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Economic Implications of Hepatic Arterial Infusion Chemotherapy in Treatment of Nonresectable Colorectal Liver Metastases.txt
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Economic Implications of Hepatic Arterial Infusion Chemotherapy in Treatment of Nonresectable Colorectal Liver Metastases.txt
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http://jnci.oxfordjournals.org/content/89/11/790.full
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<div class="article fulltext-view" itemprop="articleBody"><span class="highwire-journal-article-marker-start"></span><h1 id="article-title-1" itemprop="headline">Economic Implications of Hepatic Arterial Infusion Chemotherapy in Treatment of Nonresectable Colorectal Liver Metastases</h1>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-1">
<li class="contributor" id="contrib-1" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Isabelle+Durand-Zaleski&sortspec=date&submit=Submit">Isabelle Durand-Zaleski</a></span>,
</li>
<li class="contributor" id="contrib-2" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=B%C3%A9atrice+Roche&sortspec=date&submit=Submit">Béatrice Roche</a></span>,
</li>
<li class="contributor" id="contrib-3" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Pierre-Louis+Fagniez&sortspec=date&submit=Submit">Pierre-Louis Fagniez</a></span>,
</li>
<li class="contributor" id="contrib-4" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Jean-Paul+Le+Bourgeois&sortspec=date&submit=Submit">Jean-Paul Le Bourgeois</a></span> and
</li>
<li class="last" id="contrib-5"><span class="name"><a class="name-search"
href="/search?author1=Pascal+Piedbois&sortspec=date&submit=Submit">Pascal Piedbois</a></span></li>
</ol>
<ol class="affiliation-list">
<li class="aff"><a id="aff-1" name="aff-1"></a><address>Henri Mondor Hospital, <span class="addr-line">Paris, France</span></address>
</li>
</ol>
<ol class="corresp-list">
<li class="corresp" id="corresp-1"><em>Correspondence to:</em> Isabelle Durand-Zaleski, M.D., Ph.D., Santé Publique, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny,
94010 Créteil, France.
</li>
</ol>
</div>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-2">
<li class="contributor" id="contrib-6" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Marc+Buyse&sortspec=date&submit=Submit">Marc Buyse</a></span>,
</li>
<li class="contributor" id="contrib-7" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Robert+Carlson&sortspec=date&submit=Submit">Robert Carlson</a></span>,
</li>
<li class="contributor" id="contrib-8" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Michael+J.+O'Conell&sortspec=date&submit=Submit">Michael J. O'Conell</a></span> and
</li>
<li class="last" id="contrib-9"><span class="name"><a class="name-search"
href="/search?author1=Philippe+Rougier&sortspec=date&submit=Submit">Philippe Rougier</a></span></li>
</ol>
<ol class="affiliation-list">
<li class="aff"><a id="aff-2" name="aff-2"></a><address>International Institute for Drug Development, <span class="addr-line">Brussels, Belgium</span></address>
</li>
<li class="aff"><a id="aff-3" name="aff-3"></a><address>Stanford University, <span class="addr-line">Palo Alto, CA</span></address>
</li>
<li class="aff"><a id="aff-4" name="aff-4"></a><address>Mayo Clinic, <span class="addr-line">Rochester, MN</span></address>
</li>
<li class="aff"><a id="aff-5" name="aff-5"></a><address>Groupe d'Etudes et de Recherches des Tumeurs Hépatiques and Association Universitaire de Recherche en Chirurgie, <span class="addr-line">Paris</span></address>
</li>
</ol>
</div>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-3">
<li class="contributor" id="contrib-10" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Alfred+E.+Chang&sortspec=date&submit=Submit">Alfred E. Chang</a></span> and
</li>
<li class="last" id="contrib-11"><span class="name"><a class="name-search"
href="/search?author1=Vernon+K.+Sondak&sortspec=date&submit=Submit">Vernon K. Sondak</a></span></li>
</ol>
<ol class="affiliation-list">
<li class="aff"><a id="aff-6" name="aff-6"></a><address>University of Michigan Medical Center, <span class="addr-line">Ann Arbor</span></address>
</li>
</ol>
</div>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-4">
<li class="contributor" id="contrib-12" itemprop="author" itemscope="itemscope"
itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search"
href="/search?author1=Margaret+M.+Kemeny&sortspec=date&submit=Submit">Margaret M. Kemeny</a></span> and
</li>
<li class="last" id="contrib-13"><span class="name"><a class="name-search"
href="/search?author1=Tim+G.+Allen-Mersh&sortspec=date&submit=Submit">Tim G. Allen-Mersh</a></span></li>
</ol>
<ol class="affiliation-list">
<li class="aff"><a id="aff-7" name="aff-7"></a><address>North Shore University Hospital, <span class="addr-line">Manhasset, NY</span></address>
</li>
<li class="aff"><a id="aff-8" name="aff-8"></a><address>Chelsea and Westminster Hospital, <span class="addr-line">London, U.K</span></address>
</li>
</ol>
<ul class="history-list">
<li xmlns:hwp="http://schema.highwire.org/Journal" class="received"
hwp:start="1997-01-28"><span class="received-label">Received </span>January 28, 1997.
</li>
<li xmlns:hwp="http://schema.highwire.org/Journal" class="rev-recd"
hwp:start="1997-03-18"><span class="rev-recd-label">Revision received </span>March 18, 1997.
</li>
<li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted"
hwp:start="1997-03-28"><span class="accepted-label">Accepted </span>March 28, 1997.
</li>
</ul>
</div>
<div class="section abstract" id="abstract-1" itemprop="description">
<div class="section-nav">
<div class="nav-placeholder"> </div><a href="#sec-1" title="Subjects and Methods" class="next-section-link"><span>Next Section</span></a></div>
<h2>Abstract</h2>
<p id="p-5"><em>Background:</em> Approximately 20% of patients with colorectal cancer die of metastases confined to the liver. A metaanalysis recently performed
by our group confirmed that in these patients hepatic arterial infusion of 5-fluoro-2′- deoxyuridine, compared with intravenous
chemotherapy with fluoropyrimidines or supportive care (including symptom palliation when necessary), improved tumor response.
<em>Purpose:</em> Because of the high cost of hepatic arterial infusion, we undertook a cost-effectiveness analysis that related the cost of
such therapy to its medical efficacy. <em>Methods:</em> The patient population was drawn from the seven randomized clinical trials included in the meta-analysis and included individual
data on 654 patients. Of these seven trials, five compared hepatic arterial infusion and intravenous chemotherapy and two
compared hepatic arterial infusion and a control group in which some patients could be left untreated. Patients assigned to
receive hepatic arterial infusion made up the hepatic arterial infusion group; the other patients constituted the control
group. The measures of efficacy were survival and tumor response. Health-care costs (in 1995 U.S. dollars) were computed over
the duration of patient followup and were derived from actual costs in two centers, one at Henri Mondor Hospital (Paris, France)
and the other at Stanford University Medical Center (Palo Alto, CA). The total cost of treatment included the initial procedure,
chemotherapy cycles, and main complications. <em>Results:</em> The mean gain in life expectancy in the hepatic arterial infusion group compared with the control group was 3.2 months (standard
error = 1.0 month). For patients treated by hepatic arterial infusion in Paris, the hepatic arterial infusion pump, initial
hospitalization, and the entire process (including follow- up and complications) cost, on average, $8400, $15 172, and $29
562, respectively; in Palo Alto, these costs were $4700, $13 784, and $25 208, respectively. For patients in the control groups
in Paris and Palo Alto, the total treatment costs were, on average, $9926 and $5928. The additional costs of hepatic arterial
infusion over control treatment were $19 636 in Paris and $19 280 in Palo Alto. The costeffectiveness (i.e., the additional
cost divided by the additional benefit) with respect to survival of the patients in the hepatic arterial infusion group compared
with the patients in the control group was $73 635 per life-year in Paris and $72 300 per life-year in Palo Alto. <em>Conclusions and Implications:</em> The cost-effectiveness of localized chemotherapy for colorectal liver metastases is within the range of accepted treatments
for serious medical conditions, although it might be considered borderline by policy-makers in some countries. Prospective
clinical trials should be conducted to more definitively answer this question.
</p>
</div>
<p id="p-6">Economic analysis is an increasingly important component in the evaluation of new procedures for their ability to improve
medical outcomes for patients with diseases. The objective of economic analysis applied to innovative therapeutic procedures
is to relate their costs to the improvement produced in medical outcome. In a recently published meta-analysis (<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1"><em>1</em></a>), our group confirmed that, among patients with nonresectable liver metastases from colorectal cancer, hepatic arterial infusion
of 5-fluoro-2′-deoxyuridine, compared with intravenous chemotherapy with fluoropyrimidines, tripled the likelihood of tumor
response. The meta-analysis also showed a statistically significant advantage for hepatic arterial infusion over intravenous
chemotherapy in terms of survival when all trials were taken into account (<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2"><em>2</em></a>–<a id="xref-ref-8-1" class="xref-bibr" href="#ref-8"><em>8</em></a>) and a trend in favor of hepatic arterial infusion when survival analyses were restricted to trials comparing hepatic arterial
infusion with intravenous chemotherapy (<a id="xref-ref-2-2" class="xref-bibr" href="#ref-2"><em>2</em></a>–<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6"><em>6</em></a>).
</p>
<p id="p-7">Colorectal cancer is one of the most common cancers in developed countries and results in liver metastases in 30%-40% of affected
individuals (<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9"><em>9</em></a>). Approximately 20% of patients die of metastases confined to the liver. The medical effectiveness and the cost of chemotherapy
for patients with incurable liver metastases are important public health issues, but the high cost of hepatic arterial infusion
could become a disincentive to hospital administrators and third-party payors (<a id="xref-ref-10-1" class="xref-bibr" href="#ref-10"><em>10</em></a>). At a time when most developed countries face increasing constraints from their health-care budgets, high-cost procedures
affecting a large number of individuals are a primary concern to decision-makers.
</p>
<p id="p-8">As suggested by the editorial accompanying the publication of the meta-analysis on hepatic arterial infusion (<a id="xref-ref-10-2" class="xref-bibr" href="#ref-10"><em>10</em></a>), we undertook an economic analysis that relates the additional cost of hepatic arterial infusion over conventional treatments
to its additional medical benefits. Our objective was to determine the cost-effectiveness of treatments from the perspective
of a decision- maker involved in prospective health-care choices.
</p>
<div class="section" id="sec-1">
<div class="section-nav"><a href="#abstract-1" title="Abstract" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-7" title="Results" class="next-section-link"><span>Next Section</span></a></div>
<h2>Subjects and Methods</h2>
<div id="sec-2" class="subsection">
<h3>Patient Population and Clinical End Points</h3>
<p id="p-9">Individual patient data were retrieved for the meta-analysis by the Meta-Analysis Group In Cancer in 1996. All seven clinical
trials were included in the economic analysis. Five of these trials directly compared hepatic arterial infusion with intravenous
chemotherapy (<a id="xref-ref-2-3" class="xref-bibr" href="#ref-2"><em>2</em></a>–<a id="xref-ref-6-2" class="xref-bibr" href="#ref-6"><em>6</em></a>), and two compared hepatic arterial infusion with symptom palliation or ad libitum intravenous chemotherapy (in most cases,
with fluorouracil alone) (<a id="xref-ref-7-1" class="xref-bibr" href="#ref-7"><em>7</em></a>,<a id="xref-ref-8-2" class="xref-bibr" href="#ref-8"><em>8</em></a>). The total number of patients included in these trials was 654. We will hereafter refer to the group of patients assigned
to receive hepatic arterial infusion as the HAI group and to the group of patients who received either symptom palliation
or intravenous chemotherapy as the control group.
</p>
<p id="p-10">The clinical end points were survival and tumor response, both of which provided estimates of effectiveness in the cost-effectiveness
analysis. All analyses of the end points were made following the intention-to-treat principle. The cost-effectiveness analysis
considered the additional costs of obtaining a longer survival or a higher tumor response rate through the use of hepatic
arterial infusion. One trial (<a id="xref-ref-2-4" class="xref-bibr" href="#ref-2"><em>2</em></a>) was included in the tumor response analysis but not in the survival analysis, since individual patient data were not available
in this trial. The life expectancy was estimated by the mean survival obtained from the Kaplan-Meier curve, which is equal
to the area under the survival curves (<a id="xref-fig-1-1" class="xref-fig" href="#F1">Fig. 1</a>). Gains in life expectancy were discounted at a 5% yearly rate. The gain in life expectancy in the HAI group compared with
the control group was estimated by the difference in mean survival (<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11"><em>11</em></a>). Computations were made by use of the SAS statistical software package (SAS Institute, Inc., Cary, NC).
</p>
<div id="F1" class="fig pos-anchor odd">
<div class="fig-inline"><img alt="Fig. 1." src="790/F1.medium.gif" /></div>
<div class="fig-caption"><span class="fig-label"><strong>Fig. 1.</strong></span>
<p id="p-11" class="first-child">Overall survival curves among patients treated with hepatic arterial infusion (HAI) compared with control patients. Survival
time was discounted at a 5% yearly rate. <em>P</em> value is two-sided.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
</div>
<div id="sec-3" class="subsection">
<h3>Economic Analysis</h3>
<p id="p-12">We computed costs on an intention-to-treat basis rather than on the basis of actual treatment for the following reasons: 1)
to ensure consistency between computations of costs and outcome and 2) to provide decision-makers with planning and budgetary
tools that would allow prospective estimations of the cost of alternative therapeutic strategies (<a id="xref-ref-11-2" class="xref-bibr" href="#ref-11"><em>11</em></a>–<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13"><em>13</em></a>). The valuation method used health-care (hospital and ambulatory) costs standardized in one European center (Henri Mondor
Hospital, Paris, France) and one U.S. center (Stanford University Medical Center, Palo Alto, CA). Thus, health-care costs
were obtained from the accounting records of patients recently or currently treated at one of the two sites and are not based
on the actual costs of treating the patients in the trials. This method of indirect standardization allowed us to compute
the costs of a therapeutic strategy undertaken in different medical centers and has been applied to multicenter trials as
well as to meta-analyses (<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14"><em>14</em></a>–<a id="xref-ref-16-1" class="xref-bibr" href="#ref-16"><em>16</em></a>).
</p>
</div>
<div id="sec-4" class="subsection">
<h3>Type of Analysis</h3>
<p id="p-13">We computed a cost per year of added survival. The additional cost of hepatic arterial infusion over control treatment was
divided by the additional medical benefit. Let <em>C1</em> and <em>C2</em> be the respective costs of control treatment and hepatic arterial infusion treatment, whose medical outcomes are <em>R1</em> and <em>R2</em>, respectively; the cost-effectiveness ratio of hepatic arterial infusion was defined as (C2 − C1)/(R2 − R1), where <em>C1</em> and <em>C2</em> are expressed in monetary terms and <em>R1</em> and <em>R2</em> in unidimensional medical units. The issue of quality of life was not addressed, since no data were available on this end
point (<a id="xref-ref-11-3" class="xref-bibr" href="#ref-11"><em>11</em></a>,<a id="xref-ref-17-1" class="xref-bibr" href="#ref-17"><em>17</em></a>).
</p>
</div>
<div id="sec-5" class="subsection">
<h3>Cost Computations</h3>
<p id="p-14">Costs were computed over the duration of patient follow-up. The perspective of the health-care system was used in all cost
estimates. Costs to society were not included because individual data on work status were not available (<a id="xref-ref-11-4" class="xref-bibr" href="#ref-11"><em>11</em></a>–<a id="xref-ref-13-2" class="xref-bibr" href="#ref-13"><em>13</em></a>).
</p>
<p id="p-15">Direct medical costs included the following: 1) cost of purchasing the devices (nonreusable implanted arterial pump and systemic
port) and cost of the procedures and of hospitalizations; 2) cost of ambulatory treatment facilities (Paris) or outpatient
clinic without hospitalization (Palo Alto) for administering chemotherapy; 3) cost of chemotherapy drugs, computed from data
on the number of chemotherapy cycles per patient in the trials; 4) costs of follow-up tests— angioscintigraphy in the HAI
group (three in Paris and one in Palo Alto), an abdominal computed tomography scan every 3rd month, chest x ray, liver function
tests, and blood cell counts every month; and 5) cost of treatment for therapy-related severe toxic effects (i.e., complications).
Overhead costs included administrative and support services and capital costs. Protocol-driven costs were excluded. No costs
were attached to patients assigned to the symptom palliation groups (<a id="xref-ref-7-2" class="xref-bibr" href="#ref-7"><em>7</em></a>,<a id="xref-ref-8-3" class="xref-bibr" href="#ref-8"><em>8</em></a>), assuming that the costs of symptom palliation were the same for all patients in the trials, regardless of their randomized
treatment group.
</p>
<p id="p-16">Values of hospital resources were drawn from two cost-accounting systems, one in Palo Alto by use of a computer software package
from TSI 2-Transition Systems Inc. (Boston, MA) and the other in Paris by use of the hospitalaccounting charts. These costs
were retrieved by one of us (I. Durand-Zaleski), who visited both sites. They were actual costs (not charges) in the oncology,
surgery, and outpatient clinic departments.
</p>
<p id="p-17">Hospital costs of treatments included medical and nonmedical salaries, secretarial and housekeeping expenses, office supplies,
medical tests, drugs, blood products, and medical supplies. Drug costs were taken from the pharmacy formulary; delivery costs
were included either in the drug costs (Palo Alto) or in the overhead costs (Paris). The costs of supplies were the purchase
prices from the manufacturer. Overhead costs represented 25% of total costs in Paris and were computed as a separate line
item, whereas they were included in the cost of each item in Palo Alto.
</p>
<p id="p-18">The toxic effects of treatment were considered for the purpose of this study, insofar as they generated costs for the health-care
system. The frequency of these toxic effects was estimated from the published trials included in the metaanalysis (2-8). The
cost of treatment for toxic effects was estimated by multiplying the unit cost for treatment of each toxic effect by the frequency
of its occurrence (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Table 1</a>). Data on practice patterns for the management of toxic effects related to treatment and hospital costs were derived from
the hospitalaccounting systems.
</p>
<div id="F2" class="fig pos-anchor even">
<div class="fig-inline"><img alt="Figure" src="790/F2.medium.gif" /></div>
</div>
<p id="p-19">The reference year for cost computations was 1995. All costs were converted to 1995 U.S. dollars. Costs were discounted at
a 5% yearly rate.
</p>
</div>
<div id="sec-6" class="subsection">
<h3>Sensitivity Analysis</h3>
<p id="p-20"><strong>Alternative comparator.</strong> The reference strategy used to compute the additional cost of hepatic arterial infusion in the baseline analysis was a combination
of intravenous chemotherapy and ad libitum symptom palliation, as was found in the control groups considered in the meta-analysis.
A relevant therapeutic option is intravenous chemotherapy, which is preferred to symptom palliation in some countries. We
performed a sensitivity analysis of the cost-effectiveness ratios, assuming that the only comparator for hepatic arterial
infusion was intravenous chemotherapy and excluding from the analysis patients who received only symptom palliation. The trials
kept for this analysis were the five trials that directly compared hepatic arterial infusion with intravenous chemotherapy
(<a id="xref-ref-2-5" class="xref-bibr" href="#ref-2"><em>2</em></a>–<a id="xref-ref-6-3" class="xref-bibr" href="#ref-6"><em>6</em></a>) and included 391 patients. The medical outcomes were survival and tumor response, as evaluated in the meta-analysis for
the five trials considered (<a id="xref-ref-1-2" class="xref-bibr" href="#ref-1"><em>1</em></a>).
</p>
</div>
</div>
<div class="section" id="sec-7">
<div class="section-nav"><a href="#sec-1" title="Subjects and Methods" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-12" title="Discussion" class="next-section-link"><span>Next Section</span></a></div>
<h2>Results</h2>
<div id="sec-8" class="subsection">
<h3>Medical Outcomes</h3>
<p id="p-21">The results of the meta-analysis were published previously (<a id="xref-ref-1-3" class="xref-bibr" href="#ref-1"><em>1</em></a>). Mean survival time (discounted) was 16.3 months (standard error = 0.7 month) for patients assigned to receive hepatic arterial
infusion compared with 13.1 months (standard error = 0.7 month) for control patients. The mean gain in life expectancy in
the HAI group was 3.2 months (standard error = 1.0 month).
</p>
</div>
<div id="sec-9" class="subsection">
<h3>Medical Costs</h3>
<p id="p-22">Costs for the hepatic arterial infusion strategy were as follows: In France, the purchase price and cost of insertion of an
arterial pump and the cost of an 11-day hospital stay were $23 572, and the total cost of the hepatic arterial infusion treatment
was $29 562 (which included the costs of chemotherapy as well as follow-up and treatment for toxic effects related to therapy).
In Palo Alto, the pump was inserted in the course of a 7-day hospitalization, the total cost of the pump and the procedure
was $18 484, and the total cost of hepatic arterial infusion was $25 208.
</p>
<p id="p-23">In Paris, costs for control patients (intravenous chemotherapy or symptom palliation) were $629 for the initial procedure
(insertion of a systemic port or simple intravenous chemotherapy), and the total cost was $9926 (including the cost of chemotherapy
with hospitalization and tests). In Palo Alto, initial procedure costs for the control group were $512, and the total cost
was $5928. Patients did not require hospitalization for administering chemotherapy.
</p>
<p id="p-24">Costs of treatment of toxic effects per episode are presented in <a id="xref-fig-3-1" class="xref-fig" href="#F3">Table 2</a>. The cost of toxicity multiplied by the probability of its occurrence (<a id="xref-fig-2-2" class="xref-fig" href="#F2">Table 1</a>) was added to the cost of the corresponding strategy.
</p>
<p id="p-25">Detailed computations of the above costs are presented in <a id="xref-fig-4-1" class="xref-fig" href="#F4">Table 3</a>.
</p>
</div>
<div id="sec-10" class="subsection">
<h3>Cost-effectiveness</h3>
<p id="p-26">The cost-effectiveness of hepatic arterial infusion compared with control treatment is the additional cost divided by the
additional medical benefit. The cost-effectiveness ratios in Paris and in Palo Alto were, respectively, $73 635 and $72 300
per year of added survival. Cost-effectiveness ratios within the 95% confidence interval for survival are presented in <a id="xref-fig-5-1" class="xref-fig" href="#F5">Fig. 2</a>. The length of the <em>x</em> axis on <a id="xref-fig-5-2" class="xref-fig" href="#F5">Fig. 2</a> represents the full range of the 95% confidence interval for the survival advantage of hepatic arterial infusion over intravenous
chemotherapy or symptom palliation.
</p>
</div>
<div id="sec-11" class="subsection">
<h3>Sensitivity Analysis</h3>
<p id="p-27"><strong>Alternative comparator</strong>. We computed tumor response and survival in a subset of 391 patients included in the five trials comparing hepatic arterial
infusion with intravenous chemotherapy; we assumed that the reference strategy for hepatic arterial infusion chemotherapy
was intravenous chemotherapy, and we excluded from the comparison patients who were treated for symptom palliation only. The
gain in tumor response rate for the HAI group was 27% (standard error = 4%). The average gain in life expectancy for the HAI
group was 2.1 months (standard error = 1.8 months). Because these results were computed on the basis of intention to treat,
they did not take into account the fact that about 20% of the patients crossed over from intravenous chemotherapy to hepatic
arterial infusion.
</p>
<p id="p-28">The costs of the hepatic arterial infusion strategy were the same as above. In France, the costs of the intravenous chemotherapy
strategy were $1047 for the insertion of a systemic port and $16 722 in total; in the United States, these costs were $854
and $10 031, respectively.
</p>
<p id="p-29">Detailed computations of the costs used in the sensitivity analysis are presented in <a id="xref-fig-6-1" class="xref-fig" href="#F6">Table 4</a>.
</p>
<p id="p-30">When total cumulated survival was the outcome considered, the denominator of the cost-effectiveness ratio was 2.1 months,
and the cost-effectiveness ratios were $73 680 and $87 012 per year of added survival in Paris and Palo Alto, respectively.
When tumor response was the intermediate outcome considered, the denominator of the cost-effectiveness ratio was the difference
in response rate (27%), and the cost-effectiveness ratios were $47 231 and $55 776 per tumor response achieved in Paris and
in Palo Alto, respectively.
</p>
<div id="F3" class="fig pos-anchor odd">
<div class="fig-inline"><img alt="Figure" src="790/F3.medium.gif" /></div>
</div>
<div id="F4" class="fig pos-anchor even">
<div class="fig-inline"><img alt="Figure" src="790/F4.medium.gif" /></div>
</div>
<p id="p-31"><strong>Discount rate</strong>. When costs and survival were not discounted, the total costs for hepatic arterial infusion and for control treatment (symptom
palliation or intravenous chemotherapy) were, respectively, $29 582 and $9936 in Paris and $25 229 and $4920 in Palo Alto.
The undiscounted mean survivals for patients in the HAI group and for patients in the control group were 18.4 months (standard
error = 0.9 month) and 14.7 months (standard error = 0.9 month), respectively, and the mean gain in life expectancy was 3.7
months (standard error = 1.3 months) for patients in the HAI group compared with patients in the control group. The cost-effectiveness
ratios of hepatic arterial infusion compared with control treatment were $63 717 in Paris and $65 867 in Palo Alto per year
of added survival.
</p>
<div id="F5" class="fig pos-anchor odd">
<div class="fig-inline"><img alt="Fig. 2." src="790/F5.medium.gif" /></div>
<div class="fig-caption"><span class="fig-label"><strong>Fig. 2.</strong></span>
<p id="p-32" class="first-child">Cost-effectiveness ratios for hepatic arterial infusion (HAI) versus control treatment (intravenous chemotherapy or symptom
palliation). The horizontal axis represents the expected gain in life expectancy obtained by HAI treatment versus control
treatment. The vertical axis is the cost-effectiveness ratio in 1995 U.S. dollars per life-year.
</p>
<div class="sb-div caption-clear"></div>
</div>
</div>
</div>
</div>
<div class="section" id="sec-12">
<div class="section-nav"><a href="#sec-7" title="Results" class="prev-section-link"><span>Previous Section</span></a><a href="#fn-group-1" title="Footnotes" class="next-section-link"><span>Next Section</span></a></div>
<h2>Discussion</h2>
<p id="p-33">Colon cancer with unresectable liver metastases represents a major public health problem because of its frequency and the
cost of its treatment. The objective of economic analysis is to provide relevant information for health-care decision-makers
in charge of allocating resources (<a id="xref-ref-17-2" class="xref-bibr" href="#ref-17"><em>17</em></a>,<a id="xref-ref-18-1" class="xref-bibr" href="#ref-18"><em>18</em></a>). In the present costeffectiveness analysis applied to the results of a meta-analysis of cancer liver metastasis treatments,
the outcomes and the costs of hepatic arterial infusion versus intravenous chemotherapy or supportive care were compared.
The additional medical cost of hepatic arterial infusion over systemic intravenous chemotherapy or symptom palliation was
approximately $70 000 per year of added survival.
</p>
<p id="p-34">This meta-analysis and economic evaluation suggest that the cost-effectiveness of hepatic arterial infusion for treatment
of colorectal liver metastases is within the range of accepted treatments for other severe medical conditions. In a 1993 survey
by the French Ministry of Health, the costs of hemodialysis were estimated to be $70 000-$90 000 per year. The costs found
for hepatic arterial infusion were higher than the costs of the treatment of advanced colon cancer found between 1990 and
1991 (<a id="xref-ref-19-1" class="xref-bibr" href="#ref-19"><em>19</em></a>) for patients enrolled in a staff-model Health Maintenance Organization, but they were comparable for intravenous chemotherapy.
The cost per life-year of detecting and treating cancers has been estimated to vary between $20 000 and $120 000 (<a id="xref-ref-20-1" class="xref-bibr" href="#ref-20"><em>20</em></a>–<a id="xref-ref-24-1" class="xref-bibr" href="#ref-24"><em>24</em></a>).
</p>
<div id="F6" class="fig pos-anchor even">
<div class="fig-inline"><img alt="Figure" src="790/F6.medium.gif" /></div>
</div>
<p id="p-35">Laupacis et al. (<a id="xref-ref-25-1" class="xref-bibr" href="#ref-25"><em>25</em></a>) proposed a classification of technologies according to their cost-utility ratios. The cost-effectiveness ratio of hepatic
arterial infusion versus intravenous chemotherapy or symptom palliation falls within the group of strategies for which society
has to spend more than $100 000 per quality-adjusted life-year, which represented the least cost-effective category in their
classification.
</p>
<p id="p-36">The costs of infusing chemotherapy in the hepatic artery could possibly be reduced by use of a port-a-cath (a permanent catheter
that can be connected to an external pump as necessary for delivery of chemotherapeutic agents) implanted in the artery by
a procedure involving radiologic monitoring and no surgery. This approach, currently under trial in Japan and Italy, could
reduce the costs by suppressing the need for surgery as well as the need for the purchase of an expensive piece of equipment
(<a id="xref-ref-26-1" class="xref-bibr" href="#ref-26"><em>26</em></a>).
</p>
<p id="p-37">We did not consider the overall burden of the disease to society. Costs to society would include lost labor, compensations,
and other expenditures incurred by the patient or the family in the course of the disease. Data from other trials (<a id="xref-ref-8-4" class="xref-bibr" href="#ref-8"><em>8</em></a>) indicate that lost labor is higher for patients who received hepatic arterial infusion than for patients who received intravenous
chemotherapy or symptom palliation, in part because the former patients live longer without resuming work. We did not include
data on reimbursement and financial incentives; information on patient health-care insurance is relevant to the flow of money
into the medical centers, but not to the outflow (costs). Data on quality of life were not available from the trials. However,
if tumor response could be considered as a surrogate marker for quality of life in symptomatic patients, the hepatic arterial
infusion strategy would appear to be more attractive.
</p>
<p id="p-38">Costs were computed from the perspective of the health-care systems in France and in the United States, meaning that only
costs to the health-care system were included and other costs, such as societal costs, were excluded. Health-care spending
in France is comparable to that in most industrialized countries, except the United States, where spending on hospital care
is, in real terms, about two times higher (<a id="xref-ref-27-1" class="xref-bibr" href="#ref-27"><em>27</em></a>). The relatively low costs of hepatic arterial infusion found in Palo Alto compared with the costs in Paris result from a
lower price paid in the United States for the infusion device and from an efficient U.S. policy of reducing the length of
hospital stay for these patients and delivering chemotherapy in outpatient clinics.
</p>
<p id="p-39">Applying economic evaluation to the results of a metaanalysis involves some degree of modeling—first because few trials have
collected data on resource use and second because unit values of resources used have to be standardized. Using medical records
from the Henri Mondor Hospital (Paris) and from Stanford University Medical Center (Palo Alto), we modeled the medical management
of patients with complications. While practice patterns may differ from one institution to another, the overall burden of
complications represented a small percentage of the total cost and, therefore, may not have affected the results much. For
a similar reason, the uncertainty about the exact prevalence of complications in the two treatment groups cannot alter our
general conclusions.
</p>
<p id="p-40">Sensitivity analysis provides a range of possible costeffectiveness ratios. The calculations of <a id="xref-fig-6-2" class="xref-fig" href="#F6">Table 4</a> and the curves of <a id="xref-fig-5-3" class="xref-fig" href="#F5">Fig. 2</a> allow medical teams to estimate cost-effectiveness ratios from cost data at their own institutions and to decide whether
they consider additional costs to be justified in view of the expected clinical benefits. When the comparator chosen for hepatic
arterial infusion is intravenous chemotherapy, the absence of a significant difference between both strategies (<a id="xref-ref-1-4" class="xref-bibr" href="#ref-1"><em>1</em></a>) makes it impossible to statistically rule out an infinite costeffectiveness ratio. If there were no true survival benefit
to hepatic arterial infusion compared with intravenous chemotherapy, this more costly procedure would clearly not be justified
on economic grounds. This observation justifies the use of a metaanalysis to estimate clinical benefits with sufficient precision
in pharmaco-economic assessments. It is now well known that patients with advanced colorectal cancer, even in the absence
of symptoms related to metastases, benefit from immediate intravenous chemotherapy. Immediate intravenous chemotherapy increases
symptom-free survival and overall survival (<a id="xref-ref-28-1" class="xref-bibr" href="#ref-28"><em>28</em></a>,<a id="xref-ref-29-1" class="xref-bibr" href="#ref-29"><em>29</em></a>). The cost-effectiveness ratio of hepatic arterial infusion compared strictly with intravenous chemotherapy is less favorable,
because the additional medical benefit of hepatic arterial infusion over intravenous chemotherapy is less than over symptom
palliation only.
</p>
<p id="p-41">As far as the cost-effectiveness analyses are concerned, a few methodologic comments must be added. First, we used the intention-
to-treat principle throughout. As a result, patients who were randomly assigned to receive, but did not receive, hepatic arterial
infusion have been kept in this group for the estimation of both clinical benefits and costs. Likewise, we made no allowance
in our cost estimates for patients who received hepatic arterial infusion after intravenous chemotherapy had failed, although
crossover occurred for at least 20% of the patients in the trials (<a id="xref-ref-1-5" class="xref-bibr" href="#ref-1"><em>1</em></a>). This approach is voluntarily conservative and tends to increase the cost-effectiveness ratio of hepatic arterial infusion,
since it underestimates the true benefit of hepatic arterial infusion and underestimates the true cost of intravenous chemotherapy.
</p>
<p id="p-42">The intravenous chemotherapy group of trials considered in the meta-analysis consisted of fluorouracil or 5-fluoro-2′- deoxyuridine
alone. Such therapy may no longer be considered standard practice in the treatment of advanced colorectal cancer. In three
previously performed meta-analyses, we showed that the modulation of intravenous fluorouracil by leucovorin or by methotrexate
(<a id="xref-ref-30-1" class="xref-bibr" href="#ref-30"><em>30</em></a>,<a id="xref-ref-31-1" class="xref-bibr" href="#ref-31"><em>31</em></a>) or the administration of fluorouracil by continuous infusion (Meta-Analysis Group In Cancer: unpublished data) resulted
in a doubling of the tumor response rates in patients with advanced colorectal cancer.
</p>
<p id="p-43">However, these meta-analyses have also shown that the impact on survival of the modulation of fluorouracil or the administration
of fluorouracil as a continuous infusion was very small. Since our baseline analysis used survival as the principal outcome,
we do not think that the interpretation of the results of our study is invalidated by the development of these new modalities
of administration of fluorouracil.
</p>
<p id="p-44">Prospective trials should ensure that information on both medical costs and overall financial costs to society be collected.
Other outcomes of interest that should be recorded prospectively include possible return to work of patients treated and their
quality of life.
</p>
</div>
<div class="section fn-group" id="fn-group-1">
<div class="section-nav"><a href="#sec-12" title="Discussion" class="prev-section-link"><span>Previous Section</span></a><a href="#ref-list-1" title="References" class="next-section-link"><span>Next Section</span></a></div>
<h2>Footnotes</h2>
<ul>
<li class="fn-supported-by" id="fn-1">
<p id="p-1">Supported in part by the Association pour la Recherche contre le Cancer (France).</p>
<p id="p-2"><strong>Collaborators of the Hepatic Arterial Infusion Meta-Analysis Project:</strong> P. Rougier, A. Laplanche, M. Huguier, and J. M. Hay (Groupe d'Etudes et de Recherches des Tumeurs Hépatiques and Association
Universitaire de Recherche en Chirurgie, Paris, France); R. Carlson, W. Brown, D. Hohn, and A. E. Venook (Northern California
Oncology Group, San Francisco, CA); T. G. Allen-Mersh and S. Earlam (Chelsea and Westminster Hospital, London, U.K.); N. E.
Kemeny and M. Mazumdar (Memorial Sloan-Kettering Cancer Center, New York, NY); M. J. O'Connell, S. Wieand, and K. Martin (Mayo
Clinic, Rochester, MN); A. E. Chang and V. K. Sondak (University of Michigan Medical Center, Ann Arbor); M. M. Kemeny (North
Shore University Hospital, Manhasset, NY); P. Piedbois, I. Durand-Zaleski, J.-P. Le Bourgeois, and Y. Piedbois (data management),
E. Levy and B. Roche (Henri Mondor Hospital, Paris); M. Buyse (International Institute for Drug Development, Brussels, Belgium).
</p>
<p id="p-3"><strong>Board of the Meta-Analysis Group In Cancer:</strong> N. Wolmark (Allegheny Hospital, Pittsburgh, PA); P. Piedbois (Henri Mondor Hospital, Paris); M. Buyse (International Institute
for Drug Development, Brussels); R. Carlson (Stanford University, CA); Y. Rustum (Roswell Park Cancer Institute, Buffalo,
NY); C. E. Erlichman (Mayo Clinic).
</p>
<p id="p-4">We are indebted to Dr. P.-P. Sagnier (Bayer AG, Wuppertal, Germany) and Dr. B. Hillner (Medical College of Virginia, Richmond)
for their helpful comments on the manuscript. We also thank Mr. B. Sullivan (Business Manager, Stanford Health Services, CA)
for his help in retrieving cost data.
</p>
</li>
</ul>
</div>
<ul class="copyright-statement">
<li class="fn" id="copyright-statement-1">© Oxford University Press</li>
</ul>
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</div>
<h2>References</h2>
<ol class="cit-list ref-use-labels">
<li><span class="ref-label">(1)</span><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference (1) in text"
id="ref-1">↵</a>
<div class="cit ref-cit ref-journal" id="cit-89.11.790.1"
data-doi="10.1093/jnci/88.5.252">
<div class="cit-metadata"><cite><span class="cit-auth cit-collab">Meta-Analysis Group In Cancer</span>. <span class="cit-article-title">Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer</span>. <abbr class="cit-jnl-abbrev">J Natl Cancer Inst</abbr> <span class="cit-pub-date">1996</span>;<span class="cit-vol">88</span>:<span class="cit-fpage">252</span>-<span class="cit-lpage">8</span>.</cite></div>
<div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=jnci&resid=88/5/252"
class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></a></div>
</div>
</li>
<li><span class="ref-label">(2)</span><a class="rev-xref-ref" href="#xref-ref-2-1" title="View reference (2) in text"
id="ref-2">↵</a>
<div class="cit ref-cit ref-journal" id="cit-89.11.790.2">
<div class="cit-metadata">
<ol class="cit-auth-list">
<li><span class="cit-auth"><span class="cit-name-surname">Chang</span> <span class="cit-name-given-names">AE</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Schneider</span> <span class="cit-name-given-names">PD</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Sugarbaker</span> <span class="cit-name-given-names">PH</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Simpson</span> <span class="cit-name-given-names">C</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Culane</span> <span class="cit-name-given-names">M</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Steinberg</span> <span class="cit-name-given-names">SM</span></span></li>
</ol><cite>. <span class="cit-article-title">A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of
colorectal liver metastases</span>. <abbr class="cit-jnl-abbrev">Ann Surg</abbr> <span class="cit-pub-date">1987</span>;<span class="cit-vol">206</span>:<span class="cit-fpage">685</span>-<span class="cit-lpage">93</span>.</cite></div>
<div class="cit-extra"><a href="/external-ref?access_num=2961314&link_type=MED"
class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=A1987L074700001&link_type=ISI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank"
href="http://scholar.google.com/scholar_lookup?title=A%20prospective%20randomized%20trial%20of%20regional%20versus%20systemic%20continuous%205-fluorodeoxyuridine%20chemotherapy%20in%20the%20treatment%20of%20colorectal%20liver%20metastases&author=AE%20Chang&author=PD%20Schneider&author=PH%20Sugarbaker&author=C%20Simpson&author=M%20Culane&author=SM%20Steinberg&publication_year=1987&journal=Ann%20Surg&volume=206&pages=685-93">Google Scholar</a></div>
</div>
</li>
<li><span class="ref-label">(3)</span>
<div class="cit ref-cit ref-journal no-rev-xref" id="cit-89.11.790.3">
<div class="cit-metadata">
<ol class="cit-auth-list">
<li><span class="cit-auth"><span class="cit-name-surname">Hohn</span> <span class="cit-name-given-names">DC</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Stagg</span> <span class="cit-name-given-names">RJ</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Friedman</span> <span class="cit-name-given-names">MA</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Hannigan</span> <span class="cit-name-given-names">JF</span> <span class="cit-name-suffix">Jr</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Rayner</span> <span class="cit-name-given-names">A</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Ignoffo</span> <span class="cit-name-given-names">RJ</span></span>,
</li>
<li><span class="cit-etal">et al</span></li>
</ol><cite>. <span class="cit-article-title">A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic
to the liver: the Northern California Oncology Group trial</span>. <abbr class="cit-jnl-abbrev">J Clin Oncol</abbr> <span class="cit-pub-date">1989</span>;<span class="cit-vol">7</span>:<span class="cit-fpage">1646</span>-<span class="cit-lpage">54</span>.</cite></div>
<div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=jco&resid=7/11/1646"
class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-abstract">Abstract</span></a></div>
</div>
</li>
<li><span class="ref-label">(4)</span>
<div class="cit ref-cit ref-journal no-rev-xref" id="cit-89.11.790.4"
data-doi="10.1002/1097-0142(19860201)57:3<492::AID-CNCR2820570315>3.0.CO;2-M">
<div class="cit-metadata">
<ol class="cit-auth-list">
<li><span class="cit-auth"><span class="cit-name-surname">Kemeny</span> <span class="cit-name-given-names">MM</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Goldberg</span> <span class="cit-name-given-names">D</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Beatty</span> <span class="cit-name-given-names">JD</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Blayney</span> <span class="cit-name-given-names">D</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Browning</span> <span class="cit-name-given-names">S</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Doroshow</span> <span class="cit-name-given-names">J</span></span>,
</li>
<li><span class="cit-etal">et al</span></li>
</ol><cite>. <span class="cit-article-title">Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic
metastases from colorectal primaries</span>. <abbr class="cit-jnl-abbrev">Cancer</abbr> <span class="cit-pub-date">1986</span>;<span class="cit-vol">57</span>:<span class="cit-fpage">492</span>-<span class="cit-lpage">8</span>.</cite></div>
<div class="cit-extra"><a href="/external-ref?access_num=10.1002/1097-0142(19860201)57:3%3C492::AID-CNCR2820570315%3E3.0.CO;2-M&link_type=DOI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=2935243&link_type=MED"
class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a target="_blank"
href="http://scholar.google.com/scholar_lookup?title=Results%20of%20a%20prospective%20randomized%20trial%20of%20continuous%20regional%20chemotherapy%20and%20hepatic%20resection%20as%20treatment%20of%20hepatic%20metastases%20from%20colorectal%20primaries&author=MM%20Kemeny&author=D%20Goldberg&author=JD%20Beatty&author=D%20Blayney&author=S%20Browning&author=J%20Doroshow&publication_year=1986&journal=Cancer&volume=57&pages=492-8">Google Scholar</a></div>
</div>
</li>
<li><span class="ref-label">(5)</span>
<div class="cit ref-cit ref-journal no-rev-xref" id="cit-89.11.790.5"
data-doi="10.7326/0003-4819-107-4-459">
<div class="cit-metadata">
<ol class="cit-auth-list">
<li><span class="cit-auth"><span class="cit-name-surname">Kemeny</span> <span class="cit-name-given-names">N</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Daly</span> <span class="cit-name-given-names">J</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Reichman</span> <span class="cit-name-given-names">B</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Geller</span> <span class="cit-name-given-names">N</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Botet</span> <span class="cit-name-given-names">J</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Oderman</span> <span class="cit-name-given-names">P</span></span></li>
</ol><cite>. <span class="cit-article-title">Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized
trial</span>. <abbr class="cit-jnl-abbrev">Ann Intern Med</abbr> <span class="cit-pub-date">1987</span>;<span class="cit-vol">107</span>:<span class="cit-fpage">459</span>-<span class="cit-lpage">65</span>.</cite></div>
<div class="cit-extra"><a href="/external-ref?access_num=10.7326/0003-4819-107-4-459&link_type=DOI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=2957943&link_type=MED"
class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=A1987K293000004&link_type=ISI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank"
href="http://scholar.google.com/scholar_lookup?title=Intrahepatic%20or%20systemic%20infusion%20of%20fluorodeoxyuridine%20in%20patients%20with%20liver%20metastases%20from%20colorectal%20carcinoma.%20A%20randomized%20trial&author=N%20Kemeny&author=J%20Daly&author=B%20Reichman&author=N%20Geller&author=J%20Botet&author=P%20Oderman&publication_year=1987&journal=Ann%20Intern%20Med&volume=107&pages=459-65">Google Scholar</a></div>
</div>
</li>
<li><span class="ref-label">(6)</span><a class="rev-xref-ref" href="#xref-ref-6-1" title="View reference (6) in text"
id="ref-6">↵</a>
<div class="cit ref-cit ref-journal" id="cit-89.11.790.6"
data-doi="10.1001/archsurg.1990.01410200086013">
<div class="cit-metadata">
<ol class="cit-auth-list">
<li><span class="cit-auth"><span class="cit-name-surname">Martin</span> <span class="cit-name-given-names">JK</span> <span class="cit-name-suffix">Jr</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">O#x0027;Connell</span> <span class="cit-name-given-names">MJ</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Wieand</span> <span class="cit-name-given-names">HS</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Fitzgibbons</span> <span class="cit-name-given-names">RJ</span> <span class="cit-name-suffix">Jr</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Mailliard</span> <span class="cit-name-given-names">JA</span></span>,
</li>
<li><span class="cit-auth"><span class="cit-name-surname">Rubin</span> <span class="cit-name-given-names">J</span></span>,
</li>
<li><span class="cit-etal">et al</span></li>
</ol><cite>. <span class="cit-article-title">Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial</span>. <abbr class="cit-jnl-abbrev">Arch Surg</abbr> <span class="cit-pub-date">1990</span>;<span class="cit-vol">125</span>:<span class="cit-fpage">1022</span>-<span class="cit-lpage">7</span>.</cite></div>
<div class="cit-extra"><a href="/external-ref?access_num=10.1001/archsurg.1990.01410200086013&link_type=DOI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=2143063&link_type=MED"
class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=A1990DT47600012&link_type=ISI"
class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank"
href="http://scholar.google.com/scholar_lookup?title=Intra-arterial%20floxuridine%20vs%20systemic%20fluorouracil%20for%20hepatic%20metastases%20from%20colorectal%20cancer.%20A%20randomized%20trial&author=JK%20Martin&author=MJ%20O%23x0027%3BConnell&author=HS%20Wieand&author=RJ%20Fitzgibbons&author=JA%20Mailliard&author=J%20Rubin&publication_year=1990&journal=Arch%20Surg&volume=125&pages=1022-7">Google Scholar</a></div>
</div>