily initiated
48hours before the procedure as well as 1g of oral neomycin
and 1g of oral erythromycin administered at 1p.m., 2p.m.,
and 11p.m. on the day prior to the procedure. Intravenous
levooxacin and metronidazole should then be continued on
the same schedule while the patient is in hospital and should
be resumed using preprocedure oral regimen for 2 weeks
following discharge.63 While this regimen has been demonstrated to decrease the incidence of sepsis in patients with a
history of bilioeneteric anastomosis, postprocedural sepsis is
still more frequent than in patients without bilioenteric anastomosis. Asimpler monotherapy with moxioxacin has also
been reported to be eective.
64
e distribution of hepatic metastases is an essential consideration in planning embolization. In the case where the
patient’s disease is located in a single hepatic lobe or selective
catheterization of individual tumors is possible, direct targeting of each tumor is recommended. When there is a bilobar
disease with multiple tumors, a two-stage approach is recommended wherein half of the liver is treated in each session, with
sessions separated by 4–8 weeks. While patients with preserved
liver function are not at risk for posttreatment liver insuciency, those with the constellation of more than 50% of liver
involvement, lactate dehydrogenase>425IU/L, aspartate aminotransferase>100IU/L, or bilirubin>2mg/dL are at risk for
posttreatment liver failure. Segmental or lobar embolization
should be repeated according to clinical and biological tolerance until the entire tumor burden is treated.
Premedication with somatostatin analog therapy (octreotide 500g subcutaneously or intravenously) in order to reduce
the risk of inducing carcinoid crisis is a standard recommendation, though not evidence-based. Patients should receive vigorous intravenous hydration (200cc/hour) and receive corticoid
and antiemetic therapy that will help mitigate postembolization
syndrome. Follow-up imaging is performed 4weeks following
treatment to assess the completeness of the treatment and identify potential complications, such as non-target embolization,
hepatic necrosis, or liver abscesses. CT is the most commonly
used technique for follow-up imaging; however, there is growing interest in the use of MRI for follow-up imaging given its
application of non-ionizing radiation among a patient population that will receive many scans over their lifetime. If Lipiodol
has been used, a high degree of Lipiodol uptake by the tumors
on CT is associated with improved ecacy.
ere are clear data that intra-arterial therapies provide
a therapeutic benet over systemic therapies. Touzios et al.
reported a signicantly better 5-year survival rate aer chemoembolization (50%) than aer medical therapies (25%) in
patients with metastatic gastrointestinal NETs.18 Similarly,
Chamberlain etal. reported a 76% and 39% survival at 1 and
3years, respectively, following medical therapy, as compared
to 94%, 83%, and 50% at 1, 3, and 5years aer bland embolization.16 Roche etal. reported complete symptom relief in 53
and partial relief in 25 of 64 patients with gastrointestinal NETs
treated with chemoembolization.65 Adecrease in tumor burden was achieved in 74% of patients, while disease remained
stable in 15%. Several studies demonstrate superior response
rates for extrapancreatic as compared to pancreatic NETs of
the gastrointestinal system, including Gupta,66 who reported
a signicantly higher morphologic response rate and longer
progression-free survival for extrapancreatic neuroendocrine
neoplasms (66.7% and 22.7months) than for islet cell carcinoma (35.2% and 16.1months).
67,68
ere are no denitive data demonstrating the relative
superiority of chemoembolization over bland embolization,
or vice versa (Table19.3). While Gupta66 found no dierence
in the response rates for patients with hepatic metastases of
extrapancreatic gastrointestinal NETs, the author reported
longer overall survival (31.5 vs. 18.2months) and improved
response (50% vs. 25%) for patients with hepatic metastases
of islet cell tumors treated with chemoembolization versus
bland embolization, noting that these data did not reach statistical signicance. Ruutaianen etal. reported a retrospective review of 67 patients with hepatic metastases of NETs
who underwent 219 embolization procedures and concluded
that chemoembolization demonstrated improvement in time
to progression, symptom control, and overall survival.69
Except for time to progression among patients with carcinoid tumors, statistical signicance was not achieved for the
other outcome measures due to the small cohort and crossover between treatment modalities, emphasizing the need for
a multicenter prospective randomized trial. e limited clinical experience with drug-eluting bead chemoembolization
171
Section IV:Liver metastases
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Table 19.3 Disease control and survival outcomes for various forms of embolotherapy for neuroendocrine tumors liver metastases
Source n Agent
Chamberlain et al.,
16
2000
Eriksson et al., 1998
Loewe et al., 2003
Swärd et al., 2009
Pitt et al., 2008
Gupta et al., 2005
67
77
78
79
80
Ruutiainen et al., 2007
Sofocleous et al., 2014
Pitt et al., 2008
Gupta et al., 2005
Varker et al., 2007
79
80
81
Ruutiainen et al., 2007
Hur et al., 2013
Gaur et al., 2011
82
57
Whitney et al., 2011
Whitney et al., 2011
Kennedy et al., 2008
King et al., 2008
83
Paprottka et al., 2012
Memon et al., 2012
76
Gade and Soulen,
73
73
72
33 Bland 94% 83% 50%
41 Bland 11 80 60%
23 Bland 89 96% 65%
107 Bland 56
51 Bland 25.7 70% 54% 13%
74 Bland 17
69
23 Bland 6 0 0 0 68% 46% 33%
46
137 Bland 9 36% 19% 11% 43 82% 57% 36%
49 cTA CE 25.5 69% 52%
49 cTA CE 21
122 cTACE 10 18% 33 58% 28%
69
44 cTA CE 27 49% 49% 35% 86% 67% 50%
46 cTA CE 16.2 38.6
18 DEB 14 48%
28 DEB 18 25
23 Y90 14 18
148 Y90 70
34 Y90 29.4
84
42 Y90
40 Y90 72.5% 62.5% 45%
26 Y90 20 70% 38.5% 14.5%
Median
PFS
1-year
PFS
2-year
PFS
3-year
PFS
Median
OS 1year 2year 3year 5year
unpublished
PFS = progression-free survival; OS = overall survival; cTACE = conventional transarterial chemoembolization; DEB = drug-eluting beads; Y90 = ytrrium-90
radioembolization.
is encouraging, with Gaur etal. reporting a median time to
progression of 419days in patients with hepatic metastases of
gastrointestinal NETs.
57
Initially applied for the treatment of hepatocellular cancer
and hepatic metastases from colorectal cancer, the application of radioembolization with yttrium-90 (Y90) microspheres
for treatment of hepatic metastases of NETs is growing. is
approach involves the loading of non-degradable glass or resin
microspheres with the β-emitter Y90, which has a half-life of
2.67 days, an energy level of 0.94 MeV, and demonstrates a
mean so-tissue penetration of 2.5mm.70 Y90-loaded microspheres are commercially available in two formulations, including eraSpheres, in which the isotope is embedded within
glass spheres (eraSphere; MDS Nordion, ON, Canada) or
SIR-Spheres, in which the isotope is bonded to the surface
of the resin microsphere through sulfonyl group activation
(SIR-Spheres; SIRTex Medical, Sydney, Australia). Importantly,
there is no clinically signicant leaching of the Y90 from either
type of microsphere. Astandard dose of approximately 4million glass spheres has an activity ranging from 3 to 10Gbq.
A standard dose of approximately 50 million resin spheres
constitutes an activity of 0.75–3.03 GBq. While Rhee et al.
reported that a statistically signicant greater median radiation dose was delivered to patients with hepatic metastases of
NETs using glass microspheres, no dierence in response was
appreciated.
71
Studies reporting the application of Y90 radioembolization
for the treatment of hepatic metastases of NETs have increased
over the past several years, and suggest that this technique oers
similar benets to chemoembolization, with the largest series
reported by Kennedy et al. demonstrating stable disease in
22.7%, partial response in 60.5%, complete response in 2.7%,
and progression of disease in 4.9% based on imaging criteria,
with a median survival of 70months.72 Anotable exception to
these ndings is a study by Whitney etal., who reported a signicantly lower response rate aer 12months of follow-up in
patients treated with Y90 radioembolization as compared with
patients treated with drug-eluting beads.73 In contrast to the
severe side-eect prole typically associated with chemoembolization, Y90 radioembolization is an outpatient procedure and
does not result in signicant toxicities in liver synthetic parameters; however, Y90 radioembolization may be associated with
a are phenomenon which involves a spike in tumor markers
immediately following treatment.74 is nding may correspond
with the timing of postprocedural abdominal pain with exacerbation of carcinoid and neuroendocrine symptoms. e similar
ecacy of Y-90 radioembolizaton in combination with the more
benign toxicity prole compared to chemoembolization makes
172
Chapter19:Neuroendocrine tumor metastases
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integration of this technique into the treatment paradigm for
patients with metastatic NETs attractive.
75,76
Randomized controlled studies are needed in order to elucidate the role of Y90
radioembolization relative to chemoembolization, including
cost–benet and quality-of-life analyses.
13. Carrasquillo JA, Chen CC. Molecular imaging of
neuroendocrine tumors. Semin Oncol 2010; 37:662–679.
14. Orlefors H, Sundin A, Garske U, etal. Whole-body (11)
C-5-hydroxytryptophan positron emission tomography
as a universal imaging technique for neuroendocrine
tumors:comparison with somatostatin receptor scintigraphy
Conclusion
NETs are a complex group of malignancies whose high prevalence is second only to colon cancer among patients with
hepatic malignancies. eir indolent course leads to a variety of
interventions over many years, such that this disease will grow
to occupy a substantial portion of a liver oncology practice.
Interventional oncologists should be familiar with all aspects
of the care of these patients, and assemble a team of specialists
with similar expertise in order to provide optimal care to this
oen-misunderstood population.
and computed tomography. J Clin Endocrinol Metab 2005;
90:3392–3400.
15. Abgral R, Leboulleux S, Deandreis D, etal. Performance of
(18)uorodeoxyglucose-positron emission tomography and
somatostatin receptor scintigraphy for high Ki67 (>/=10%)
well-dierentiated endocrine carcinoma staging. J Clin
Endocrinol Metab 2011; 96:665–671.
16. Chamberlain RS, Canes D, Brown KT, etal. Hepatic
neuroendocrine metastases:does intervention alter outcomes?
J Am Coll Surg 2000; 190:432–445.
17. Knox CD, Anderson CD, Lamps LW, Adkins RB, Pinson CW.
Long-term survival aer resection for primary hepatic carcinoid
References
1. Yao JC, Hassan M, Phan A, etal. One hundred years aer
“carcinoid”:epidemiology of and prognostic factors for
neuroendocrine tumors in 35,825 cases in the United States.
J Clin Oncol 2008; 26:3063–3072.
2. Singh S, Law C. Multidisciplinary reference centers:the care of
neuroendocrine tumors. J Oncol Pract 2010; 6:e11–e16.
3. Zikusoka MN, Kidd M, Eick G, Latich I, Modlin IM. e
molecular genetics of gastroenteropancreatic neuroendocrine
tumors. Cancer 2005; 104:2292–2309.
4. Bosman FT, Carneiro F, Hruban RH, eise ND. WHO
Classication of Tumours of the Digestive System, 4th edn.
Lyon:IARC Press;2010.
5. Klimstra DS, Modlin IR, Adsay NV, etal. Pathology reporting
of neuroendocrine tumors:application of the Delphic consensus
process to the development of a minimum pathology data set.
Am J Surg Pathol 2010; 34:300–313.
6. Volante M, Righi L, Berruti A, Rindi G, Papotti M. e
pathological diagnosis of neuroendocrine tumors:common
questions and tentative answers. Virkows Arch 2011; 458:393–402.
7. Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors
of the diuse neuroendocrine system. Curr Opin Oncol 2008;
20:1–12.
8. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD.
Current status of gastrointestinal carcinoids. Gastroenterology
2005; 128:1717–1751.
9. Dromain C, de Baere T, Lumbroso J, etal. Detection of liver
metastases from endocrine tumors:a prospective comparison of
somatostatin receptor scintigraphy, computed tomography, and
magnetic resonance imaging. J Clin Oncol 2005; 23:70–78.
10. Rodrigues M, Traub-Weidinger T, Li S, Ibi B, Virgolini I.
Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and
111In-DOTA-lanreotide scintigraphy and dosimetry in patients
with neuroendocrine tumours. Eur J Nucl Med Mol Imaging
2006; 33:532–540.
11. Janson ET. Treatment of neuroendocrine tumors with
somatostatin analogs. Pituitary 2006; 9:249–256.
12. Hofmann M, Maecke H, Borner R, etal. Biokinetics and
imaging with the somatostatin receptor PET radioligand
(68)Ga-DOTATOC:preliminary data. Eur J Nucl Med 2001;
28:1751–1757.
tumor. Ann Surg Oncol 2003; 10:1171–1175.
18. Touzios JG, Kiely JM, Pitt SC, etal. Neuroendocrine hepatic
metastases:does aggressive management improve survival? Ann
Surg 2005; 241:776–783; discussion83–85.
19. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K,
Steinmüller T, Anlauf M, Wiedenmann B, Salazar R; Barcelona
Consensus Conference participants. ENETS Consensus
Guidelines for the management of patients with liver and other
distant metastases from neuroendocrine neoplasms of foregut,
midgut, hindgut, and unknown primary. Neuroendocrinology
2012; 95 (2):157–176.
20. Kvols LK, Moertel CG, O’Connell MJ, Schutt AJ, Rubin J, Hahn
RG. Treatment of the malignant carcinoid syndrome. Evaluation
of a long-acting somatostatin analogue. N Engl J Med 1986;
315:663–666.
21. Rinke A, Muller HH, Schade-Brittinger C, etal.
Placebo-controlled, double-blind, prospective, randomized
study on the eect of octreotide LAR in the control of tumor
growth in patients with metastatic neuroendocrine midgut
tumors:a report from the PROMID Study Group. J Clin Oncol
2009; 27:4656–4663.
22. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch
D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin
EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study
Group. Everolimus plus octreotide long-acting repeatable
for the treatment of advanced neuroendocrine tumours
associated with carcinoid syndrome (RADIANT-2):a
randomised, placebo-controlled, phase 3 study. Lancet 2011;
378:2005–2012.
23. Yao JC, Shah MH, Ito T, etal. Everolimus for advanced
pancreatic neuroendocrine tumors. N Engl J Med 2011;
364:514–523.
24. Raymond E, Dahan L, Raoul JL, etal. Sunitinib malate for the
treatment of pancreatic neuroendocrine tumors. N Engl J Med
2011; 364:501–513.
25. Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S,
Tsushima DA, Mowatt KB, Dinnen RD, Mao Y, Stevens PD,
Schrope B, Allendorf J, Lee JA, Sherman WH, Chabot JA.
Capecitabine and temozolomide (CAPTEM) for metastatic,
well-dierentiated neuroendocrine cancers:e Pancreas
Center at Columbia University experience. Cancer Chemother
Pharmacol 2013; 71 (3):663–670.
173
Section IV:Liver metastases
http://internalmedicinebook.com
26. Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H,
Willinek W, Grünwald F, Guhlke S, Biersack HJ, Sabet
A. Predictors of long-term outcome in patients with
well-dierentiated gastroenteropancreatic neuroendocrine
tumors aer peptide receptor radionuclide therapy with
177Lu-octreotate.J Nucl Med 2014; 55 (2): 183–190.
27. van Vliet EI, Teunissen JJ, Kam BL, de Jong M, Krenning
EP, Kwekkeboom DJ. Treatment of gastroenteropancreatic
neuroendocrine tumors with peptide receptor radionuclide
therapy. Neuroendocrinology 2013; 97 (1):74–85.
28. Carrasquillo JA, Pandit-Taskar N, Chen CC. Radionuclide
therapy of adrenal tumors. J Surg Oncol 2012; 106 (5):632–642.
29. Gurusamy KS, Ramamoorthy R, Sharma D, Davidson BR. Liver
resection versus other treatments for neuroendocrine tumours
in patients with resectable liver metastases. Cochrane Database
Syst Rev 2009; CD007060.
30. Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA.
Isolated liver metastases from neuroendocrine tumors:does
resection prolong survival? J Am Coll Surg 1998; 187:88–92;
discussion93.
31. Hellman P, Lundstrom T, Ohrvall U, etal. Eect of surgery on
the outcome of midgut carcinoid disease with lymph node and
liver metastases. World J Surg 2002; 26:991–997.
32. Musunuru S, Chen H, Rajpal S, etal. Metastatic neuroendocrine
hepatic tumors:resection improves survival. Arch Surg 2006;
141:1000–1004; discussion1005.
33. Capurso G, Bettini R, Rinzivillo M, Boninsegna L, Delle Fave
G, Falconi M. Role of resection of the primary pancreatic
neuroendocrine tumour only in patients with unresectable
metastatic liver disease:a systematic review. Neuroendocrinology
2011; 93:223–229.
34. Norton JA, Kivlen M, Li M, Schneider D, Chuter T, Jensen RT.
Morbidity and mortality of aggressive resection in patients
with advanced neuroendocrine tumors. Arch Surg 2003;
138:859–866.
35. Osborne DA, Zervos EE, Strosberg J, etal. Improved outcome
with cytoreduction versus embolization for symptomatic
hepatic metastases of carcinoid and neuroendocrine tumors.
Ann Surg Oncol 2006; 13:572–581.
36. Pathak S, Dash I, Taylor MR, Poston GJ. e surgical
management of neuroendocrine hepatic metastases. Eur J Surg
Oncol 2013; 39:224–228.
37. Le Treut YP, Grégoire E, Klempnauer J, Belghiti J, Jouve E, Lerut
J, Castaing D, Soubrane O, Boillot O, Mantion G, Homayounfar
K, Bustamante M, Azoulay D, Wolf P, Krawczyk M, Pascher A,
Suc B, Chiche L, de Urbina JO, Mejzlik V, Pascual M, Lodge JP,
Gruttadauria S, Paye F, Pruvot FR, orban S, Foss A, Adam R;
For ELITA. Liver transplantation for neuroendocrine tumors
in Europe-results and trends in patient selection:a 213-case
European liver transplant registry study. Ann Surg 2013; 257
(5):807–815.
38. Gamblin TC, Christians K, Pappas SG. Radiofrequency ablation
of neuroendocrine hepatic metastasis. Surg Oncol Clin N Am
2011; 20:273–279, vii–viii.
39. Solbiati L, Ierace T, Tonolini M, Osti V, Cova L. Radiofrequency
thermal ablation of hepatic metastases. Eur J Ultrasound 2001;
13:149–158.
40. Wettstein M, Vogt C, Cohnen M, etal. Serotonin release
during percutaneous radiofrequency ablation in a patient with
symptomatic liver metastases of a neuroendocrine tumor.
Hepatogastroenterology 2004; 51:830–832.
41. Elias D, Di Pietroantonio D, Gachot B, Menegon P, Hakime
A, De Baere T. Liver abscess aer radiofrequency ablation of
tumors in patients with a biliary tract procedure. Gastroenterol
Clin Biol 2006; 30:823–827.
42. Akyildiz HY, Mitchell J, Milas M, Siperstein AE, Berber
E. Laparoscopic radiofrequency thermal ablation of
neuroendocrine hepatic metastases:long-term follow-up.
Surgery 2010; 148:1288–1293.
43. Henn AR, Levine EA, McNulty W, Zagoria RJ. Percutaneous
radiofrequency ablation of hepatic metastases for symptomatic
relief of neuroendocrine syndromes. AJR Am J Roentgenol 2003;
181:1005–1010.
44. Karabulut K, Akyildiz HY, Lance C, etal. Multimodality
treatment of neuroendocrine liver metastases. Surgery 2011;
150:316–325.
45. Livraghi T, Vettori C, Lazzaroni S. Liver metastases:results of
percutaneous ethanol injection in 14 patients. Radiology 1991;
179:709–712.
46. Sofocleous CT, Petre EN, Gonen M, Reidy-Lagunes D, Ip
IK, Alago W, Covey AM, Erinjeri JP, Brody LA, Maybody
M, ornton RH, Solomon SB, Gertrajdman GI, Brown KT.
Factors aecting periprocedural morbidity and mortality
and long-term patients survival aer embolization of hepatic
neuroendocrine metastases. J Vasc Interv Radiol 2014;
25:22–30.
47. Roche A, Girish BV, de Baere T, etal. Trans-catheter arterial
chemoembolization as rst-line treatment for hepatic
metastases from endocrine tumors. Eur Radiol 2003;
13:136–140.
48. Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO, Jr.
Streptozocin plus uorouracil versus doxorubicin therapy for
metastatic carcinoid tumor. J Clin Oncol 1984; 2:1255–1259.
49. Schell SR, Camp ER, Caridi JG, Hawkins IF, Jr. Hepatic artery
embolization for control of symptoms, octreotide requirements,
and tumor progression in metastatic carcinoid tumors. J
Gastrointest Surg 2002; 6:664–670.
50. Pueyo I, Jimenez JR, Hernandez J, etal. Carcinoid syndrome
treated by hepatic embolization. AJR Am J Roentgenol 1978;
131:511–513.
51. Lunderquist A, Ericsson M, Nobin A, Sanden G. Gelfoam
powder embolization of the hepatic artery in liver metastases of
carcinoid tumors. Radiologe 1982; 22:65–70.
52. Ajani JA, Carrasco CH, Charnsangavej C, Samaan NA, Levin
B, Wallace S. Islet cell tumors metastatic to the liver:eective
palliation by sequential hepatic artery embolization. Ann Intern
Med 1988; 108:340–344.
53. Mado DC, Gupta S, Ahrar K, Murthy R, Yao JC. Update on
the management of neuroendocrine hepatic metastases. J Vasc
Interv Radiol 2006; 17:1235–1249; quiz1250.
54. Dominguez S, Denys A, Madeira I, etal. Hepatic arterial
chemoembolization with streptozotocin in patients with
metastatic digestive endocrine tumours. Eur J Gastroenterol
Hepatol 2000; 12:151–157.
55. de Baere T, Dufaux J, Roche A, etal. Circulatory alterations
induced by intra-arterial injection of iodized oil and emulsions
of iodized oil and doxorubicin:experimental study. Radiology
1995; 194:165–170.
174
Chapter19:Neuroendocrine tumor metastases
http://internalmedicinebook.com
56. de Baere T, Denys A, Briquet R, Chevallier P, Dufaux J, Roche
A. Modication of arterial and portal hemodynamics aer
injection of iodized oils and dierent emulsions of iodized oils
in the hepatic artery:an experimental study. J Vasc Interv Radiol
1998; 9:305–310.
57. Gaur SK, Friese JL, Sadow CA, etal. Hepatic arterial
chemoembolization using drug-eluting beads in gastrointestinal
neuroendocrine tumor metastatic to the liver. Cardiovasc
Intervent Radiol 2011; 34:566–572.
58. Carter S, Martin II RC. Drug-eluting bead therapy in primary and
metastatic disease of the liver. HPB (Oxford) 2009; 11:541–550.
59. Vogl TJ, Lammer J, Lencioni R, Malagari K, Watkinson A,
Pilleul F, Denys A, Lee C. Liver, gastrointestinal, and cardiac
toxicity in intermediate hepatocellular carcinoma treated with
PRECISION TACE with drug-eluting beads:results from the
PRECISION V randomized trial. AJR Am J Roentgenol 2011;
197:W562–W570.
60. Guiu B, Deschamps F, Aho S, Munck F, Dromain C, Boige V,
etal. Liver/biliary injuries following chemoembolisation of
endocrine tumours and hepatocellular carcinoma:Lipiodol vs.
drug-eluting beads. J Hepatol 2011; 56:609–617.
61. Bhagat N, Reyes D, Lin M, Kamel I, Pawlik TM, Frangakis
C, Geschwind JF. Phase II study of chemoembolization with
drug-eluting beads in patients with hepatic neuroendocrine
metastases:high incidence of biliary injury. Cardiovasc Intervent
Radiol 2013; 36:449–459.
62. Kim W, Clark, TWI, Baum RA, Soulen MC. Risk factors for
liver abscess formation following hepatic chemoembolization.
JVIR 2001; 12:965–968.
63. Patel S, Tuite CM, Mondschein JI, Soulen MC. Eectiveness
of an aggressive antibiotic regimen for chemoembolization in
patients with previous biliary intervention. J Vasc Interv Radiol
2006; 17:1931–1934.
64. Khan W, Sullivan KL, McCann JW, Gonsalves CF, Sato T,
Eschelman DJ, Brown DB. Moxioxacin prophylaxis for
chemoembolization or embolization in patients with previous
biliary interventions:a pilot study. AJR Am J Roentgenol 2011;
197:W343–W345.
65. Roche A, Girish BV, de Baere T, etal. Prognostic factors for
chemoembolization in liver metastasis from endocrine tumors.
Hepatogastroenterology 2004; 51:1751–1756.
66. Gupta S. Intra-arterial liver-directed therapies for
neuroendocrine hepatic metastases. Semin Intervent Radiol
2013; 30:28–38.
67. Eriksson BK, Larsson EG, Skogseid BM, Loerg AM, Lorelius
LE, Oberg KE. Liver embolizations of patients with malignant
neuroendocrine gastrointestinal tumors. Cancer 1998;
83:2293–2301.
68. Stokes KR, Stuart K, Clouse ME. Hepatic arterial
chemoembolization for metastatic endocrine tumors. J Vasc
Interv Radiol 1993; 4:341–345.
69. Ruutiainen AT, Soulen MC, Tuite CM, etal.
Chemoembolization and bland embolization of neuroendocrine
tumor metastases to the liver. J Vasc Interv Radiol 2007;
18:847–855.
70. Kennedy A, Nag S, Salem R, etal. Recommendations for
radioembolization of hepatic malignancies using yttrium-90
microsphere brachytherapy:a consensus panel report from the
radioembolization brachytherapy oncology consortium. Int J
Radiat Oncol Biol Phys 2007; 68:13–23.
71. Rhee TK, Lewandowski RJ, Liu DM, etal. 90Y
Radioembolization for metastatic neuroendocrine liver
tumors:preliminary results from a multi-institutional
experience. Ann Surg 2008; 247:1029–1035.
72. Kennedy AS, Dezarn WA, McNeillie P, etal. Radioembolization
for unresectable neuroendocrine hepatic metastases using resin
90Y-microspheres:early results in 148 patients. Am J Clin Oncol
2008; 31:271–279.
73. Whitney R, Valek V, Fages JF, etal. Transarterial
chemoembolization and selective internal radiation for the
treatment of patients with metastatic neuroendocrine tumors:a
comparison of ecacy and cost. Oncologist 2011; 16:594–601.
74. Liu DM, Kennedy A, Turner D, etal. Minimally invasive
techniques in management of hepatic neuroendocrine
metastatic disease. Am J Clin Oncol 2009; 32:200–215.
75. Kennedy A, Coldwell D, Sangro B, Wasan H, Salem R.
Integrating radioembolization into the treatment paradigm for
metastatic neuroendocrine tumors in the liver. Am J Clin Oncol
2012; 35 (4): 393–398.
76. Memon K, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu R, Sato
KT, Gupta R, Nikolaidis P, Miller FH, Yaghmai V, Gates VL,
Atassi B, Newman S, Omary RA, Benson AB 3rd, Salem R.
Radioembolization for neuroendocrine liver metastases:safety,
imaging, and long-term outcomes. Int J Radiat Oncol Biol Phys
2012; 83:887–894.
77. Loewe C, Schindl M, Cejna M, Niederle B, Lammer J,
urnher S. Permanent transarterial embolization of
neuroendocrine metastases of the liver using cyanoacrylate and
Lipiodol:assessment of mid- and long-term results. AJR Am J
Roentgenol 2003; 180:1379–1384.
78. Swärd C, Johanson V, Nieveen van Dijkum E, Jansson S, Nilsson
O, Wängberg B, Ahlman H, Kölby L. Prolonged survival aer
hepatic artery embolization in patients with midgut carcinoid
syndrome. Br J Surg 2009; 96:517–521.
79. Pitt SC, Knuth J, Keily JM, McDermott JC, Weber SM, Chen
H, Rilling WS, Quebbeman EJ, Agarwal DM, Pitt HA. Hepatic
neuroendocrine metastases:chemo- or bland embolization? J
Gastrointest Surg 2008; 12:1951–1960.
80. Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Mado
DC, McRae SE, Hicks ME, Rao S, Vauthey JN, Ajani JA, Yao
JC. Hepatic arterial embolization and chemoembolization
for the treatment of patients with metastatic neuroendocrine
tumors:variables aecting response rates and survival. Cancer
2005; 104:1590–1602.
81. Varker KA, Martin EW, Klemanski D, Palmer B, Shah MH,
Bloomston M. Repeat transarterial chemoembolization (TACE)
for progressive hepatic carcinoid metastases provides results
similar to rst TACE. J Gastrointest Surg 2007; 11 (12):1680–1685.
82. Hur S, Chung JW, Kim H-C, Oh D-Y, Lee S-H, Bang Y-J, Kim
WH. Survival outcomes and prognostic factors of transcatheter
arterial chemoembolization for hepatic neuroendocrine
metastases. J Vasc Intervent Radiol 2013; 24:947–956.
83. King J, Quinn R, Glenn DM, Janssen J, Tong D, Liaw W, Morris
DL. Radioembolization with selective internal radiation
microspheres for neuroendocrine liver metastases. Cancer 2008;
113:921–929.
84. Paprottka PM, Homann RT, Haug A, Sommer WH,
Raessler F, Trumm CG, Schmidt GP, Ashoori N, Reiser MF,
Jakobs TF. Radioembolization of symptomatic, unresectable
neuroendocrine hepatic metastases using yttrium-90
microspheres. Cardiovasc Intervent Radiol 2012; 35:334–342.
175
Section IV
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Chapter
Preoperative portal vein embolization
20
David Li and David C.Mado
With advances in perioperative care, major liver resections
are being increasingly performed for primary and metastatic
liver tumors. Although fatal liver failure and major technical complications are now rare aer resection, complications
associated with cholestasis, uid retention, and impaired synthetic function still contribute to protracted recovery time and
extended hospital stay.
1,2
Although the risk for perioperative
liver failure is multifactorial, one of the most important factors
associated with this complication is the volume of functional
liver remaining aer surgery. Patients considered at high risk
are those with normal underlying liver in whom more than
80% of the functional liver mass will be removed or those with
chronic liver disease who undergo resection of more than 60%
of their functional liver mass.
2,3,4,5
One strategy used to improve the safety of extensive liver
surgery in patients with small remnant livers is preoperative
portal vein embolization (PVE).
5,6,7,8,9,10,11,12,13,14,15
PVE redirects
portal ow to the intended future liver remnant (FLR) in an
attempt to initiate hypertrophy of the non-embolized segments, and PVE has been shown to improve the functional
reserve of the FLR before surgery. In appropriately selected
patients, PVE can reduce perioperative morbidity and allow for
safe, potentially curative hepatectomy for patients previously
considered ineligible for resection based on anticipated small
remnant livers.
5,6,7,8,9,10,11,12,13,14,15
For this patient subset, PVE is
now utilized as the standard of care at many comprehensive
hepatobiliary centers prior to major hepatectomy.
e clinical use of PVE is based on experimental observations rst reported in 1920 by Rous and Larimore,16 who studied the consequences of segmental portal venous occlusion in
rabbits and found progressive atrophy of the hepatic segments
with ligated portal veins and hypertrophy of the hepatic segments with patent portal veins. Later investigators reported
clinical studies showing that portal vein or bile duct occlusion
secondary to tumor invasion or ligation leads to ipsilateral liver
atrophy (i.e., liver to be resected) and contralateral liver hypertrophy (i.e., liver to remain in situ aer resection).
17,18,19
In the
mid-1980s, Kinoshita etal.20 used PVE to limit extension of segmental portal tumor thrombi from hepatocellular carcinoma
(HCC) for which transcatheter arterial embolization (TAE)
was ineective. In 1990, Makuuchi etal.9 rst reported the use
of PVE solely to induce le-liver hypertrophy prior to major
hepatic resection in 14 patients with hilar cholangiocarcinoma.
Since these seminal publications, many investigators have
described the usefulness of preoperative PVE in their multidisciplinary management of patients with HCC, biliary cancer,
and liver metastases. Given this, considerable research eorts
into the mechanisms of liver regeneration, indications for PVE,
methods of measuring the FLR before and aer PVE, technical aspects of PVE, and potential surgical strategies are under
way and in continual evolution. is chapter reviews the current indications for and technical aspects of PVE before hepatic
resection, with an emphasis on strategies to improve outcomes.
Mechanisms of liver regeneration
e ability of the liver to regenerate following injury or resection has long fascinated scientists, physicians, and laypersons.
e earliest reference to the liver’s capacity to regenerate is
from classical Greek mythology, in Hesiod’s eogony (750–700
).21 However, the human liver’s regenerative ability was not
documented scientically until 1890.
Despite its considerable metabolic load, the liver is essentially a quiescent organ in terms of hepatocyte replication,
with only 0.0012–0.01% of hepatocytes undergoing mitosis
at any time.
21,23,24
However, this low cell turnover in healthy
liver can be altered by toxic injury or surgical resection, which
stimulates sudden, massive hepatocyte proliferation, resulting
in recovery of the functional liver mass within 2weeks of the
loss of up to two-thirds of the liver. is regenerative response
is typically mediated by the proliferation of surviving hepatocytes within the acinar architecture of the remnant liver.
Following resection, this response results in hypertrophy of
the remnant liver rather than restoration of the resected lobes,
a phenomenon that is correctly termed compensatory hyper-
plasia rather than true regeneration.24 e term hypertrophy
actually means an increase in cell size and may be misleading, because the primary mechanism of volume restitution
aer liver resection or embolization is more precisely termed
hyperplasia, or an increase in cell number.
studies also suggest that both hypertrophy and hyperplasia
aid in restoring functional hepatic volume.
22
25,26,27
However,
28,29,30
e term
Interventional Oncology, Second Edition, ed. Jean-François H. Geschwind and Michael C. Soulen. Published by Cambridge University Press.
©Cambridge University Press2016
176
Chapter20:Preoperative portal vein embolization
http://internalmedicinebook.com
18
Figure 20.1 Degree of hypertrophy of the
standardized future liver remnant (sFLR)
16
14
12
10
8
6
Hypertrophy Rate (%)
4
2
0
14 21 28
hypertrophy aer PVE or resection is used throughout this
chapter since this is the term used throughout the published
literature.
Most information about the molecular and cellular events
during liver regeneration comes from studies of partial hepatectomy in animal models.21 In brief, the events that occur in
hepatocytes result from growth-factor stimulation in response
to injury. Hepatocyte growth factor is the most potent mito-
Days after PVE
56 381
Steatosis also seems to impair liver regeneration in animal
models, but regeneration may still occur aer PVE.39 Currently,
the severity of clinically signicant steatosis is unknown. In
laboratory animals, exposure to a high-fat diet impairs liver
regeneration aer partial hepatectomy and is also associated
with increased hepatocellular apoptosis. us, a high-fat diet
may not only impair liver regeneration but may also increase
the risk for hepatic injury (steatohepatitis).
over time after portal vein embolization
(PVE) with kinetics of FLR growth, plotted
as median degree of hypertrophy after
PVE (with interquartile ranges). The shaded
zone, days 22–56 after PVE, represents
the “plateau” period during which the
degree of hypertrophy did not change
significantly between measurement
points. (Reproduced with permission from
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.)
35
40
gen for hepatocyte replication, and in combination with other
mitogenic growth factors (i.e., transforming growth factor-α
and epidermal growth factor), it can induce the production of
cytokines, including tumor necrosis factor-α and interleukin-6,
and activate immediate-response genes that ready the hepatocytes for cell cycle progression and regeneration. Insulin
is synergistic with hepatocyte growth factor, resulting in
slower regeneration rates seen in patients with diabetes.
31,32
Extrahepatic factors are transported primarily from the gut via
the portal vein and not the hepatic artery.
6,22,33,34
Rate of liver regeneration
Regeneration of the liver is dependent on both the stimulus of
injury and the condition of the liver parenchyma (Figure20.1).
Hepatocyte proliferation is directly proportional to the degree
of severity of the insult to the liver; minor injuries (i.e., <10%
parenchymal involvement) induce only localized mitotic reactions, whereas major injuries (i.e., >50% parenchymal involvement) induce multiple mitotic waves throughout the entire
liver.21 Liver regeneration rates are dependent on the time from
injury, with the greatest rate of regeneration aer PVE occurring within the rst 2 weeks.
Hepatocyte removal or necrosis is a stronger stimulus for
liver regeneration as compared to cell-mediated apoptosis.
Apoptosis is the predominant mechanism of cell death in PVE,
thus regeneration aer PVE occurs at a slower rate compared
with hepatectomy.35 Cirrhotic livers are known to have both a
reduced rate and capacity for liver regeneration.37 Both a suboptimal hepatocyte microenvironment with brosis reducing
delivery of portal ow and a blunted response of the diseased
hepatocytes to hepatotrophic factors are thought to contribute
to the reduced regeneration ability of cirrhotics.
35
25,36
38
Pathophysiology of preoperativePVE
Makuuchi etal.9 published the initial experience using preoperative PVE to induce le-liver hypertrophy before right
hepatectomy. e rationale for using PVE in this setting was
to minimize the abrupt rise in portal pressure at resection
that can lead to hepatocellular damage to the FLR, to dissociate portal pressure-induced hepatocellular damage from the
direct trauma to the FLR during physical manipulation of the
liver at the time of surgery, and to improve overall tolerance
to major resection by increasing hepatic mass prior to resection in order to reduce the risk of postresection metabolic
changes.
Following PVE, alterations in liver function tests are typically minor and transient. When transaminase levels rise, they
usually peak at levels less than three times baseline 1–3days
aer PVE and return to baseline within 10days, regardless of
the embolic agent used.
blood cell count and total serum bilirubin concentration may
be seen aer PVE, and prothrombin time is almost never
aected.
Unlike arterial embolization, PVE is not associated with
the postembolization syndrome; nausea and vomiting are rare,
and fever and pain are minimal.6 is is because PVE produces
no distortion of the hepatic anatomy, minimal inammation
except immediately around the embolized vein, and little, if
any, parenchymal or tumor necrosis.
shown that hepatocytes undergo apoptosis and not necrosis
aer portal venous occlusion,
lack of systemic symptoms followingPVE.
Portal blood ow to the non-embolized hepatic segments
measured by Doppler sonography increases signicantly and
9,11,32,41,42,43,44
46,47
which explains the relative
Slight changes in white
9,45
Animal studies have
177
Section IV:Liver metastases
http://internalmedicinebook.com
A B
Segments II+III = 282 cm
FLR 282
–794 + 1267 × 1.8
*
C
Segment III
Volume = 208 cm
Segment II
Volume = 74 cm
3
3
Pre-PVE Post-PVE
3
283 cm
2036 cm
= 14%
3
Segment III
Volume = 258 cm
Segment II
Volume = 182 cm
3
3
440 cm
2036 cm
==14%
2014
*
Total Liver Volume Based on Body Surface Area
3
= 21%
3
3
Figure 20.2 Hypertrophy of the future liver remnant (FLR) after portal vein embolization (PVE), as determined by three-dimensional reconstruction of computed
tomography images. (A) Three-dimensional volumetric measurements are determined by outlining the hepatic segmental contours and then calculating the
volumes from the surface measurements of each slice. (B) The formula for calculating total liver volume is based on the patient’s body surface area. (C) Before
embolization, the volume of segments 2 and 3 was 283 cm3, or 14% of the total liver volume (2,036 cm3). After embolization, the volume of segments 2 and 3 was
440 cm3, or 21% of the total liver volume (an increase of 7 percentage points). (B modified from Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and
body weight predict total liver volume in Western adults. Liver Transplantation 2002; 8 (3): 233–24014; C modified from 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): 512–519,3 with permission.)
then falls to near-baseline values aer 11days. e resultant
hypertrophy rate correlates with the portal ow rate.
6,48,49
FLR volume measurement and predicting
Computed tomography (CT) volumetry serves as the
standard for FLR measurement as it is accurate within ±5%
of estimating normal liver parenchymal volumes.
3,51
Several
methods have been used to measure TELV, including those
based upon CT volumetry, body surface area (BSA), or body
function afterPVE
PVE is indicated when the anticipated FLR is insucient to
support hepatic function, particularly in the perioperative
period, before the liver has had time to regenerate. Accurate
calculation of the FLR is essential in triaging the potential
hepatectomy candidates for which PVE is indicated. Liver volume is directly correlated with a patient’s size; hence, normalizing the anticipated liver volume to a patient’s size results in
a more accurate assessment of the FLR.
3,50
is principle led
to the proposal and clinical validation of a standardized FLR
(sFLR) by Vauthey etal., expressed as a ratio of the FLR over the
total estimated functioning liver volume (TELV):sFLR=FLR/
3
TELV.
weight (Figure20.2). Vauthey etal. derived the following formula for estimating TELV by analyzing liver size and BSA in
292 Western adults:TELV=–794.41+1,267.28× (BSA), which
has been demonstrated to be the least biased and most accurate in adult patients by meta-analysis as compared to similar
formulas.
14,52
Other formulas for determining total liver volume (TLV)
from CT volumetry are both tedious and imprecise, since
measurements of the tumor volume must be performed and
excluded from the overall liver volume using this method.
Ribero etal. veried that CT volumetry was less accurate than
BSA for calculating sFLR, by identifying a subset of patients
for whom CT volumetry underestimated the risk of hepatic
178