BaillieÁre's Clinical Gastroenterology

Vol. 13, No. 4, pp. 593±610, 1999

Non-surgical treatment for liver metastases

Nancy E. Kemeny MD
Professor of Medicine
Cornell University Medical College; Memorial Sloan-Kettering Cancer Center, New York, USA

Omar T. Atiq MD, FACP

Associate Clinical Professor of Medicine
University of Arkansas for Medical Sciences; Cancer Treatment Program, Je€erson Regional Medical Center,
Pine Blu€, Arkansas, USA

The liver is a common site for developing metastatic disease. Although any malignancy can
spread to the liver, the direct passage of blood from the gastrointestinal tract to the liver via
the portal circulation results in a high rate of liver metastasis from gastrointestinal tract
tumours. Various radiographical tests including computed tomography and magnetic reson-
ance imaging can detect the majority of liver metastases. Surgical resection if feasible is the
treatment of choice since it produces a 5-year survival rate of about 30%. However, the
majority of the patients relapse after hepatic resection, 50% relapsing in the liver. Systemic
chemotherapy produces response rates of 15±30% with a median survival of 10±12 months. It
is estimated that 30 000 patients each year in the USA are candidates for regional hepatic
therapy. Hepatic arterial chemotherapy, hepatic artery embolization, chemoembolization,
cryosurgery, ethanol injection of the tumour and radiation therapy are being investigated as
potential treatment options for such patients.

Key words: liver metastases.

HEPATIC METASTASES, ARTERIAL CHEMOTHERAPY

AND TOXICITY

Hepatic metastases are commonly seen in patients with a wide variety of malignancies.
Gastrointestinal cancers are especially prone to spread to the liver because of the
direct passage of blood from the gastrointestinal tract to the liver via the portal
circulation. Metastasis to the liver from other malignancies is less common, breast
cancer, lung cancer and malignant melanoma being the main cancers associated with
this. In contrast to colorectal cancer, in which 60% of patients will develop liver
involvement, 4% of breast cancer patients, 15% of lung cancer patients and 24% of
patients with malignant melanoma show liver metastases.
The treatment of liver metastases from extra-gastrointestinal tumours varies
according to the sensitivity of the tumour type to chemotherapy. Tumours such as
breast that are sensitive to certain chemotherapeutic agents may bene®t from
aggressive systemic chemotherapy or even a regional approach such as resection, while
those that are resistant to chemotherapy, for example melanoma, may only be
1521-6918/99/040593+18 $12.00/00 *
c 1999 Harcourt Publishers Ltd.
594 N. E. Kemeny and O. T. Atiq

considered for a regional approach. Unfortunately, most patients with such malig-
nancies have extrahepatic disease, making them unlikely to bene®t from regional
therapeutic intervention.
The natural history of the hepatic metastases from various gastrointestinal tumours
di€ers according to the site of the origin of the metastases. Hepatic metastases from
gastric and pancreatic cancers often denote widespread metastasis and a short median
survival. Regional therapeutic manoeuvres such as hepatic resection or hepatic artery
infusion are usually inappropriate interventions. In contrast, hepatic metastases from
colorectal cancer lend themselves to a variety of interventions since 30% of such
patients will have disease con®ned to the liver. Hepatic arterial chemotherapy may
play an important role in the management of such patients.

Role of systemic chemotherapy

The response rate of hepatic metastases to systemic chemotherapy is dependent on the
sensitivity of the primary tumour to such treatment. For patients with breast cancer,
the response rate is as high as 60%1, whereas patients with gastrointestinal tumours
have a much lower response rate, one not usually greater than 30%.2 When hepatic
metastases accompany metastatic disease elsewhere, responses to systemic therapy are
not usually categorized according to the site of disease. Hepatic metastases usually have
a lower response rate than soft tissue or pulmonary disease. Hepatic disease may also
denote a more aggressive disease. In a Southwest Oncology Group Study, 47% of
patients with liver metastases responded versus 71% of patients without liver involve-
ment.3
Metastatic disease to the liver from gastrointestinal malignancies responds to
chemotherapy in about 30% of patients. Because of lower response rates, it is accept-
able to consider expectant observation in older asymptomatic patients with low-
volume disease. However, in patients with a good performance status, earlier treat-
ment may increase survival as well as quality of life. These patients need to be started
on systemic chemotherapy as soon as possible. On the other hand, patients with
metastatic breast cancer generally need to be started on systemic chemotherapy early
on because of their rapid progression and their high response rate to such an
intervention.

Role of hepatic arterial chemotherapy

Hepatic arterial chemotherapy is of major interest because of both anatomical and
pharmacological advantages. The following factors elucidate this concept:
1. Although colorectal metastases appear to migrate to the liver via the portal vein,
they derive their blood supply almost exclusively from the hepatic artery once they
are greater than 1 cm in diameter.4 In contrast, the normal hepatocytes derive their
blood supply predominantly from the portal circulation. Therefore, the injection of
chemotherapy into the hepatic artery allows the agent to be delivered selectively to
the metastases with a relative sparing of the normal hepatocytes.
2. The liver is often the ®rst and only site of metastatic disease. The theory of step-wise
metastatic progression assumes that the haematogenous spread of disease occurs
®rst via the portal vein to the liver, then from the liver to the lungs, and then to
other organs of the body.5 Thus, the aggressive treatment of hepatic metastases from
colorectal cancer may prolong survival in some patients.
 Non-surgical treatment for liver metastases 595

Table 1. Drugs for hepatic arterial chemotherapy.

Half-life Estimated increased exposure

Drug (min) by hepatic arterial infusion-fold
Fluorouracil 10 5±10
5-Fluoro-2-deoxyuridine 510 100±400
Bischlorethylnitrosourea 55 6±7
Mitomycin C 510 6±8
Cisplatin 20±30 4±7
Adriamycin (doxorubicin hydrochloride) 60 2

3. Certain drugs are largely extracted by the liver during the ®rst pass through the
arterial circulation. This results in a high local concentration of the drug with
minimal systemic toxicity. The pharmacological advantages of various chemothera-
peutic agents for hepatic arterial infusion are summarized in Table 1.6 In comparison
to a 19±45% liver extraction of 5-¯uorouracil (5-FU) during the ®rst pass, 94±99% of
¯urodeoxyuridine (FUDR) is extracted by the liver. After the injection of FUDR
into either the hepatic artery or the portal vein, mean liver concentrations of the
drug do not di€er depending on the route of injection, but mean tumour FUDR
levels are 15-fold higher when the drug is administered via the hepatic artery.
Newer drugs such as irinotecan have not yet been shown to have an advantage when
given via the hepatic artery.7
4. Drugs with a high total body clearance and short plasma half-life are more useful for
hepatic artery infusion because of the high regional exchange rate (100±1500 ml per
minute) of hepatic arterial blood ¯ow.8 If a drug is not rapidly cleared, recirculation
through the systemic circulation diminishes the advantages of hepatic arterial
delivery.
5. Drugs with a steep dose±response curve are more useful when given via the hepatic
artery since a small increase in the concentration of the drug may result in a large
improvement in response.
Regional hepatic arterial chemotherapy can be administered via either a hepatic
arterial port or a percutaneously placed catheter connected to an external pump or a
totally implantable pump. Early studies with percutaneously placed hepatic artery
catheters produced high response rates, but clotting of the catheters in the hepatic
artery as well as bleeding led physicians to abandon this method.9 The development of
a totally implantable pump allowed long-term hepatic artery infusion with good
patency of the catheter in the hepatic artery and a low incidence of infection. One
study compared three groups with:
1. surgical placement of a hepatic artery catheter;
2. percutaneous placement of a hepatic artery catheter;
3. an operative implantable reservoir connected to the hepatic artery catheter.
The reported ability of each technique to administer chemotherapy for the three
groups was 31, 25 and 115 days respectively.5

Hepatic artery pump insertion and complications.

One of the objectives of pump placement is to enable bilobar hepatic perfusion with
chemotherapy while preventing seepage of chemotherapeutic agents into the stomach
596 N. E. Kemeny and O. T. Atiq

and duodenum. Prior to the operation, the patient with metastatic colorectal cancer
should have a complete staging work-up including colonoscopy, chest radiography and
computed axial tomography of the abdomen and pelvis. Coeliac and superior
mesenteric artery arteriograms should be taken to identify the arterial anatomy of the
liver and the vessels to the stomach, duodenum and pancreas, as well as to con®rm the
patency of the portal vein. Portal vein occlusion is a contra-indication to hepatic
arterial therapy because of the possibility of hepatic failure in the event of hepatic
artery occlusion. The catheter is not placed directly into the hepatic artery because of
the risk of thrombosis but into an accessible side branch arising up to but not beyond
the junction of the hepatic artery. The catheter is secured with non-absorbable ties.
The arterial collaterals to the stomach, duodenum and pancreas are identi®ed and
ligated. Liver perfusion, as well as absence of perfusion to other vital organs, is
con®rmed intra-operatively with ¯uorescein injection and a Wood's lamp. A chole-
cystectomy is performed at the same time to avoid drug-induced cholecystitis. A post-
operative macroaggregated albumin scan is performed through the side port of the
pump to check for perfusion of the liver and to ensure the absence of extrahepatic
perfusion.
The operative mortality of implantable pump insertion is less than 1%.10 In this review
of data from Memorial Sloan-Kettering Cancer Center (MSKCC) over an 8-year period,
arterial catheter thrombosis was seen in 4.7% of the patients, extrahepatic perfusion in
3% and incomplete perfusion in 1.7%. Other rarer complications included gastric
ulceration, haemorrhage, pneumonia, pocket infection and a faulty pump. Overall,
morbidity was seen in 34 out of 303 patients (11.8%).

Randomized trials of hepatic arterial chemotherapy

To understand the impact of hepatic arterial therapy on the natural history of patients
with hepatic metastases, prospective randomized studies were initiated in the 1980s
comparing hepatic arterial infusion with systemic chemotherapy. The patients were
strati®ed for parameters known to in¯uence tumour response and survival, for
example, performance status, the degree of liver involvement and serum lactate
dehydrogenase level.
In one of the ®rst randomized trials conducted at the MSKCC, patients received
FUDR either systemically or via the hepatic artery as a continuous 14-day infusion.11
The dose of FUDR was lower in the systemic group than the hepatic arterial group
since the higher dose could not be tolerated by systemic infusion. The patients were
strati®ed by serum lactate dehydrogenase level and percentage liver involvement. All
patients underwent exploratory laparotomy for pump placement and to ensure the
absence of intra-abdominal extrahepatic disease. The patients receiving systemic
therapy had their hepatic artery catheter connected to a subcutaneously implanted
Infusa-port, and the pump was connected to an additional catheter placed in the
cephalic vein. The study design allowed a cross-over from systemic therapy to hepatic
arterial therapy by a minor surgical procedure±ligation of the systemic catheter
followed by connection of the pump to the hepatic artery catheter±if tumour
progression occurred on systemic therapy.
Of 178 patients referred, 12 refused randomization and 4 had an inadequate arterial
blood supply. Therefore, 162 were randomized; at laparotomy, however, 33 had
extrahepatic disease, 25 had their tumour resected, 4 had no tumour and 1 had an
abdominal infection. Of the 99 evaluable patients, there were 2 complete and 23 partial
responses (53%) in the group receiving hepatic arterial therapy and 10 partial
 Non-surgical treatment for liver metastases 597

responses (21%) in the systemic group (P ˆ 0.001). Thirty-one patients randomized to

systemic chemotherapy crossed over to hepatic arterial therapy after tumour
progression, 25% of whom went on to demonstrate a partial response and 60% of
whom showed a decrease in carcinoembryonic antigen level. Median survival for the
hepatic arterial and systemic groups was 17 and 12 months respectively (P ˆ 0.424).
Survival is dicult to interpret because of the cross-over from systemic to hepatic
therapy. The patients who were unable to cross over because of various factors such as
clotting of the arterial catheter had a median survival of 8 months, compared with
18 months for those who were able to undergo the cross-over to hepatic therapy
(P ˆ 0.04). An analysis of the base-line characteristics in the cross-over and the non-
cross-over groups revealed no major di€erences. Table 2 summarizes the results of this
trial, including toxicity.

Table 2. Memorial Sloan-Kettering Cancer Center study: hepatic arterial (HAI) versus systemic
¯urodeoxyuridine infusion.

HAI Systemic
(n ˆ 48) (n ˆ 51) P
Complete response 2 0
Partial response 23 (52%) 10 (20%) 0.001
450% decrease in carcinoembryonic 29 13
antigen level
Extrahepatic metastases 27 19 0.09
Toxicity
Ulcer 8 3
Elevated enzyme levels 20 (42%) 12
Bilirubin 43 mg/dl 9 2
Diarrhoea 1 36 (70%)
Survival
Total 17 months 12 months 0.424
Cross±over 18 Months
No cross-over 8 months 0.04

The North California Oncology Group conducted a similar study, stratifying

patients prior to randomization by the extent of liver involvement based on computed
tomography (CT) scans.12. Complete and partial responses were noted in 42% of the
patients in the hepatic arterial group and 10% of those in the systemic group
(P 5 0.0001). The median time to progression was 401 days for the hepatic arterial
group and 201 days for the systemic group (P ˆ 0.0009). The median survival was
503 and 484 days for the hepatic and systemic groups respectively. Although a cross-
over design was not built into the study, 43% of the systemic group patients received
hepatic therapy, possibly obscuring any di€erences in survival. The survival analysis is
made more dicult by the inclusion in the study of patients with hepatic lymph node
metastases.
A National Cancer Institute study compared hepatic arterial infusion with the
systemic infusion of FUDR in 64 patients.13 The response rates were 62% in the hepatic
arterial arm and 17% in the systemic arm (P ˆ 0.003). The survival data are impossible
to interpret because 34% of the patients in the hepatic arterial group never received
treatment and 38% had metastatic disease of the portal lymph nodes. However, in
598 N. E. Kemeny and O. T. Atiq

patients without extrahepatic disease, the 2-year survival rate was 47% in the hepatic
arterial group and 13% in the systemic group (P ˆ 0.03).
The Mayo Clinic conducted a randomized trial comparing hepatic arterial FUDR
with systemic bolus 5-FU in 69 patients.14 Only symptomatic patients were entered
into the trial, and no cross-over was allowed. The response rate was 48% for patients
receiving hepatic arterial therapy and 21% for those receiving systemic 5-FU
(P ˆ 0.02). The time to hepatic progression was 15.7 and 6 months respectively
(P ˆ 0.001). Survival was 12.6 months for the hepatic arterial group versus 10.5 months
for the systemic group. Again, several factors must be considered when interpreting
the survival data. First, this was a small trial with a very low power to detect survival
advantage. Second, 38% of the patients in the hepatic arterial group were either not
adequately treated for a variety of reasons or had extrahepatic disease. All of these
patients were included in the survival analysis. There is no comment in the report on
the survival of the patients who did not have extrahepatic disease and who were
adequately treated.
In a large multicentre trial in France, 163 patients were randomized to either
hepatic arterial FUDR for 14 days or systemic bolus 5-FU for 5 days every 4 weeks.15
The two groups had comparable clinical and laboratory characteristics, including the
percentage of liver involvement and the base-line serum lactate dehydrogenase level.
In patients with measurable disease, the response rate was 49% in the hepatic arterial
group and 14% in the systemic group. The median time to hepatic progression was
15 months for the former group and 6 months for the latter. Median survival was
14 months versus 10 months, favouring the hepatic arterial group. The 2-year survival
was 22% for the hepatic group and 10% for the systemic group (P ˆ 0.002). In this trial,
systemic chemotherapy was initiated only when the patients became symptomatic,
which makes the survival data open to question.
In a similar study carried out in England, 100 patients were randomized to either
hepatic arterial FUDR or systemic 5-FU.16 Again, patients were only treated if they
were symptomatic. Median survival was 405 days for the patients who received hepatic
arterial therapy and 198 days for the patients who received systemic chemo-
therapy (P ˆ 0.003). This study also addressed the quality of life issue, demonstra-
ting that patients who received hepatic arterial therapy had a signi®cantly improved
quality of life.
There are now eight randomized trials in patients with hepatic metastases from
colorectal carcinoma that demonstrate a signi®cantly high response rate for hepatic
arterial therapy in comparison to systemic chemotherapy (Table 3). All studies
show high response rates for the hepatic arterial group. However, several factors
complicate the issue of the translation of this high response rate into increased
survival. First, many of these studies allowed patients receiving systemic chemo-
therapy to cross-over to hepatic therapy after tumour progression. Second, most of
these trials included a relatively small number of patients, decreasing the power to
observe di€erences in survival. These studies do demonstrate survival advantage for
the group who received subsequent hepatic arterial therapy, with a mean 1-year
survival rate of 69% for the patients who received such treatment versus 35% for those
who did not (Table 4).

Role of adjuvant hepatic arterial therapy after liver resection

A randomized trial was conducted at the City of Hope, California, in patients who
underwent the resection of hepatic metastases from colorectal carcinoma.18 A total of
 Non-surgical treatment for liver metastases 599

Table 3. Randomized studies of intrahepatic versus systemic chemotherapy for hepatic metastases from
colorectal cancer.

Response (%) Survival (months)

Number of
Reference patients HAI Systemic P HAI Systemic P
11
Kemeny et al (1987) 162 52 20 0.001 18* 12
Hohn et al (1989)12 143 42 10 0.0001 16.6 16
Chang et al (1987)13 64 62 17 0.003 20 11
Niederhuber (1985)17 43 58 38 ± ± ±
Wagman et al (1990)18 41 56 0 ± ± ±
Martin et al (1990)14 69 48 21 0.02 12.6 10.5
Rougier et al (1992)15 163 49 14 ± 15 11 0.02
Allen-Mersh et al (1994)16 100 50 0 0.001 13 6.3 0.03

(±) Not stated.

* Updated.

Table 4. Randomized study of hepatic arterial therapy (HAI) versus systemic chemotherapy.

Survival (%)

1 year 2 year 1-year 2-year

Cross- No cross- Cross- No cross-

Group HAI Systemic HAI Systemic over over over over
Kemeny et al 60 50 25 20 60 28 25 14
(1987)11
Hohn et al 60 42 30 20 78 42 40 17
(1989)12
Chang et al 85 60 44 13
(1987)13*
Rougier et al 61 44 22 10
(1992)15

Mean 66 49 30 18 69 35 37 15

* Excluding patients with hepatic lymph nodes.

99 patients were entered in three di€erent groups. In group A, after the resection of a
solitary metastasis, patients were randomized to either no further treatment (A1) or
hepatic arterial therapy (A2). In Group B, after the resection of multiple metastases,
patients were randomized to no further treatment (B2) or hepatic arterial therapy
(B1). In group C, there were no resections, and patients were randomized to hepatic
arterial therapy (C1) or systemic 5-FU followed by hepatic arterial therapy (C2). In the
group with a solitary liver metastasis, the time to failure was 9 months in the
resection-alone group and 31 months in the resection plus hepatic arterial therapy
group (P 5 0.003). In group B, 30% of patients who received resection plus hepatic
arterial therapy were alive at 5 years compared with 7% of those who underwent
resection alone.
The use of adjuvant hepatic arterial therapy after liver resection has been addressed
by two large studies that have recently been completed. In the study at MSKCC,
600 N. E. Kemeny and O. T. Atiq

patients who had undergone a resection of colorectal hepatic metastases were

randomized to receive combined hepatic arterial FUDR plus decadron and systemic
5-FU plus leucovorin versus systemic 5-FU plus leucovorin alone. Six months of
therapy were administered in each arm. Treatment end-points were 2-year recurrence
rate and 2-year survival. A preliminary analysis of the study appears to support the use
of hepatic arterial infusion after the resection of metastatic disease. The 2-year disease-
free survival rate was 57% and 41% for the hepatic arterial plus systemic infusion group
and the systemic infusion alone group (P ˆ 0.07). Two-year survival was 86% for the
hepatic arterial plus systemic infusion group and 66% for the systemic infusion alone
group. Two-year hepatic disease-free survival was 89% and 57% respectively
(P 5 0.001).19 Another such trial was recently completed by the Eastern Cooperative
Oncology Group, in which patients were randomized to observation alone or a com-
bination of hepatic arterial FUDR and systemic infusional 5-FU. An increase in disease-
free survival was seen in the hepatic arterial plus systemic infusion group.20
Another adjuvant approach is immunochemotherapy with the hepatic arterial
infusion of interleukin-2 with chemotherapeutic agents. In a phase II trial of
interleukin-2, mitomycin-C and 5-FU, after curative resection of colorectal hepatic
metastases, 66% of patients remained disease free, with a median post-operative follow
up of 28.5 months. Twenty-two per cent of the patients developed recurrences,
although none of these occurred in the liver.21

Approaches to increase the response rate of hepatic arterial therapy

In view of data showing an improved response rate for combination chemotherapy
over single agents, the potential bene®ts of multidrug hepatic arterial therapy have
been evaluated in various studies. In a randomized trial at MSKCC, comparing
mitomycin-C, BCNU and FUDR versus FUDR alone, the response rate was 48% for
the three drugs versus 24% for FUDR alone (P ˆ 0.03).22 The median survival from the
initiation of hepatic arterial therapy was 18.9 months and 14.9 months respectively. All
67 patients who entered this trial had received prior systemic chemotherapy. Thus,
the response rates in both arms were higher than would be expected with a second-
line systemic chemotherapy regimen. Therefore, in addition to its role as a front-line
treatment, hepatic arterial infusion should also be considered for patients who have
failed systemic chemotherapy.
In another attempt to improve survival and response rate, a combination of hepatic
arterial FUDR and leucovorin was evaluated.23 This study was based on the success of
systemic regimens including leucovorin, as well as on laboratory studies suggesting the
modulation of FUDR by leucovorin. Sixty-four patients were treated at ®ve dose
levels. The overall response rate was 62%, 5% of the patients developing biliary
cirrhosis. Nevertheless, 86% of the patients were alive at 1 year, 62% at 2 years, 33% at
3 years and 10% at 5 years.24 FUDR plus leucovorin appears to have a higher response
rate but also greater toxicity than FUDR alone.
In a further attempt to improve response rate and survival, and to reduce biliary
toxicity, a phase II trial was conducted for unresected liver metastases with hepatic
arterial FUDR, leucovorin and dexamethasone.25 The response rate was 78% in
previously untreated patients and 52% in previously treated patients with a median
survival of 24.8 months. The 1- and 2-year survival rates were 91% and 57%, respec-
tively. In the previously treated group, 66% of the patients were alive at 1 year and 28%
alive at 2 years, with a median survival time of 13.5 months. Another form of systemic
therapy in previously treated patients with metastatic colorectal cancer produced
 Non-surgical treatment for liver metastases 601

response rates of 5±15% in comparison with 33±66% with the use of hepatic arterial
therapy. The probability of surviving 1 or 2 years with systemic chemotherapy ranges
between 54±65% and 19±27% respectively. In contrast, the probability of surviving 1 or
2 years with hepatic arterial therapy is 76±91% and 38±76% respectively.

Toxicity of intrahepatic therapy

The side-e€ects of systemic chemotherapy are almost never observed with hepatic
arterial infusion. Myelosuppression does not occur with the hepatic arterial infusion of
FUDR. Mitomycin-C and BCNU via side port injections may cause mild myelosup-
pression. Nausea, emesis and diarrhoea do not occur unless there is an inadvertent
perfusion of the stomach or duodenum from the hepatic artery.26
The most common problems in hepatic arterial infusion are peptic ulceration and
hepatic toxicity.27 Severe ulcer disease results from the inadvertent perfusion of the
stomach and the duodenum via small collateral branches from the hepatic artery; it can
be prevented with careful dissection of these collaterals at the time of pump
placement. However, even without radiologically visible perfusion of the stomach and
duodenum, mild gastritis and duodenitis can occur. This toxicity can be reduced by
careful dose reduction when any gastrointestinal symptoms occur.
Hepatobiliary toxicity is the most problematic and potentially dangerous toxicity
seen with hepatic arterial infusion. Although there is some evidence of hepatocellular
necrosis and cholestasis, an ischaemic and in¯ammatory e€ect on the bile ducts appears
to be the most important aetiology of this toxicity. The bile ducts are particularly
sensitive to hepatic arterial chemotherapy because they, like hepatic metastases, derive
their blood supply almost exclusively from the hepatic artery. Clinically, biliary
toxicity is manifested as an elevation of hepatic enzyme levels. The aspartate amino-
transferase (AST) level rises early on, and then alkaline phosphatase and bilirubin levels
rise, indicating further damage. In the early stages of toxicity, serum hepatic enzyme
elevations will return to normal when the drug is withdrawn and the patient is rested.
In more advanced cases, jaundice does not resolve. In patients with severe toxicity,
endoscopic retrograde cholangiopancreatography demonstrates lesions resembling
primary sclerosing cholangitis. Since the ducts are sclerotic and nondilated, sonograms
are usually normal. However, duct obstruction from metastases should be excluded by
a CT scan of the liver.
Close monitoring of the hepatic enzymes is necessary to avoid biliary cirrhosis. If the
serum bilirubin level becomes elevated, no further treatment should be given until it
returns to normal, and then only a small test dose should be employed. In patients
who cannot tolerate even a low dose for 2 weeks, it may be possible to continue
treatment by giving an FUDR infusion for 1 week rather than the usual 2. A review of
the hepatic enzymes obtained every 2 weeks has shown that liver function tests
increase at the end of FUDR infusion and then return to normal or almost normal
levels prior to the next dose. This pattern occurred in all patients who later developed
severe hepatic toxicity. In some studies with excessive biliary sclerosis, hepatic
enzymes were measured only on a monthly basis. These studies may have missed the
2-week elevation and may therefore not have reduced the doses appropriately at the
time of next treatment. At the MSKCC, the dose of hepatic artery chemotherapy is
modi®ed as outlined in Table 5.
602 N. E. Kemeny and O. T. Atiq

Table 5. Flurodeoxyuridine (FUDR) dose modi®cation schema.

SGOT reference 450 mg/l 450 mg/l % FUDR

value dose
SGOT (at pump emptying or on day of planned re-treatment, whichever is
higher)
0 to 53  reference value 0 to 52  reference value 100
3 to 54  reference value 2 to 53  reference value 80
4 to 55  reference value 3 to 54  reference value 50
55  reference value 54  reference value HoldA
Alkaline 490 mg/l 490 mg/l
phosphatase Alkaline phosphatase (at pump emptying or on day of planned re-treatment,
reference value whichever is higher)
0 to 51.5  reference value 0 to 51.2  reference value 100
1.5 to 52  reference value 1.2 to 51.5  reference value 50
52.0  reference value 51.5  reference value HoldB
Total bilirubin 41.2 mg/dl 41.2 mg/dl
reference value Total bilirubin (at pump emptying or on day of planned re-treatment,
whichever is higher)
0 to 51.5  reference value 0 to 51.2  reference value 100
1.5 to 52  reference value 1.2 to 51.5  reference value 50
52.0  reference value 51.5  reference value HoldC
Recommencing treatment after hold
Reason for treatment Chemotherapy resumed when value has returned to: % FUDR
delay dose
A
SGOT elevation 4  reference value if reference value 450 mg/l 50
3  reference value if reference value 550 mg/l
B
Alkaline 1.5  reference value if reference value 490 mg/l 25
phosphatase 1.2  reference value if reference value 590 mg/l
elevation
CTotal bilirubin 1.5  reference value if reference value 51.2 mg/dl 25
elevation 1.2  reference value if reference value 41.2 mg/dl

If the total bilirubin is 43.0 mg/dl, the drug is held and dexamethasone 20 mg added to the pump. Once
there is no longer evidence of toxicity, the dose of dexamethasone is tapered in increments of 5 mg every
14 days. Tapering continues unless enzyme levels increase.
`Reference value' is de®ned as the value obtained on the day the patient received the last FUDR dose. To
determine whether an FUDR dose modi®cation is necessary, the value should be compared with either
the value obtained on the day the pump was emptied or that obtained on the day of planned pump
®lling, whichever is higher.

New approaches to decrease hepatic toxicity

The hepatic toxicity induced by hepatic arterial infusion of FUDR may be related to
portal triad in¯ammation, which could lead to ischaemia for the bile ducts. Therefore,
the hepatic arterial administration of dexamethasone may decrease biliary toxicity. In
patients with established biliary toxicity from hepatic arterial infusion, dexamethasone
promotes the resolution of hepatic enzyme abnormalities. A prospective, double-blind,
randomized trial of hepatic FUDR with dexamethasone versus FUDR alone was con-
ducted at the MSKCC in order to determine whether the simultaneous administration
of dexamethasone with FUDR would prevent biliary toxicity and thereby allow for the
administration of high doses of chemotherapy.28 Although a signi®cant increase in
 Non-surgical treatment for liver metastases 603

administered FUDR dose was not documented, the response rate in 49 evaluable
patients was 70% for FUDR plus dexamethasone compared with 40% for FUDR alone.
A signi®cant increase in bilirubin level was seen in 9% of patients receiving FUDR plus
dexamethasone and in 30% of those receiving FUDR alone (P ˆ 0.07).
Using a circadian modi®cation of hepatic arterial FUDR infusion is another method
to decrease hepatic toxicity. A constant infusion of FUDR versus a circadian-modi®ed
arterial hepatic FUDR infusion was given to 50 patients with metastatic colorectal
cancer in a non-randomized trial. The group with circadian modi®cation received 68%
of each daily dose between 3 p.m. and 9 p.m., 2% between 3 a.m. and 9 a.m. and 15%
between each of the adjacent 6-hour periods. Over 9 courses of treatment, the
patients with circadian-modi®ed infusion tolerated almost twice the daily dose of
FUDR. Circadian-modi®ed infusion resulted in 46% of patients showing no hepatic
toxicity compared with 16% of patients with the constant FUDR infusion.29
Information on response rates was not presented.
Hepatic arterial toxicity may also be decreased by alternating drugs such as FUDR
and 5-FU. A weekly hepatic arterial bolus of 5-FU does not cause hepatobiliary
toxicity; however, it does produce arteritis. In a phase II trial, the hepatic infusion of
FUDR for 7 days was followed by a hepatic arterial bolus of 5-FU via the pump side
port.30 The response rate was 51% and the median survival 22.4 months. No patient
terminated treatment because of drug toxicity. Davidson et al31, using a similar
alternating regimen on 54 patients, produced a 54% response rate, 3.5% of patients
developing biliary cirrhosis. Another study using the weekly hepatic arterial infusion
of 5-FU with intravenous folinic acid produced a 45% response rate in 31 patients
without hepatic toxicity and with only mild systemic toxicity.32 Schlag et al33, using the
hepatic arterial infusion of 5-FU 1000 mg per day for 5 days via a surgically placed port
connected to an external pump, reported a 27% partial response in 33 patients and a
median survival of 14 months. Hepatobiliary toxicity was seen in only 5% of the
patients.

Approaches to decrease extrahepatic disease

Extrahepatic disease develops in 40±70% of patients receiving hepatic arterial therapy.
Such metastases can occur even when the patient's liver is still responding. The use of
systemic chemotherapy and concurrent hepatic arterial therapy may reduce the
incidence of extrahepatic metastases. In a randomized trial, comparing patients
receiving either hepatic arterial FUDR or a combination of hepatic arterial FUDR and
intravenous FUDR, given concurrently34, the response rates were 60% for both
groups, with no di€erence in survival. The incidence of extrahepatic disease was 79% in
the group receiving hepatic arterial therapy alone compared with 56% in the group
receiving combined arterial and intravenous therapy (P 5 0.01). In another study,
combined hepatic arterial therapy and systemic chemotherapy did not decrease the
development of extrahepatic disease.35
In a recently published report, 40 patients with colorectal cancer who had
unresectable hepatic metastases received hepatic arterial FUDR for 14 days followed
by systemic 5-FU for 5 days.36 The response rate was 62%. The median time to
progression was 9 months, 3% of patients remaining progression-free at 24 months. The
median survival was 18 months. Eighteen out of 40 patients (45%) initially progressed
at extrahepatic sites, a ®gure no lower than that obtained with hepatic arterial therapy
alone. Further studies of combined systemic and hepatic arterial regimens are
in progress.
604 N. E. Kemeny and O. T. Atiq

Intrahepatic therapy: conclusion

During the past 20 years, the survival of patients with metastatic colorectal carcinoma
has not changed. More than 2000 patients have been randomized to 5-FU plus
leucovorin versus 5-FU alone. A meta-analysis of these studies demonstrates a median
survival of 11 months and a 2-year survival of less than 20% for both treatment arms.37
Newer active drugs in colorectal cancer such as irinotecan, tomudex and oxalaplatin
have produced response rates similar to those obtained with 5-FU and leucovorin. On
the other hand, the 2-year survival rate in patients receiving hepatic arterial therapy
has been shown to be approximately 45±60% in pilot studies (Table 6).
Because of this apparent survival advantage of hepatic arterial infusion, the Cancer
and Leukemia Group B is conducting a trial in which patients with isolated hepatic
metastases from colorectal cancer are being randomized to receive a hepatic arterial
infusion of FUDR, leucovorin and dexamethasone or systemic 5FU plus leucovorin.
Patients with less than 70% liver involvement and no previous chemotherapy are
eligible, and there is no cross-over from systemic to hepatic arterial therapy. This study
will address not only survival bene®ts, but also di€erences in the quality of life and
®nancial cost. The use of hepatic arterial therapy for other tumour types has not been

Table 6. One- and two-year survival with HAI or systemic chemotherapy.

% Survival

% Response 1-Year 2-Year

Previously untreated patients with colorectal cancer
Intravenous
FU ‡ LV (bi-monthly)38 32.6 56 27
FU ‡ LV (bi-monthly)38 14.5 54 23
CPT-1139 30 40 25
FU ‡ LV40 14 50 20
FU ‡ LV41 43 40 22
42
FU ‡ LV 18 45 25

Hepatic arterial infusion

FUDR ‡ LV25 66 82 71
FUDR ‡ D ‡ LV24 78 91 76
FUDR ‡ D28 71 85 45
Mito ‡ FUDR ‡ D43 73 80 38
FUDR alone27 50 76 42

Previously treated patients with colorectal cancer

Intravenous
FU cont44 1 32 ±
CPT-1145 13 36 ±
CPT-1144 4 45 ±

Hepatic arterial infusion

FUDR ‡ D ‡ LV31 50 66 28
Mito ‡ FUDR ‡ D43 64 65 15
Mito ‡ BCNU ‡ FUDR29 47 60 21
FUDR alone29 33 60 10

FU ˆ ¯uorouracil; LV ˆ leucovorin; FUDR ˆ ¯urodeoxyuridine; D ˆ dexamethasone;

Mito ˆ mitomycin C.
 Non-surgical treatment for liver metastases 605

studied as extensively. However, there are some encouraging data emerging in

patients with metastatic breast cancer and hepatocellular carcinoma.

HEPATIC ARTERIAL EMBOLIZATION

Since hepatic metastases as well as primary hepatic malignancies receive their blood
supply from the hepatic artery, hepatic arterial ligation and embolization have been
used to reduce the tumours' blood supply.46 In most hepatic tumours, hepatic arterial
ligation produces only a transitory bene®t because of the rapid development of
collateral blood supply (see chapter 8). The development of collateral blood supply
may be minimized by injecting vaso-occlusive particles into the hepatic artery, which
also provides the opportunity for re-treatments since only the microvasculature is
occluded.47 This is called hepatic arterial embolization. Although hepatic artery
ligation and embolization have not proved to be of much bene®t in metastatic
colorectal cancer, they appear to have a de®nite role in highly vascular tumours such
as neuroendocrine tumours of the liver.48
However, interference with the hepatic blood ¯ow can exacerbate the underlying
liver disease and can be dangerous in patients with portal venous thrombosis, which is
present more often in patients with primary liver tumours than in those who have
metastatic disease. Other complications of embolization include nausea, vomiting,
fever, pain and elevation of liver enzyme levels. Rare problems include injury to the
gallbladder, ischaemic necrosis of the bowel, pancreatic infarction and pancreatitis, and
dyspnoea secondary to embolization to the lungs. In neuroendocrine tumours, tumour
lysis syndrome as well as carcinoid crisis have been seen. Somatostatin analogues
should be given prior to embolization.49

Chemoembolization
When a drug is used with the embolic agent, there is a local entrapment of the drug in
the agent (chemoembolization), which provides a prolonged exposure of the tumour
to the drug with less systemic drug circulation. In a study of 51 patients with
unresectable hepatocellular carcinoma treated with gelfoam, and a mixture of three
drugs±doxorubicin, mitomycin-C and cisplatin±given via a percutaneous hepatic
artery catheter, 24% had a partial response and 68% a reduction in alphafetoprotein
level.50 The response rate and survival for colorectal metastases using chemoemboliza-
tion are low.51,52
Lipiodol (iodized oil contrast) has been found to remain selectively in the primary
and secondary liver cancers when injected into the hepatic artery, allowing the
visualization of tumours as small as 4 mm in diameter. Lipiodol can be used to deliver
local radiation or chemotherapy.53

CRYOSURGERY

Cryosurgery is an in situ destruction of tissue using subzero temperatures. The rapid

freeze±thaw of tissues results in cellular damage and death.54 Cryosurgery spares
normal tissue if the tumour is well de®ned and the amount of freezing is accurately
monitored. The 2-year survival after cryosurgery varies from 72% to 12%.55 Adam
et al56 have reported a 2-year survival rate of 50% for patients with colorectal
606 N. E. Kemeny and O. T. Atiq

metastases versus 67% for patients with hepatocellular carcinoma, with a local
recurrence rate of 44%. In one study, 75% of patients undergoing cryosurgery had an
elevation in carcinoembryonic antigen level by 6 months.57 Since local recurrence is
high, hepatic arterial infusion after cryosurgery may be useful. One small non-
randomized study doubled survival with the use of hepatic arterial infusion after
cryosurgery.58 Haemorrhage, biliary ®stula formation and tumour lysis syndrome are
some of the complications of cryosurgery.

Percutaneous ethanol injection

Percutaneous ethanol injection therapy (PEIT) is a procedure in which 30 ml absolute
ethanol is injected into the lesion under ultrasound guidance.59 In the pooled data of
patients with hepatocellular carcinoma from Japan, the 3-year survival rates after
surgical resection, PEIT and embolization were 58%, 53% and 20% respectively.60 The
size of the lesion a€ects the outcome, with low response rates for lesions over 4 cm in
diameter.

Radiation
Whole liver irradiation has been limited by the low tolerance of the liver to
irradiation, so that doses greater than 30±35 Gy given to the entire liver will produce
radiation hepatitis.61 Attempts to improve upon the modest results of whole liver
irradiation have combined systemic or regional chemotherapy with radiation.62 Newer
approaches allow higher doses of radiation to be applied to localized areas. Micro-
spheres can be infused into the hepatic artery to deliver local radiation, for example
with yttrium-90.63 Interstitial brachytherapy with an iridium-192 afterloader can be
placed at the time of laparotomy to give high-dose local radiation.64 Conformal three-
dimensional treatment planning, in which beams can enter the patient from almost any
angle, can substantially reduce the irradiation of normal liver and also increase the
local radiation dose.65

NEW THERAPIES

Isolation perfusion, microwave coagulation and gene therapy are new approaches being
developed. A recent report of the hyperthermic isolation perfusion of tumour necrosis
factor and melphalan produced a 75% response rate in metastatic colorectal cancer.66
Since cancer cells may be more sensitive to heat as a result of the decreased vaso-
dilatory capacity of the neurovascular bed, microwave coagulation has been used.67
Gene therapies have been hampered by the ability to get the therapy to the
tumour. One trial involving an adenovirus vector carrying the wild type p53 gene
produced no responses in 19 patients.68 Other gene therapies involve:

1. the use of pro-drug genes to convert innocuous drugs69 into active chemo-
therapeutic agents;
2. directed immunotherapy carried on a liposomal vector70;
3. injecting genes that express thymidine kinase and then using ganciclovir.71
 Non-surgical treatment for liver metastases 607

CONCLUSIONS

Liver metastases, especially from colorectal primaries, are treatable and potentially
curable. In older patients, or in patients with medical conditions preventing surgery,
expectant follow-up can be endorsed. When the tumour starts growing and local
techniques cannot be used, systemic chemotherapy should be considered. In patients
with progressive metastatic disease of the liver, systemic therapy or hepatic arterial
infusion may be initiated. In young patients with metastatic disease, either locoregional
therapy (resection or regional infusion) or systemic chemotherapy followed by
regional therapy should be considered.
In patients with neuroendocrine tumours metastatic to the liver, the ®rst approach
is not to treat since there may be a long period of stable disease. If the tumour
progresses and the symptoms are not controlled, these vascular tumours can be
treated by embolization or chemoembolization, with high expectations of a response.
Newer approaches to liver metastases, such as cryosurgery, interstitial radiation and
alcohol injections, are also available. The usefulness of these techniques compared with
surgery or regional therapy is being investigated, as are other newer approaches such
as gene therapy and isolation perfusion.

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