Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_815_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 7
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 metastases, little or no extrahepatic disease, the
projected future liver remnant and well- to
moderately-differentiated cancer.9 Unfortunately, no
single measure of tumour biology yet exists though
intensive research on molecular classification will
lead to improved selection over the next decade.
10–12
Pathophysiology and molecular
basis of liver metastases
Achieving cancer cure requires the complete
eradication of all tumour cells. Thus, for most solid
tumours, complete surgical excision is the cornerstone
of treatment, often with adjuvant systemic 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
metastatic disease is based on the concept of sitespecific 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.
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.
14
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 accurately predict
prognosis in breast cancer,
melanoma.
17
Similarly, in CRC the genotype of
microsatellite instability correlates with a decreased
likelihood of metastatic spread.
15
ovarian cancer16 and
18
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’.
19
Every cancer has
a type-specific pattern of cytokine expression that
13
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.
20
Thus, the primary tumour both chooses and alters
the sites to which it metastasises. For reasons not
yet understood, many solid tumours preferentially
metastasise 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 offer 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.
suppression correlates with the tumour burden
21
The degree of immune
22
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.
23,24
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 etal.
Campbell etal.
26
describe the existence of multiple
25
and
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. Alternatively, Notta etal. have
recently challenged the timing of tumour evolution
of pancreas cancer whereby a ‘single cataclysmic’
event, such as chromothripsis, spawns a highly
metastatic clone capable of seeding multiple organs
very rapidly.
27
122
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Non-colorectal hepatic metastases
Studies investigating single nucleotide polymorphisms in genes associated with tumour dormancy
and immune response checkpoints have associated
certain mutations with survival outcomes in
patients undergoing resection of CRLM.
28,29
These
findings could assist oncology teams in better
risk-stratifying patients for surgical resection and
theoretically similar studies could be performed on
patients with non-CRLM, though at present there
are few validated data available. Future studies on
the biology of metastases are likely to improve our
understanding of this complex process, translating
into more effective therapy.
Clinical approach to
non-colorectal 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 (US), contrast-enhanced ultrasound
(CEUS), contrast-enhanced 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 (e.g.
CA-125 for epithelial ovarian cancer, chromogranin
A for NETs). Nuclear imaging (octreotide scans)
can detect NETs expressing somatostatin receptors
with 80–90% sensitivity. Whole-body PET using a
new somatostatin analogue, [
been found to be accurate for the detection of new
metastases in NETs following radionuclide therapy.
Occasionally, the original presentation of a NET will
be a liver metastasis from an unidentified primary,
and the investigative focus is aimed at localisation
of the primary tumour. Novel biomarkers, such as
circulating tumour cells and cell-free DNA will soon
be used to guide decision-making.
When a patient is considered 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 extrahepatic disease. The anatomical
areas targeted for investigation (brain, lung, bone)
will be determined by the known metastatic pattern of
the primary tumour. Multidisciplinary input from
specialists with expertise in hepatic surgery and
management of the primary cancer is essential.
68
Ga]DOTA-TOC, has
31,32
30
Certain tumours, such as gastric, breast and ovarian
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.
33
For many
of these equivocal cases, diagnostic laparoscopy
has been recommended. Routine laparoscopy with
laparoscopic ultrasound for patients with potentially
resectable non-CRLM has been found to result in a
change in management in 20% of cases and may be
used selectively in preoperative staging.
34
While the discussion that follows will review
management and outcomes of liver resection for
hepatic metastases based on primary tumour type,
general considerations as proposed by Adam etal.
in 2006 remain relevant.
5
In their review of 1452
patients from 41 centres undergoing liver resection
for non-colorectal and non-neuroendocrine primary
tumours, age >60 years, presence of extrahepatic
disease, R2 resection and major hepatectomy were
associated with decreased overall survival. These
factors should be considered when contemplating
liver resection for these patients.
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. Treatment
decisions in this context can only be determined
properly by a multidisciplinary oncology team.
Non-surgical 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,
ovarian cancer
36
and NETs.37 The major limitation
of RFA is the difficulty in achieving complete
necrosis for tumours >
3 cm, as well as limited utility
when tumours are close to major vascular or biliary
structures. Novel techniques such as microwave
ablation (MWA), stereotactic radiotherapy and
irreversible electroporation (IRE), need to be
assessed in prospective randomised trials as they
may supplant surgical resection in some cases.
Transarterial embolisation (TAE) takes advantage
of the differential blood supply of liver metastases,
which depends 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
38–40
35
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
123
Chapter 7
well described for the treatment of unresectable
hepatocellular carcinoma
relief of NETs.
42
41
and the symptomatic
Finally, it behooves the surgical oncologist to
keep abreast of the explosion of recent advances in
systemic therapy, such as immunotherapy, to ensure
proper selection of patients who will benefit from
resection.
43
Management of liver
metastases by primary
tumour
Neuroendocrine tumours
NETs represent a diverse group of tumours
originating throughout the gastrointestinal tract.
They are classified by site of origin and include
gastrointestinal and pancreatic histological
subtypes.
commonly in the midgut and may secrete serotonin
and other bioactive amines. Pancreatic NETs (PNETs)
can be non-functional or hormonally active (e.g.
insulinoma, glucagonoma, gastrinoma, VIPoma),
manifesting varied clinical syndromes.
Ki67 proliferative index on a scale from 1 to 3.
Grade 1 and 2 tumours are considered to have
indolent growth patterns. Despite this 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%.
chemotherapy with platinum-based regimens has
shown a response rate of up to 67% in grade 3 NETs.
Nevertheless, the survival benefit of chemotherapy
is limited and associated with significant toxicity.
lanreotide can achieve symptomatic relief in 70–
80% of patients with functional tumours.
have also been shown to confer improvement in
progression-free survival compared to placebo.
There is emerging evidence that pasireotide, a
somastatin analogue that binds more somatostatin
receptors than octreotide or lantreotide, may have an
even greater antiproliferative effect.
agents such as the receptor tyrosine kinase inhibitor
sunitinib, the mammmalian target of rapamycin
(mTOR) inhibitor everolimus, and the antivascular
endothelial growth factor (anti-VEGF) bevacizumab
have shown promise in metastatic NETs.
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 surgery
44
Neuroendocrine tumours arise most
NETs are graded based on mitotic rate and
45
Systemic
44
46
Somatostatin analogues such as octreotide and
47–49
Both
47,49
50
Furthermore,
46,51
NETs metastasise preferentially to the liver, and
45
(Fig. 7.1a,b). Liver resection may be
a
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.
52
The metastatic
pattern of spread in the liver for NETs also has
prognostic implications and is categorised into three
morphological subtypes:
52,53
(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 within
and between lobes. Patients with type I or II disease
(25% and 15% of cases, respectively), in the absence
of extrahepatic metastases, can be considered for
curative surgical resection.
52,53
The aim of liver
resection with curative intent in NETs is to leave
124
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Non-colorectal hepatic metastases
no residual disease (R0 resection) in both primary
and secondary sites, and this may be associated with
5-year survival rates of up to 85%.
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, challenging the dogma that
surgery should be reserved only for patients most
likely to have an R0 resection. Cytoreduction aims to
reduce tumour volume by at least 90% in situations
where R0 resection is not feasible. 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
54–56
survival.
and durable palliation from symptoms for patients
with functional tumour syndromes.
surgical debulking has been advocated for both
functional and non-functional tumours.58 An
aggressive approach, sometimes combining liver
resection with other ablative strategies, is warranted
(Fig.7.2a,b). Liver transplantation is an emerging
option for NET liver metastases that are otherwise
unresectable but is controversial.
Cytoreduction can also offer effective
Despite resection, hepatic recurrence occurs in
up to 84% of patients at 5 years post-surgery.
42,45
55–57
As a result,
56
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.
59
Non-surgical treatment modalities used for NET
metastases 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 <
diameter, involving up to 20% of liver volume.
7 cm in
46,56
TAE 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
56
Duration of response is routinely short
RFA.
as the tumour rapidly develops collaterals and
thus repeat treatments are often required.
58
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.
58
Symptom
control with non-surgical approaches, recognising
that repeat treatments may be required, can limit
the need for cytoreductive surgery in many patients.
a
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 hepatectomy with wedge resections from segment 2.
b
125
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Chapter 7
Liver transplantation has been advocated for
patients with extensive, unresectable liver metastases
with no extrahepatic disease. A retrospective study
of 150 patients who underwent transplantation for
metastatic NET reported 5-year survival comparable
to patients with hepatocellular carcinoma.
60
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
Concerns remain regarding tumour recurrence in
the context of immunosuppression, so while liver
transplantation does appear to confer long-term
survival in carefully selected patients, optimal
patient selection criteria remain in evolution.
61,62
.
Gastrointestinal stromal tumours
Gastrointestinal stromal tumours (GIST) are
the most common gastrointestinal mesenchymal
malignancies and originate from the interstitial
cells of Cajal.
harbour a mutated c-Kit proto-oncogene, which
results in the constitutive activation of this receptor
tyrosine kinase leading to unregulated cell growth.
Two-thirds of c-Kit mutations are located on
exon 11.
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 (55–60%),
small intestine (30–35%), colon/rectum (5–10%)
and oesophagus (5%).
can be classified into four prognostic categories
ranging from very low risk to high risk, according
to site of the primary lesion, size of the primary
lesion, and the number of mitotic figures identified
on histology.
treatment of primary GIST.
Imatinib mesylate is a selective tyrosine kinase
inhibitor that has revolutionised the treatment of
68
GIST.
microscopic negative margins, recurrence (local or
distant) occurs in 50% of patients.
imatinib in the adjuvant setting was investigated
in the phase III ACOSOG placebo-controlled trial
(Z9001) for patients with resected GIST >
size. A statistically significant 1-year recurrencefree 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 in patients with moderate to
high-risk primary tumours.
is greatest in tumours that harbour the c-Kit exon
11 mutation, with resistance rates higher in patients
harbouring exon 9 or platelet-derived growth factor
receptor α mutations.
63
Approximately 70–80% of GISTs
64
C-Kit exon 9 and PDGFRA mutations,
65
66,67
The primary tumour
68
Resection remains the standard
Despite complete surgical resection with
68
The use of
3 cm in
68
Response to imatinib
68
The treatment of metastatic and recurrent GIST has
similarly been transformed by imatinib. Recurrence
of GIST most commonly occurs with one of two
metastatic patterns: local recurrence with peritoneal
disease or liver metastases.
69
Most patients with
recurrent or metastatic GIST 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.
70
However,
many patients develop imatinib resistance and
disease progression caused by the development of
secondary mutations.
third-line agents (e.g. nilotinib and masitinib) have
shown promise in patients resistant to imatinib.
71
Second- (e.g. sunitinib) and
72
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
GIST. Although evidence guiding surgical management
in metastatic GIST is limited, a 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.
73
A recent Dutch study evaluated 48 patients
who underwent liver resection for GIST metastases,
36 of whom received TKI therapy either pre- or
postoperatively. Median survival was 7.5 years and
5-year overall survival was 76%. Multivariate analysis
demonstrated that R0 resection of the liver metastasis
was the only significant predictor of survival.
74
A
multicenter European study retrospectively evaluated
239 patients undergoing hepatic metastectomy, all of
whom received adjuvant imatinib. R0/R1 resection
was found to be a significant predictor of survival and
median survival in this group was 8.7 years. Other
significant predictors of survival were female gender
and metastases confined to the liver (compared to liver
plus peritoneum).
GIST liver metastases are usually unresectable and
therefore imatinib is generally accepted as first-line
treatment for metastatic disease. The efficacy and low
side-effect profile of imatinib has promoted enthusiasm
for the combined use of surgery and imatinib in the
management of metastatic GIST. High-quality evidence
is lacking but retrospective series studying the
combination of surgery with imatinib in patients with
resectable metastases demonstrate good results with
5-year survival rates of over 70%.
75
Disease progression is managed by imatinib dose
escalation followed by second- and third-line agents.
In the event of tumour rupture or haemorrhage,
surgery or hepatic artery embolisation may be
performed in an emergency setting. Six to twelve
months of imatinib therapy is recommended for
patients with unresectable hepatic metastases and if
the tumour responds, resection can be considered if
an R0 resection can be anticipated.
67
126
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Non-colorectal hepatic metastases
Breast cancer
The liver is the third most common site of breast
cancer metastases after bone and the lungs.
widely held concept that liver metastases in breast
cancer reflects 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 proposed for patients presenting with the
liver as the sole site of involvement. The data are
mostly retrospective and are based on heterogeneous
indications, making it difficult to provide strong
evidence-based guidelines.
Although metastatic breast cancer is common,
isolated liver lesions in metastatic breast cancer are
seen in less than 10% of patients.
77,78
series of 11 000 breast cancer patients treated over an
18-year period only 34 patients had resectable liver
metastases.
79
Selection criteria for such metastases
are inconsistent in surgical series, with some centres
considering resection only for disease confined to the
liver while others advocate a more liberal approach. In
short, there are no clear selection criteria for resection.
Oestrogen receptor-positive primary tumours and a
prolonged disease-free interval of >48months before
development of metastases have been associated with
improved survival.
76
Response to chemotherapy also
appears to be an important predictor of survival. In one
study, patients who progressed during prehepatectomy
chemotherapy had a 5-year survival rate of 0%
compared to 11% in responders.
80
Therefore, surgery
should only be considered in patients who have
responded to preoperative chemotherapy or hormonal
therapy, or both.
Isolated liver metastases from breast cancer are
rare. Previous response to systemic therapy appears
to be an important predictor of survival following liver
resection for metastatic breast cancer.
A meta-analysis of 36 studies including 1025
patients undergoing liver resection for breast cancer
metastases showed a median overall survival of
41 months (data from 25 studies) after curative
intent surgery with a median time to recurrence
of 11.5 months (from 6 studies).
76,81
overall survival rates range from 25-60%.
Five-year disease-free survival rates are lower than
overall survival rates, suggesting that liver resection
may function as a cytoreductive rather than curative
procedure in these highly selected patients.
Most of these data come from retrospective
surgical case series. A recent study of patients with
isolated hepatic metastases from the Memorial Sloan
Kettering Cancer Center compared the outcomes of
69 patients treated with resection or ablation with
98 patients treated with systemic therapy. In this
series the median overall survival of the surgical
76
The
In a Japanese
Five-year
76,79,82–84
76,81
cohort was 50 months, which was similar to the
45 months for the chemotherapy cohort. This
finding persisted after propensity score matching
of 49 patients in each group. However, 10 (15%)
of the surgically treated patients had a disease-free
survival of >5 years, indicating there are selected
patients who benefit from an aggressive surgical
approach.
78
This is reinforced by a French report
of 19 patients who underwent repeat hepatectomy
for breast cancer metastases with 5-year overall
survival (following the second liver resection) of
46% and median survival of 41months.
85
Ovarian cancer
Epithelial ovarian cancer represents the most
common malignancy of the ovary and cytoreductive
surgery and platinum-based chemotherapy are the
mainstays of treatment. Unfortunately, most patients
develop chemoresistance after 24–36months and the
median survival for advanced disease is 3.5years.
Aggressive surgical debulking is advocated in
advanced cases, with optimal cytoreduction targeted
1 cm of residual disease.89 Intraperitoneal
at <
chemotherapy has been demonstrated to further
improve survival compared to intravenous therapy
and requires optimal debulking in order to be
effective.
step in the management of advanced ovarian cancer.
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 –
or intraparenchymal metastases (stage IV –
Survival is improved for patients with stage IV
disease who have undergone adequate debulking
surgery including hepatectomy.
metastases that invade the liver parenchyma may be
difficult to distinguish from parenchymal metastases
that spread haematogenously and can reflect
different disease biology and response to therapy,
including liver resection.
be made preoperatively those with haematogenous
liver metastases can be considered to have advanced
disease (similar to those with pulmonary metastases)
and are treated with palliative systemic therapy
rather than surgery.
inversely correlated with volume of residual disease,
disease stage and tumour differentiation. Similarly,
survival following hepatectomy for recurrent disease
is dependent on optimal cytoreduction, negative
margin status, greater pelvic than abdominal disease
and a longer recurrence-free interval.
demonstrated that when complete cytoreduction of
90
Successful cytoreduction is thus a crucial
Although the liver is rarely the only site of
91,92
Peritoneal
87,88
If this distinction can
87,88
Survival following primary surgical debulking is
93
It has been
86–88
Fig.7.3)
Fig.7.4).
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
127
Chapter 7
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.
recurrent disease is possible hepatic resection should
be considered as the median survival is improved.
87
TACE and RFA offer potential alternative
therapeutic options in achieving local control in
patients with contraindications to resection or as
adjuncts to systemic therapy.
87,94
Renal cell carcinoma
Approximately 20–30% of patients with renal cell
carcinoma (RCC) present with synchronous metastatic
disease and another 20–40% of patients with previous
nephrectomy will develop metastatic disease.
than 5% of patients have metastases restricted to the
liver and liver metastases portend a poor prognosis
of 7–12 months.
97,98
Systemic therapy options for
RCC are limited. Interleukin-2 and interferon-α were
previously used as first-line therapy for metastatic
95,96
Fewer
RCC and were not found to be active against liver
metastases.
98,99
Current regimens employ tyrosine
kinase inhibitors like sunitinib, which is associated with
an improved progression-free survival in phase III trials,
and emerging data suggest that immune checkpoint
inhibitors are effective in metastatic RCC.
99,100
The available data on hepatic resection for RCC
metastases are limited to retrospective reports. A
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
95
The median overall survival was 33 months.
A
second retrospective study compared 68 patients
who underwent surgery to a cohort of 20 patients
who were eligible but refused an operation. Disease
in these patients was mostly confined to the liver.
Overall 5-year survival in the treatment arm was
62% in comparison to 29% in the control group.
101
A review of six studies including 140 patients
who underwent liver resections reported 5-year
overall survival rates ranging between 34% and
43% and a median survival of 16–48 months.
96
Factors associated with better survival included
metachronous metastases, R0 metastectomy and
non-sarcomatoid histology.
95,96,98,101
More contemporary series have examined liver
resection for RCC metastases in the context of TKI
use. In one series of 39 patients undergoing liver
resection (37 patients) or ablation (2 patients) the
overall median survival was 42 months. During
a median follow-up period of 2.2 years, 74% of
patients who received no targeted therapy recurred,
compared to 40% of patients, maintained on
postoperative treatment. Multivariate analysis
identified postoperative TKI therapy as a predictor
of survival.
been shown to downsize unresectable RCC liver
metastases in order to facilitate safe liver resection.
102
Preoperative TKI therapy has also
103
Melanoma
The prognosis for patients with metastatic melanoma
is poor and the median survival for patients with
stage IV disease has historically been 6–9months.
Gastrointestinal and liver metastases occur in
2–4% of individuals with stage IV disease,
palliative radiotherapy and systemic chemotherapy
have largely been ineffective in conferring a survival
advantage. Biological agents such as interferon-α
and interleukin-2 have yielded modest response
rates that are rarely durable and are associated with
significant toxicity.
104
Favourable results in patients
undergoing metastasectomy in the lung, soft tissues
or abdomen have provided some enthusiasm for
surgery in a selected patient population.
105
104
and
128
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Non-colorectal hepatic metastases
The available evidence for hepatectomy for
metastatic melanoma is limited and consists largely of
subset analyses from larger series of patients with nonCRLM. One retrospective study evaluated all patients
who presented with metastatic melanoma over the last
decade at a single Australian institution. In this series,
13 patients underwent resection for liver metastases.
Median disease-free interval from resection of the
primary was 49months, median disease-free survival
was 14 months and median overall survival was
21 months.
105
An American series of 24 patients
undergoing liver resection had similar results with a
reported median disease-free survival of 12 months
and median overall survival of 28months.
106
The biological behaviour of metastatic melanoma
depends in part on the site of origin of the primary
tumour.
than ocular melanoma.
107
Cutaneous melanoma is more common
108
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, and is more likely to
be associated with isolated liver metastases than
cutaneous melanoma.
107,108
Survival following
hepatectomy appears to be more favourable in
this highly selected but rare group of patients with
melanoma of ocular origin. Pawlik etal. reported a
5-year survival rate of 21% for liver resection for
ocular melanoma, with a 0% 5-year survival rate
for cutaneous melanoma. However, 75% of resected
patients in this study developed recurrent disease,
and the rate of recurrence was similar between the
ocular and cutaneous groups.
108
Liver resection with postoperative tumour infiltrating
lymphocyte (TIL) therapy has been explored. TIL
involves resection of metastatic lesions followed by
extraction and culture of infiltrating lymphocytes
exvivo 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.
109
New molecular therapies have become standard
of care in treatment of metastatic melanoma.
BRAF and MEK inhibitors (e.g. vemurafenib and
trametinib, respectively) are used for patients with
tumour mutations in the BRAF gene. Imatinib has
been used in patients with tumours harbouring
mutations in the KIT gene. Immunomodulators
targeting CTLA-4 (e.g. ipilimumab) and PD-1 (e.g.
nivolumab) are used increasingly in all patients
with advanced melanoma. These agents collectively
have improved overall survival for patients with
advanced melanoma compared to interleukin-2
and conventional cytotoxic chemotherapy.
110
The widespread use of these agents may lead
to an increased number of patients referred for
consideration for resection of isolated hepatic
metastases. It is difficult to estimate the impact that
liver resection will have on these patients, but it
seems reasonable to adopt a resectional approach
in highly selected patients, i.e. those with a long
disease-free interval from treatment of the primary
tumour to development of metastases, and patients
who can be rendered disease-free following surgery.
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 bile duct. Hepatic resection has generally
been considered to be contraindicated in these cases.
Oesophagus
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.
Two case reports in the English-language literature
describe hepatectomy for isolated, synchronous liver
metastases.
performed simultaneously with oesophagectomy
and was followed by hepatic arterial chemotherapy.
Both patients developed multiple liver metastases at
6 and 7months postoperatively. These recurrences
responded partially to systemic chemotherapy,
and the patients were alive with disease at 14
and 18 months following hepatectomy. A report
of four cases of liver resection for metachronous
oesophageal cancer metastases has also been
published. All patients received chemotherapy
before liver resection. Two patients died at 10
and 21 months following liver resection, one was
alive at 22months, and one patient had prolonged
survival of 92 months after chemotherapy and
liver resection.
hepatectomy may provide a limited survival benefit
in chemosensitive oesophageal cancer with isolated
liver metastases. Given the small number of cases in
the literature, liver resection in this context should
be offered rarely and only in highly selected patients.
Stomach
Gastric adenocarcinoma is the second most common
cause of cancer-related death worldwide, and the liver
is a major site of spread in 9–40%, though in most
cases the metastatic pattern is diffuse involving the
peritoneum and distant lymph nodes.
5-year survival in patients with liver metastases ranges
from 0 to 10% and surgery has historically been
contraindicated. There is some emerging literature that
112,113
In both cases hepatectomy was
114
Thus, although rarely feasible,
115–118
111
Overall
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
129
Chapter 7
liver resection or ablation may provide a therapeutic
benefit in the rare situation when hepatic metastases
are isolated. A meta-analysis of 23 retrospective
studies including 802 patients reported a 5-year
overall survival of 23.8% and a median survival of
22months.
117
Size and number of hepatic metastases
correlated with overall survival. A subsequent metaanalysis of 39 studies (many the same as in the
previous study) including 909 patients had similar
findings: 27.8% overall 5-year survival and median
overall survival of 29 months with better outcomes
seen in Asian studies compared to Western series.
119
A Japanese group reported on their experience
using an aggressive approach to gastric cancer liver
metastasis, adopting the same patient selection criteria
as for CRLM. Median recurrence-free survival was
similar between both groups (15.2months for CRLM
versus 16.4 months for gastric cancer metastases),
while the 5-year overall survival in patients with CRC
(193 patients) was 55% compared to 14% in patients
with gastric cancer (26 patients). Metachronous
metastases, solitary metastasis and moderate or welldifferentiated tumours were associated with longer
survival in the gastric cancer group.
118
A second
Japanese group restricted liver resection to those
patients with three or fewer metastases. In their series
of 28 patients, overall 5-year survival was 32% and
median survival was 49months.
120
A contemporary
series of 94 patients from 28 Japanese hospitals used
a mix of resection and ablation for liver-only gastric
metastases. They reported a 5-year overall survival
rate of 42.3% with no differences between resection,
ablation, or combined approaches for the liver
metastases. Patients with solitary liver metastases and
<3 positive lymph nodes had an improved survival.
121
The Italian Research Group for Gastric Cancer has
recently advocated resection of synchronous hepatic
metastases if an R0 resection can be performed of both
the primary and the metastases.
116,122
A cohort of 53
patients who underwent curative intent synchronous
R0 resection had a median survival of 13 months
and a 5-year overall survival rate of 9.3%. This was
significantly improved compared to a median survival
of 6.6months in 98 contemporary patients undergoing
palliative gastrectomy and a 3-month median survival
for 44 patients who underwent surgical bypass.
These results suggest that a highly selected subset
of patients with gastric cancer liver metastases can
achieve long-term survival with an aggressive surgical
approach. Whether Asian results can be extrapolated
to Western populations remains unclear.
Small bowel
Primary small-bowel malignancies represent an
exceedingly rare but histologically diverse subgroup
accounting for 2% of all GI malignancies.
bowel adenocarcinoma (SBA) represents the majority
of these tumours and is seen in up to 5% of patients with
123
Small-
familial adenomatous polyposis (FAP). By virtue of its
non-specific clinical presentation and the limitations
of radiological and endoscopic diagnostic modalities
to examine the small bowel, approximately 80% of
patients present with advanced disease. In addition,
the low prevalence of SBA limits our understanding
of the natural history of tumour spread, restricting
the development of clear treatment guidelines. A
multicentre retrospective French study examining the
efficacy of chemotherapy in 93 patients with advanced
SBA, compared various chemotherapeutic regimens
for progression-free survival (PFS) and overall
survival (OS). Median PFS and OS were 6.6 and
15.1 months, respectively, with best outcomes seen
with FOLFOX.
85
Negative prognostic factors include
a poor baseline WHO performance status, elevated
carbohydrate antigen (CA) 19-9/carcinoembryonic
antigen (CEA) levels and the presence of a duodenal
primary. The ability of surgery to prolong PFS in
hepatic SBA metastases has only been described in
a single case report of an FAP patient with a PFS of
3 years following neoadjuvant chemotherapy and
123
surgery.
Future studies examining liver resections in
metastastic SBA will provide further guidance as to its
role in this disease. At present metastectomy should be
considered contraindicated.
Pancreas
Pancreatic ductal adenocarcinoma (PDAC) accounts
for 90% of all histological subtypes of pancreatic
cancer and confers a poor overall prognosis.
the last 50years, PDAC has continued to rank as the
tenth most common cancer in the Western world and
the fourth leading cause of cancer death. PDAC presents
in a non-specific manner, often when disease is already
at an advanced stage. Improvements in chemotherapy,
surgical technique and knowledge of tumour biology
have translated into marginal improvements in
survival. Currently, only 15–20% of patients present
with disease amenable to curative resection, of whom
20% are alive at 5years.
124
The overall average 5-year
survival for unresectable PDAC is 5%, with a median
survival of 8–11months for patients with metastatic
disease receiving chemotherapy.
124–126
Due to the dismal
prognosis in patients with localised resectable disease,
surgery for metastatic PDAC has been contraindicated.
Yamada et al. examined the role of hepatectomy in
non-neuroendocrine pancreatic cancer, including
five patients with PDAC, one with adenosquamous
carcinoma and one with cystadenocarcinoma.
Patients were chosen for surgery if complete excision
of hepatic disease was deemed feasible, reliable control
of the primary disease was possible and the liver was
the only site of spread. Overall 5-year survival in this
cohort was 16.7%; however, five patients developed
recurrence and subsequently died of their disease
within 4–52 months. Prognostic factors appear to
correlate with disease-free interval from primary
124
Over
127
130
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
Non-colorectal hepatic metastases
to metastases and the presence of negative surgical
margins at metastasectomy.
127
A study of 69 patients
from six European centres evaluated synchronous
pancreas and liver resections for patients with PDAC
and isolated hepatic metastases. Outcomes were
compared with 69 matched patients who did not
undergo resection and median survival was greater in
the resection group (14.5months vs 7.5months). Four
patients were alive longer than 5years in the resection
group compared to none in the non-resection group.
128
Although these authors highlight the potential role
of liver resection in metastatic PDAC there is need
for future studies to clarify the true benefit of this
approach and identification of factors that can assist
clinicians in selecting patients appropriately. Molecular
stratification biomarkers may prove useful in this rare
10,129
setting.
The available evidence for hepatectomy in the
management of metastases from non-colorectal,
non-neuroendocrine GI primaries is limited, and few
meaningful statements can be made as to the utility
of this treatment strategy. Gastric cancer specifically
may be the exception to this with some encouraging
reports from Asia of acceptable survival after liver
resection from multiple centres. With improvements
in safety of liver resection coupled with encouraging
results from other malignancies metastasising to the
liver, future prospective studies will shed light on
the role of hepatic resection for non-colorectal, nonneuroendocrine GI cancers.
The available evidence for hepatectomy in the
management of metastases from non-colorectal,
non-neuroendocrine GI primaries is limited, and few
meaningful statements can be made as to the utility of
this treatment strategy. There is emerging evidence
from both Asia and Europe that acceptable results can
be achieved for highly selected patients undergoing
liver resection for gastric cancer metastases.
Testicular cancer
Metastasectomy is well established in the management of disseminated non-seminomatous germ
cell testicular carcinoma that does not completely
respond to chemotherapy, though isolated liver
metastases are rare.
reported an overall 10-year survival of 62% after
resection of hepatic metastases.
A single institution experience of 57 liver resections
performed over the last two decades demonstrated
that surgery for hepatic metastases is safe and
efficacious. Based on the presence and histological
type of tumour in the liver, 40–70% of patients
remain disease-free at 20 months.
prognostic indicators included viable tumour in the
resected specimen, metastases >
pure embryonal carcinoma in the primary lesion.
130
One series of 15 patients
131
132
Negative
3 cm in diameter and
Urothelial cancer
Data for metastasectomy in the management of
disseminated urothelial cancer are sparse, and no
studies specifically address the role of hepatectomy.
Of those patients treated for primary urothelial
cancer, 30% will recur, of which 75% will have distant
spread. Five-year survival of 28% has been reported
following resection of lung, brain, adrenal, smallbowel or lymph node metastases with variation in the
use of adjuvant chemotherapy.
133
Metastasectomy
has also been employed for palliation.
Lung cancer
The management of metastatic lung cancer is largely
restricted to radiation and chemotherapy. Although
the surgical management of hepatic metastases
remains controversial, most cases have been reviewed
within the broader context of non-colorectal, nonneuroendocrine GI tumours. Hepatic metastases
appear most commonly in right-sided non-small-cell
lung tumours with concomitant bone metastases.
A small case series of highly selected patients with
one or two liver lesions has shown that surgery may
confer a marginal survival benefit.
134
Nevertheless,
the role of surgery as well as other treatment
modalities (RFA, TAE/TACE) cannot be definitively
made with current evidence. Recent advances in
targeted therapy and immunotherapy may guide
decision-making in the future in this context.
135
Adrenocortical tumours
Adrenocortical tumours with liver metastases are
rare, and literature on the management of this
disease scenario is mostly anecdotal. Case reports
have provided no clear guidance regarding the
role of surgical or ablative strategies but disease
control after resection of hepatic metastases has
been reported.
with a disease-free interval >1year from primary to
metastasis may derive benefit from metastectomy.
136
Metachronous liver metastases
137
Endometrial cancer
Metastatic endometrial cancer is usually multifocal
and rarely managed operatively. A single-centre report
described the results of five patients who developed
metastatic disease to the liver ranging from 11months
to 10 years after primary resection. All patients
underwent hepatic surgery, with disease-free survival
of 8–66 months. Based on these results, the authors
advocate referral to a hepatobiliary specialist with the
intent of pursuing surgery.
138
Other isolated reports of
Downloaded for Anonymous User (n/a) at Rutgers University - NERL from ClinicalKey.com by Elsevier on March 22, 2019.
For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
131