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Chapter 6
82. Nordlinger B, Van Cutsem E, Gruenberger T,
et al. Combination of surgery and chemotherapy
and the role of targeted agents in the treatment
of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol
2009;20(6):985–92.
83. Rubbia-Brandt L, Giostra E, Brezault C, et al.
Importance of histological tumor response assessment in predicting the outcome in patients with
colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann
Oncol 2007;18(2):299–304.
84. Blazer 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):5344–51.
85. Adam R, Wicherts DA, de Haas RJ, et al. Complete
pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality?
J Clin Oncol 2008;26(10):1635–41.
86. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint
Committee on Cancer sixth edition staging. J Natl
Cancer Inst 2004;96(19):1420–5.
87. 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):3939–45.
88. Vauthey J-N, 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):2065–72.
89. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe
hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic
colorectal cancer. Ann Oncol 2004;15(3):460–6.
90. Aloia TA, Vauthey J-N, Loyer EM, et al. Solitary
colorectal liver metastasis: resection determines
outcome. Arch Surg 2006;141(5):460–7.
91. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of
steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200(6):845–53.
92. Chun YS, Vauthey J-N, Boonsirikamchai P, et al.
Association of computed tomography morphologic
criteria with pathologic response and survival in
patients treated with bevacizumab for colorectal
liver metastases. JAMA 2009;302(21):2338–44.
93. Karoui M, Penna C, Amin-Hashem M, et al.
Influence of preoperative chemotherapy on the risk
of major hepatectomy for colorectal liver metastases. Ann Surg 2006;243(1):1–7.
94. Welsh FKS, Tilney HS, Tekkis PP, et al. Safe liver
resection following chemotherapy for colorectal metastases is a matter of timing. Br J Cancer
2007;96(7):1037–42.
95. Chaudhury P, Hassanain M, Bouganim N, et al.
Perioperative chemotherapy with bevacizumab and
liver resection for colorectal cancer liver metastasis.
HPB (Oxford) 2010;12(1):37–42.
96. Kesmodel SB, Ellis LM, Lin E, et al. Preoperative
bevacizumab does not significantly increase postoperative complication rates in patients undergoing
hepatic surgery for colorectal cancer liver metastases. J Clin Oncol 2008;26(32):5254–60.
97. Mocellin S, Pilati P, Lise M, et al. Meta-analysis of
hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J
Clin Oncol 2007;25(35):5649–54.
98. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durability of hepatic artery infusion
pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive
cases. J Am Coll Surg 2005;201(1):57–65.
99. Kemeny NE, Melendez FDH, 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):3465–71.
100. Shitara K, Munakata M, Kudo T, et al. Combination
chemotherapy with hepatic arterial infusion of
5-fluorouracil (5-FU) and systemic irinotecan
(CPT-11) in patients with unresectable liver metastases from colorectal cancer. GanTo Kagaku Ryoho
2006;33(13):2033–7.
101. Gallagher DJ, Capanu M, Raggio G, et al. Hepatic
arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from
colorectal cancer previously treated with systemic
oxaliplatin: a retrospective analysis. Ann Oncol
2007;18(12):1995–9.
102. House MG, Kemeny NE, Gönen 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):851–6.
103. Martin RCG, Howard J, Tomalty D, et al.
Toxicity of irinotecan-eluting beads in the treatment of hepatic malignancies: results of a multiinstitutional registry. Cardiovasc Intervent Radiol
2010;33(5):960–6.
104. Martin RCG, Joshi J, Robbins K, et al. Hepatic
intra-arterial injection of drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver
metastases refractory to systemic chemotherapy:
results of multi- institutional study. Ann Surg Oncol
2011;18(1):192–8.
105. Gulec SA, Fong Y. Yttrium 90 microsphere selective internal radiation treatment of hepatic colorectal metastases. Arch Surg 2007;142(7):675–82.
106. Hoffmann RT, Jakobs TF, Kubisch CH, et al.
Radiofrequency ablation after selective internal
radiation therapy with Yttrium90 microspheres in
130
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metastatic liver disease – Is it feasible? Eur J Radiol
2010;74(1):199–205.
107. Cosimelli M, Golfieri R, Cagol PP, et al. Multicentre phase II clinical trial of yttrium-90 resin
microspheres alone in unresectable, chemotherapy
refractory colorectal liver metastases. Br J Cancer
2010;103(3):324–31.
108. Wong SL, Mangu PB, Choti MA, et al. American
Society of Clinical Oncology 2009 clinical evidence review on radiofrequency ablation of hepatic
metastases from colorectal cancer. J Clin Oncol
2010;28(3):493–508.
109. Oshowo A, Gillams A, Harrison E, et al.
Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver
metastases. Br J Surg 2003;90(10):1240–3.
110. Jansen MC, van Duijnhoven FH, van Hillegersberg
R, et al. Adverse effects of radiofrequency ablation of liver tumours in the Netherlands. Br J Surg
2005;92(10):1248–54.
111. Ruers T, van Coevorden F, Pierie J, et al.
Radiofrequency ablation (RFA) combined with
chemotherapy for unresectable colorectal liver
metastases (CRC LM): interim results of a randomised phase II study of the EORTC-NCRI
CCSG-ALM Intergroup 40004 (CLOCC). ASCO
Meeting Abstr 2008;26(Suppl. 15):4012.
112. Mulier S, Ni Y, Jamart J, et al. Local recurrence
after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing
factors. Ann Surg 2005;242(2):158–71.
113. Pathak S, Jones R, Tang JM, et al. Ablative
therapies for colorectal liver metastases
(CRLM): a systematic review. Colorectal Dis
2011;13(9):e252–65.
114. Simon CJ, Dupuy DE, Mayo-Smith WW.
Microwave ablation: principles and applications.
Radiographics 2005;25(Suppl. 1):S69–83.
115. Jones RP, Kitteringham NR, Terlizzo M, et al.
Microwave ablation of ex vivo human liver
and colorectal liver metastases with a novel
14.5 GHz generator. Int J Hyperthermia
2012;28(1):43–54.
116. Morris EJ, Forman D, Thomas JD, et al. Surgical
management and outcomes of colorectal cancer
liver metastases. Br J Surg 2010;97(7):1110–1118.
117. Poston GJ, Adam R, Alberts S, et al. OncoSurge;
a strategy for improving resectability with curative
intent in metastatic colorectal cancer. J Clin Oncol
2005;23:7125–34.
131
7
Non-colorectal hepatic metastases
Zaheer Kanji
Lynn Mikula
Carol-Anne Moulton
Steven Gallinger
Introduction
Colorectal cancer (CRC) is the most common
source of secondary hepatic tumours, although
almost any solid malignancy can metastasise to
the liver. Tumour cells from gastrointestinal tract
malignancies reach the liver directly via the portal
circulation. Liver metastases may occur either in
apparent isolation, as is sometimes seen in CRC,
or in association with widespread systemic disease, as in pancreatic and gastric adenocarcinoma.
In contrast, metastases from non-gastrointestinal
tumours reach the liver via the systemic circulation and are generally indicative of disseminated
disease.
The development of liver metastases was previously
considered a preterminal event with treatment limited to palliation; however, the success of hepatectomy in improving outcomes in metastatic CRC
has generated renewed enthusiasm in considering
resection of liver metastases from non-colorectal
primary cancers. Liver resection has become the
standard of care for CRC liver metastases and
many centres have adopted an increasingly aggressive approach, with reported 5-year survival
rates exceeding 50%.
of portal vein embolisation, radiofrequency ablation and staged resection strategies has increased
the proportion of patients eligible for resection.
At the same time, advances in surgical technique
and knowledge of liver anatomy have reduced
1,2
The complementary use
significantly the morbidity and mortality associated with liver resection to less than 20% and 5%,
respectively.
Liver metastases of non-colorectal origin constitute a diverse group of tumours, most commonly
arising from gastrointestinal sites. These tumours
can be broadly divided into neuroendocrine and
non-neuroendocrine malignancies, encompassing unique and markedly varied natural histories.
Neuroendocrine tumours (NETs) have historically
been described as indolent malignancies with hepatectomy for NET liver metastases associated with
5- and 10-year survival rates of 77.4% and 50.4%,
respectively.4 While hepatectomy is an increasingly
accepted management strategy for NETs, it is performed less frequently for non-neuroendocrine
tumours.
The evidence regarding hepatectomy for noncolorectal metastases originates largely from retrospective reviews spanning several decades of
experience.
tween NET and non-NET metastases, and when
that distinction is made, the non-NET metastases
are usually considered a single entity despite comprising a heterogeneous set of pathologies. Reports
focusing on a single tumour type are usually based
on small case series. With advances in surgical techniques and promising results observed in CRC and
NET hepatic metastases, the role of surgical treatments in non-NET liver tumours has once again
become an area of active research.
2,3
5–8
Many studies fail to distinguish be-
132
Non-colorectal hepatic metastases
Due to the paucity of prospective, controlled
data, the appropriate indications for hepatectomy
for non-CRC metastases are unclear. Factors
routinely associated with improved long-term
outcomes include a long disease-free interval
between treatment of the primary tumour and
development of liver metastasis, little or no
extrahepatic disease, the projected future liver
remnant and well to moderately differentiated
cancer.9 The inability to resect all NET liver
metastases does not appear to worsen overall
survival.4 Unfortunately, no single measure of
tumour biology yet exists.
Pathophysiology and molecular basis of liver metastases
Achieving cure in cancer requires the complete eradication of all tumour cells. Thus, for most solid tumours, complete surgical excision is the cornerstone
of treatment, often with adjuvant treatment to treat
microscopic disease. In the presence of metastases
there is an apparent contradiction in using a local
therapy – surgery – to treat what is considered disseminated disease.
The rationale behind a surgical approach to meta-
static disease is based on the concept of site-specific
metastases. First proposed by Paget in 1889, this
‘seed and soil’ hypothesis argues that solid tumours
have a distinct pattern of distant organ involvement
created by the target organ microenvironment.
Ewing proposed a ‘mechanical’ theory in which
the metastatic pattern is determined by the venous
drainage of the primary tumour.10 Neither theory
takes into account the complexity of the metastatic
process, which requires that a cancer cell gains
specific invasion and metastatic potential before it
can disseminate. The clonal selection model of the
metastatic process suggests that heterogeneity develops within a population of cancer cells through
mutational events, allowing a subpopulation to randomly acquire the necessary traits to disseminate
successfully.11 Alternatively, it has been argued that
within cancers of the same pathological type, i.e.
breast cancer, some tumours are a priori more likely
to develop metastases than others. This is supported
by gene expression data where specific molecular
signatures have been found to predict accurately
prognosis in breast cancer,12 ovarian cancer13 and
melanoma.14 Similarly, in CRC the genotype of microsatellite instability correlates with a decreased
likelihood of metastatic spread.
A recent refinement to Paget's hypothesis, based on
molecular genetic research, suggests that the primary
tumour is itself capable of preparing the soil by creating a ‘premetastatic niche’.16 Every cancer has a
15
type-specific pattern of cytokine expression that appears to direct both malignant and non- malignant
cells to specific distant organs. The influx and clustering of bone-marrow-derived haematopoietic cells
is one of the earliest events in the development of
a metastatic deposit. This is closely followed by local inflammation and the release of matrix metalloproteinases. These local events appear to mediate
remodelling of the extracellular matrix, creating a
more permissive microenvironment for the eventual
deposition and growth of malignant cells.17 Thus,
the primary tumour both chooses and alters the sites
to which it metastasises. For reasons not yet understood, many solid tumours metastasise preferentially
to the liver.
If the site-specific hypothesis of metastatic spread
is correct, complete surgical excision of liver metastases can remove the only site of disease and
offers a chance for cure. Nonetheless, residual micrometastatic disease may exist within the liver,
and hepatic recurrences are a common cause of
treatment failure following hepatectomy. Even in
the presence of micrometastases, the removal of
all macroscopic disease may have immunological
benefits. The immune-suppressing effects of cancers
are well accepted: malignant cells can induce both
adaptive and innate immune suppression, facilitating tumour growth.18 The degree of immune suppression correlates with the tumour burden19 and
if all gross metastatic disease can be removed, host
defences may attack micrometastatic deposits more
effectively. The use of neoadjuvant or adjuvant chemotherapy may improve cure rates by controlling
micrometastases.
20,21
The advent of next generation sequencing technologies and high-density oligonucleotide arrays
has further deepened our understanding of the metastatic process. Whereas the ability of a cancerous
cell to metastasise was once believed to occur following the accumulation of multiple somatic mutations in many cancer-causing genes, new findings,
specifically in pancreatic cancer, have challenged
this belief. Studies by Yachida et al.22 and Campbell
et al.23 describe the existence of multiple subclones
within a primary pancreas cancer tumour, each
containing a unique genetic signature corresponding to an eventual site of metastastic spread. These
subclones are present many years before an eventual metastasis is clinically detected, when disease
is at an early stage. Furthermore, metastases seen
in different organs share many common genetic
mutations as well as site-specific changes that confer a selective growth advantage in the respective
tissue. Future studies on the biology of metastases
are likely to improve our understanding of this
complex process, translating into more efficacious
therapy.
133
Chapter 7
Clinical approach to noncolorectal liver metastases
Routine clinical, radiological and serological assessments for liver metastases should be guided by the
propensity for liver metastases of each specific tumour type and the ability of potential treatments
to alter the outcome of the metastatic disease. In
imaging the liver, the choice of transabdominal ultrasound, contrast-enhanced ultrasound, contrastenhanced triphasic computed tomography (CT),
magnetic resonance imaging (MRI) and positron
emission tomography (PET) will be dictated by tumour type as well as local availability and expertise.
Some patients can be assessed for recurrence using
more targeted techniques and biochemical markers (i.e. CA-125 for ovarian cancer, chromogranin
A for NETs). Nuclear imaging can detect NETs
expressing somatostatin receptors with 80–90%
sensitivity. Whole-body PET scanning using a
new somatostatin analogue, [68Ga]DOTA-TOC,
has been found to be accurate for the detection of
new metastases in NETs following radionuclide
therapy.24 Occasionally, the original presentation of
an NET will be a liver metastasis from an unidentified primary, and the investigative focus is aimed at
localisation of the primary tumour.
When a patient is under consideration for
hepatic metastasectomy, the most critical
component of the clinical assessment is an
accurate determination of the extent of metastatic
spread, including a thorough assessment for
extra-abdominal disease. The anatomical areas
targeted for investigation (brain, lung, bone) will be
determined by the known metastatic pattern of the
primary tumour.
Certain tumours, such as gastric, breast and ovar-
ian cancer, have a predilection for intraperitoneal
spread. Although CT is the preferred modality for
diagnosing peritoneal carcinomatosis, its accuracy is
still limited by histological type, the anatomical site
of spread and the size of tumour deposits.25 For many
of these equivocal cases, diagnostic laparoscopy has
been recommended. Routine laparoscopy with laparoscopic ultrasound for patients with potentially
resectable non-colorectal liver metastases has been
found to result in a change in management in 20%
of cases and may be used in preoperative staging.
26
Treatment strategies
Several treatment modalities exist for metastatic
disease, and the therapeutic approach must be tailored to the tumour type, the performance status of
the patient and the extent of disease, determined
in the setting of a multidisciplinary conference.
Ablative strategies and systemic or locally delivered
chemotherapy can be used as adjuncts to resection.
Radiofrequency ablation (RFA) has been reported
to be safe and successful at achieving local control in
patients with liver metastases from breast cancer,27
ovarian cancer28 and NETs,29 but its major limitation is the difficulty of achieving complete necrosis
for tumours larger than 3 cm.
Transarterial embolisation (TAE) takes advantage
of the differential blood supply of liver metastases,
which depend mainly on the hepatic arteries, and the
normal parenchyma, which relies more heavily on the
portal vein. Transarterial chemoembolisation (TACE)
involves the local delivery of a drug prior to occluding the artery and allows prolonged exposure of the
tumour to the agent without increasing systemic toxicity. Both TAE and TACE have been well described
for the treatment of unresectable hepatocellular carcinoma30 and the symptomatic relief of NETs.
31
Neuroendocrine tumours
Gastrointestinal NETs represent a diverse group of
tumours originating throughout the gastrointestinal
tract. They are classified into carcinoid and pancreatic histological subtypes. Carcinoid tumours arise
most commonly in the midgut and may secrete serotonin and other bioactive amines. Pancreatic NETs
(PNETs) can be non-functional or hormonally active
(e.g. insulin, glucagon, gastrin, vasoactive intestinal
peptide), manifesting varied clinical syndromes.
Most NETs of gastrointestinal origin demonstrate
‘indolent’ growth. Despite such a benign description, 46–93% of patients with NETs will have liver
involvement at the time of diagnosis, with 5-year untreated survival of 0–20%.32 Systemic chemotherapy
with platinum-based regimens has shown a response
rate of up to 67% in poorly differentiated NETs.
Nevertheless, the survival benefit of chemotherapy
is limited and associated with significant toxicity.33
Somatostatin analogues such as octreotide can achieve
symptomatic relief in 70–80% of patients, but an antiproliferative effect is seen in less than 10% of cases.34
Furthermore, newer agents such as the receptor tyrosine kinase inhibitor sunitinib, the mammmalian
target of rapamycin (mTOR) inhibitor everolimus,
and the anti- vascular endothelial growth factor (antiVEGF) bevacizumab have shown promise in PNETs.
NETs metastasise preferentially to the liver, and
in many patients the liver remains the only site of
metastatic disease for a prolonged period of time.
The majority of patients have multifocal, bilobar
disease, of which less than 20% are candidates
for surgery32 (Fig. 7.1a,b). Liver resection may be
33
134
Non-colorectal hepatic metastases
surgical management for hepatic metastases and are
better treated non-operatively with chemotherapy.
36
The metastatic pattern of spread in the liver for NETs
also has prognostic implications and is categorized
into three morphological subtypes:
35,36
(I) “restricted
metastases” involving one lobe or two adjacent segments; (II) “dominant lesion with bilobar metastases”
whereby a single major focus is accompanied by multiple contralateral satellite lesions; (III) diffuse, multifocal liver metastases affecting multiple segments
a
within and between lobes. Patients with Type I or II
(25% and 15% of cases respectively) disease, in the
absence of metastases at distant extrahepatic sites are
considered for curative surgical resection.
35,36
The aim of liver resection with curative intent in
NETs is to leave no residual disease (R0 resection)
in both primary and secondary sites, and this may
be associated with 5-year survival rates of up to
31,32
85%.
Surgical indications include the presence of
a resectable well-differentiated NET without extraabdominal metastases or peritoneal carcinomatosis,
in a patient without right-sided cardiac dysfunction.35 Optimal cytoreduction aims to reduce tumour
volume by at least 90%.32 Although there are no data
from randomised trials, large series using historical
controls or contemporary cases matched for stage
have demonstrated that liver resection with optimal
cytoreduction results in improved survival.
37–39
b
Figure7.1 • (a) A 67-year-old female with a node-positive
distal jejunal carcinoid tumour and synchronous solitary
liver metastasis in segment 4B. (b) Octreotide scan of the
same patient. Transaxial single-photon emission computed
tomography (SPECT) demonstrates abnormal activity in
segment 4B corresponding to known metastasis on CT.
performed with curative intent, symptom control
or prolongation of survival in the palliative setting.
The choice of treatment for NET hepatic metastases is largely dependent on underlying tumour biology and pattern of metastatic spread.35 According
to the 2010 World Health Organization guidelines
for the management of NETs, pathological grade
(1-3) has been highlighted as an important marker
for underlying tumour biology affecting survival.36
Pathologic grade is determined microscopically by
the number of cellular mitoses per high powered
field (hpf) and through Ki-67 labelling of tumours.
NETs with <2mitoses/10hpf and <3% Ki-67 index
are classified as low grade (G1) well-differentiated
tumours whereas NETs with >20/10hpf and >20%
Ki-67 labelling are denoted as high grade (G3) and
poorly differentiated. Recent studies have shown
that G3 NETs exhibit a poor prognosis following
Hepatic resection for metastatic NETs results
in improved overall survival compared to those
receiving supportive care. Furthermore, R1 and R2
resections result in 5-year survival rates of 70%
and 60%, respectively,32 challenging the dogma
that surgery should be reserved only for patients
most likely to have an R0 resection. Cytoreduction
similarly offers the most effective and durable
palliation from symptoms.
debulking has been advocated for both functional
and non-functional tumours.41 An aggressive
approach, sometimes combining liver resection with
other ablative strategies, is warranted (Fig. 7.2a,b).
38,40
As a result, surgical
Most series of hepatic resection for metastatic NETs
include an occasional case with an unknown primary,
despite thorough imaging and endoscopy. Although
survival data are sparse, an aggressive resectional approach for these patients is reasonable (Fig. 7.2b).
Non-surgical treatment modalities include RFA,
TAE and TACE. RFA in isolation can achieve
symptomatic relief and local control of variable
duration in up to 80% of NET patients with hepatic metastases. Although studies comparing RFA
to other modalities are limited, RFA has been advocated in patients with bilobar disease with up
to 14 hepatic lesions of less than 7 cm in diameter,
encompassing up to 20% of liver volume.
33,39
TAE
135
Chapter 7
a b
Figure7.2 • (a) A 59-year-old female with an incidental finding of multiple NET metastases. There was no evidence of
primary tumour on octreotide scan and endoscopy. Note multiple hypervascular, large metastases with central necrosis.
(b) Same patient as in (a). A debulking operation to remove 90% of tumour burden would be possible by performing an
extended right hepatic lobectomy with wedge resections from segment 2.
and TACE appear to deliver comparable results and
thus one modality is not favoured over the other.
Embolisation is usually indicated for more extensive
hepatic disease or for tumours in close proximity
to biliary structures precluding RFA.39 Duration of
response is routinely short as the tumour rapidly
develops collaterals and thus repeat treatments are
often required.41 Embolisation is contraindicated in
patients with 50–75% liver involvement due to the
risk of precipitating acute hepatic failure.
In general, aggressive multimodal therapy with
embolic, ablative and systemic strategies is recommended to debulk or downstage metastatic NETs.41
Despite complete resection, hepatic recurrence
occurs in up to 84% of patients at 5 years postsurgery.39 Recurrence is suspected by the elevation
of tumour markers such as 5-hydroxyindoleacetic
acid (5-HIAA) and chromogranin A. Chromogranin
A is more sensitive than 5-HIAA in identifying disease progression and high levels have been shown
to predict poorer outcomes. A reduction in chromogranin A levels of >80% predicts a good outcome
following cytoreductive hepatectomy, even when
complete resection has not been achieved.
42
Liver transplantation has been advocated for patients
with extensive, unresectable liver metastases with
no extrahepatic disease. A recent retrospective study
of 150 patients who underwent transplantation for
metastatic NETs reported 5-year survival comparable
to patients with hepatocellular carcinoma (HCC).43
Of those transplanted, patients under the age of 55
without the need for concurrent major resection of
the primary tumour had the best overall survival.9
Therefore, liver transplantation does appear to confer
long-term survival in carefully selected patients and
should be considered in the management of NETs.
44
Gastrointestinal stromal tumours
Gastrointestinal stromal tumours (GISTs) are the
most common gastrointestinal mesenchymal malignancies originating from the interstitial cells
of Cajal. Approximately 70–80% of GISTs harbour
a mutated c-Kit proto-oncogene, which results in
the constitutive activation of the receptor tyrosine
kinase and unregulated cell growth. Two thirds of cKit mutations are located on exon 11.45 C-Kit exon 9
and PDGFRA mutations, encompassing a wild-type
kinase domain that modulates receptor inhibitor
sensitivity, account for another 5–10% of GISTs.
Primary GISTs represent 1% of all gastrointestinal
malignancies, and arise in the stomach (55%), small
intestine (35%), colon/ rectum (10%) and oesophagus
(5%), with the remainder found in various other sites
(gallbladder, appendix or mesentery).47 The primary
tumour is usually classified into four prognostic categories, ranging from very low risk to high risk, according to site of the lesion, size of the lesion and the
number of mitotic figures identified.48 Surgery remains
the gold standard for the treatment of primary GISTs.
Imatinib mesylate is a selective tyrosine kinase
inhibitor that has revolutionised the treatment of
unresectable GISTs.44 Response to imatinib is greatest
in tumours that harbour the c-Kit exon 11 mutation,
46
136
Non-colorectal hepatic metastases
with resistance rates higher in patients harbouring
exon 9 or platelet-derived growth factor receptor α
(PDGFRA) mutations.44 Despite complete surgical
resection with microscopic negative margins, recurrence (local or distant) occurs in 50% of patients.48
The use of imatinib in the adjuvant setting was investigated in the phase III ACOSOG placebo controlled
trial (Z9001) for patients with resected GISTs 3 cm
or greater in size. A statistically significant 1-year
recurrence-free survival (RFS) of 98% in the treatment group versus 83% in the placebo group was
observed, prompting the inclusion of imatinib as an
adjuvant treatment modality.48 Currently, many nomograms have emerged to guide patient selection for
those believed to be at highest risk of recurrence.
The treatment of metastatic GISTs has similarly
been transformed by imatinib. Recurrence of GISTs
most commonly occur with one of two metastatic
patterns: local recurrence with peritoneal disease or
intraparenchymal liver metastases.49 Most patients
with recurrent metastatic GISTs will receive imatinib as first-line treatment, with a clinical response
demonstrated in 80%. This response is durable with
a median survival of 48 months.50 However, many
patients develop imatinib resistance and disease
progression caused by the development of secondary mutations.51 Second- (e.g. sunitinib) and thirdline agents (e.g. nilotinib and masitinib) have shown
promise in patients resistant to imatinib.
The efficacy and low side-effect profile of
imatinib prompted initial enthusiasm for the
combined use of surgery and imatinib in the
management of metastatic GISTs. Although
evidence guiding surgical management in
metastatic GISTs is limited, a recent study
combining neoadjuvant imitanib with surgery
and adjuvant imitanib in patients with previous
R0 resection of the primary tumour has shown a
favourable 3-year survival.53 Nevertheless, future
studies are warranted prior to recommending
adjuvant imitanib in routine clinical practice for
metastatic GISTs to the liver.
52
A subset of patients with GISTs develop a pattern of
disease progression where isolated nodular foci progress
within a pre-existing tumour mass in a patient already
on imatinib. Such cases of partial progression have the
same median survival as patients who meet standard
criteria for disease progression.54 There is currently no
rationale for resection in this group. The benefit of surgical resection in the group of patients with disease
that is stable or responding to imatinib is not clear.
55
In general, GISTs metastatic to the liver are
rarely amenable to resection. Therefore, imatinib
is accepted as the first-line treatment for metastatic
disease. Disease progression is managed by dose
escalation followed by second-line agents such as
sunitinib. In the event of tumour rupture or haemorrhage, surgery or hepatic artery embolisation may
be performed in an emergency setting.
Breast cancer
The surgical management of breast cancer hepatic
metastases is controversial. The widely held concept
that liver metastases in breast cancer reflect diffuse
systemic disease has led to a nihilistic view of the
role of liver resection in this setting. However, an
aggressive surgical approach has been adopted recently for patients presenting with the liver as the
sole site of involvement. Unfortunately, the data
are mostly retrospective and are based on heterogeneous indications, making it difficult to provide
strong evidence-based guidelines.
Although breast cancer is common, isolated liver lesions in metastatic breast cancer are seen in only 7%
of patients.56 Sakamoto et al.57 reported only 34 patients with resectable liver metastases among 11 000
breast cancer patients treated over an 18-year period.
Selection criteria for such metastases are inconsistent
in surgical series, with some centres considering resection only to disease confined to the liver while others advocate a more liberal approach. In short, there
are no clear selection criteria for resection.
Response to chemotherapy appears to be an
important predictor of survival prior to liver resection
for metastatic breast cancer. For those patients who
progressed during prehepatectomy chemotherapy,
0% were alive at 5 years in comparison to 11%
in responders. Therefore, surgery should only be
considered in the setting of patients who have
responded to preoperative chemotherapy or
hormonal therapy, or both.
58
Despite heterogeneous selection criteria, 5-year
survival rates fall into two groups. Several reports
describe 5-year overall survival of approximately
57,59
25%;
between 45% and 60%.
however, others report 5-year survival
60,61
These disparate results
cannot be explained by differences in study design
or treatment factors. Outcomes following hepatic
resection may therefore merely reflect differences in
tumour biology, or publication bias. Furthermore,
5-year disease-free survival rates are much lower
than overall survival rates, suggesting that liver resection may function as a cytoreductive rather than
curative procedure in these highly selected patients.
Ovarian cancer
Epithelial ovarian cancer represents the most common malignancy of the ovary, of which surgery and
platinum-based chemotherapy remain the mainstay
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Chapter 7
of treatment. Unfortunately, most develop chemoresistance after 24–36 months and median survival for
advanced (stage III–IV) disease is 3.5 years.62 Aggressive
surgical debulking is advocated in advanced cases, with
optimal cytoreduction targeted at <1 cm of residual
disease.63 Intraperitoneal (i.p.) chemotherapy has been
demonstrated to further improve survival compared
Although the liver is rarely the only site of
metastatic disease in ovarian cancer, hepatectomy
can be an important component of a primary
cytoreduction strategy. Ovarian cancer can involve
the liver through the development of peritoneal
lesions on the surface of the liver (stage III –
Fig. 7.3) or intraparenchymal metastases (stage
IV – Fig. 7.4). Survival is improved for patients with
stage IV disease who have undergone adequate
debulking surgery including hepatectomy.
65,66
to intravenous therapy, and this is the current aim of
treatment in many large centres. To be eligible for
i.p. chemotherapy, patients must undergo maximal
debulking.64 Successful cytoreduction is thus a crucial
step in the management of advanced ovarian cancer.
A recent phase II trial investigating combined i.p.
carboplatin with i.v. paclitaxel in stage II–IV disease
is under way, with preliminary results showing minimal toxicity and appropriate response in patients with
suboptimal (>2 cm) surgical debulking.67 Furthermore,
various non-randomised observational studies have reported a benefit with varying degrees of cytoreductive
surgery combined with hyperthermic intraperitoneal
chemotherapy (HIPEC) in peritoneal carcinomatosis.
The preliminary nature of these results precludes any
definitive management recommendations.
25
Survival following primary surgical debulking is
inversely correlated with volume of residual disease,
disease stage and tumour differentiation. Similarly,
survival following hepatectomy for metastatic disease is dependent on optimal cytoreduction, negative
margin status, greater pelvic than abdominal disease
and a longer recurrence-free interval.68 TACE offers a
potential future therapeutic option in achieving local
control in patients with unresectable hepatic disease.
69
Renal cell carcinoma
Figure7.3 • Stage III ovarian cancer with hepatic
involvement. Note direct invasion of liver capsule by
peritoneal tumour plaque.
Figure7.4 • Stage IV ovarian cancer with
intraparenchymal liver metastases.
Renal cell carcinoma (RCC), often termed the ‘internist's tumour’, represents the deadliest urological malignancy. Approximately 20–30% of patients
with RCC present with synchronous metastatic
disease and another 20–40% of patients with previous nephrectomy will develop more advanced disease.70 Fewer than 5% of patients have metastases
restricted to the liver.71 Whereas interleukin-2 and
interferon-α were previously used as first-line therapy for metastatic RCC, current regimens employ
sunitinib, which has displayed a higher progressionfree survival in phase III trials.
72
The available data on hepatic resection for RCC
metastases are limited to retrospective reports. A
recent study from the Netherlands examined 33 patients who underwent resection or ablative therapy
for RCC hepatic metastases. The study documented
no operative mortality with 5-year disease-free
and overall survival of 11% and 43%, respectively. The median overall survival was 33 months.
Metachronous metastases and complete resection
were highlighted as prognostic factors.
70
Staehler et al. reported a 12-year retrospective comparative analysis of patients with metastatic RCC to
the liver. In the study, 68 patients underwent surgery and were compared to a cohort of 20 patients
who were eligible but refused an operation. Disease
in these patients was mostly confined to the liver.
138
Non-colorectal hepatic metastases
Overall 5-year survival in the treatment arm was
62% in comparison to 29% in the control group.
Prognostic features included complete resection of
liver lesions, negative margins, length of disease-free
interval from resection of the primary and a leftsided primary lesion.73 With ongoing improvements
in surgical techniques coupled with an increasingly aggressive approach to metastatic disease in
the liver, future prospective studies examining the
role of hepatectomy in RCC should provide clearer
treatment algorithms. Furthermore, an evidencebased approach to surgery combined with sunitinib
or surafenib will hopefully be forthcoming.
Melanoma
The prognosis for patients with metastatic melanoma
is poor and the median survival for patients with
American Joint Committee on Cancer (AJCC) stage IV
melanoma is 6–9 months.74 Gastrointestinal and liver
metastases occur in 2–4% of individuals with stage
IV disease,75 and palliative radiotherapy and systemic
chemotherapy have largely been ineffective in conferring a survival advantage. Although biological agents
such as interferon-α and interleukin-2 have yielded
promising response rates, these are rarely durable and
are associated with significant toxicity.74 Favourable
results in patients undergoing metastasectomy in the
lung, soft tissues or abdomen have provided some enthusiasm for surgery in a selected patient population.
The available evidence for hepatectomy for metastatic melanoma is limited and consists largely of
subset analyses from larger series of patients with
non-colorectal liver metastases. A recent retrospective study evaluated all patients who presented
with metastatic melanoma over the last decade at a
single Australian institution. In this series, 13 of 23
patients underwent resection for liver metastases.
Disease-free interval from resection of the primary
was a median of 49 months. Overall 3-year survival
was 40% with a median survival of 21 months, influenced largely by the number of metastases and
the presence of multiple sites involved. The median
disease-free interval observed prior to recurrence
was 14 months.75 Nevertheless, the authors have
outlined the potential bias in their study, including
only those patients who were most likely to achieve
complete surgical resection in the operative cohort.
Recently, liver resection with postoperative tumour infiltrating lymphocyte (TIL) therapy has been
explored. TIL involves the resection of metastatic
lesions followed by extraction and culture of infiltrating lymphocytes ex vivo with interleukin-2. A direct
comparison was performed between patients with
complete surgical resection versus those with residual hepatic disease receiving postoperative TIL. The
observed 3-year overall survival was 53% in the TIL
cohort, with prognosis largely favoured by lack of extrahepatic disease and a single hepatic metastasis.
76
The biological behaviour of metastatic melanoma
depends in part on the site of origin of the primary
tumour.77 Cutaneous melanoma is more common
than ocular melanoma.78 While both metastasise to
the liver, they appear to do so with distinct patterns
and natural history. Ocular melanoma metastasises
to the liver more frequently, but is more likely to
be associated with isolated liver metastases than cutaneous melanoma.
77,78
Survival following hepatectomy appears to be more favourable in the highly
selected but rare group of patients with melanoma
of ocular origin. Pawlik et al. reported 5-year survival of 21% for liver resection for ocular primaries, with no 5-year survivors when the initial site of
disease was cutaneous. However, 75% of resected
patients in this study developed recurrent disease,
and the rate of recurrence was similar between the
ocular and cutaneous groups.
It is impossible from the available studies to
estimate the impact that liver resection has on the
survival of patients with metastatic melanoma. It
seems reasonable to adopt a resectional approach
in highly selected patients, i.e. patients with a long
disease-free interval from primary to metastases, and
patients that can be rendered disease free following
surgery. This will occasionally lead to long-term
survival, but patients with metastatic melanoma
generally have a poor prognosis. Newer immunebased therapy combined with surgery may provide
an added benefit in metastatic melanoma to the liver.
78
Non-colorectal gastrointestinal adenocarcinoma
Liver metastases from non-colorectal gastrointestinal (GI) adenocarcinomas can arise from the oesophagus, stomach, pancreas, gallbladder, ampulla
of Vater, small bowel and distal bile duct. Hepatic
resection is controversial for these tumours and the
available literature is scant.
Metastatic oesophageal cancer is usually widely
disseminated and is associated with a 5-year survival of 3–5% when multiple sites of disease are
present and 7–8% when disease is limited to the
liver.79 Two case reports in the English-language literature describe hepatectomy for isolated, synchronous liver metastases.
was performed simultaneously with oesophagectomy and was followed by hepatic arterial chemotherapy. Both patients developed multiple liver
metastases at 680 and 781 months postoperatively.
80,81
In both cases hepatectomy
139