Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 20, 2003; DOI: 10.1124/jpet.103.049379
0022-3565/03/3053-1098-1103$20.00
JPET 305:1098-1103, 2003
GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Melphalan Antitumor Efficacy and Hepatotoxicity: The Effect of Variable Infusion Duration in the Hepatic Artery
Joost Rothbarth,
Ruud A. Woutersen,
Rolf W. Sparidans,
Cornelis J. H. van de Velde, and
Gerard J. Mulder
Department of Surgery, Leiden University Medical Center, Leiden (J.R., C.J.H.V.); Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden (J.R., G.J.M.); Department of General Toxicology, TNO Nutrition and Food Research, Zeist (R.A.W.); and Faculty of Pharmaceutical Sciences, Utrecht University, the Netherlands (R.W.S.)
Received for publication
January 21, 2003
Accepted
February 14, 2003.
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Abstract
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The optimum conditions (duration and concentration) of a fixed dose,
intra-arterial melphalan infusion in relation to its antitumor effect and
toxicity in the liver were investigated in a rat colon tumor model (CC531) of
liver metastases. We studied the difference in tumor and liver uptake, as well
as antitumor effect and hepatotoxicity after 5- and 20-min hepatic arterial
infusion (HAI) of a fixed melphalan dose. Melphalan content in perfusate,
liver, and tumor tissue was analyzed by high-performance liquid
chromatography. The antitumor effect and hepatotoxicity in rats treated either
systemically or with 5- and 20-min HAI, with a fixed dose melphalan (4.4
µmol), were assessed 2 weeks after treatment. No difference in melphalan
content of tumor/liver tissue or antitumor effect was observed between rats
treated with 5- and 20-min HAI. Hepatotoxicity was strongly affected by
perfusion duration/concentration, however. Rats treated with 5-min HAI weighed
significantly less, and liver toxicity parameters were significantly increased
compared with those of all other groups; eight of nine rats showed severe
cholangiofibrosis. Body weights and liver toxicity parameters of the rats
treated with 20-min HAI were not statistically different from the control
group. In conclusion, duration of HAI with 4.4 µmol of fixed dose melphalan
did not affect tumor uptake and antitumor effect, but the resulting increase
in melphalan concentration had major impact on hepatobiliary toxicity.
Therefore, in a clinical setting, caution should be taken when infusion
duration and concentration of melphalan are changed.
Chemotherapeutic treatment is the therapy of choice when curative resection
of liver metastases is not possible, for instance because too many metastases
are present or the localization or size of these metastases precludes total
resection. In the treatment of liver tumors, hepatic artery infusion (HAI) of
cytostatics is favored because liver tumors are mainly vascularized by the
hepatic artery (Breedis and Young,
1954
; Sigurdson et al.,
1987; Wang et al.,
1994). Therefore, HAI of cytostatics leads to a more selective
tumor exposure when compared with systemic administration
(Sigurdson et al., 1987;
Rothbarth et al., 2002a).
Extensive preclinical and clinical research has been done on the antitumor
effect and hepatotoxicity of HAI with 5-fluorouracil and fluorodeoxyuridine
(Kemeny et al., 1992;
Lorenz and Muller, 2000);
currently HAI with these compounds is a well established treatment modality
for patients with colorectal liver metastases. Isolated hepatic perfusion
(IHP) is a relatively new local treatment for liver metastases and is only
applied in a few centers in the world
(Alexander et al., 1998;
Vahrmeijer et al., 2000).
Among others, fluorouracil (Aigner et al.,
1988) and melphalan (Alexander
et al., 2000; Vahrmeijer et
al., 2000; Bartlett et al.,
2001) have been used as cytostatics. IHP involves a method of
complete vascular isolation of the liver to allow treatment with drug doses
that would cause severe toxicity when applied systemically. During IHP, the
liver is isolated from the systemic circulation for 1 h to prevent systemic
exposure to high doses of melphalan
(Vahrmeijer et al., 2000;
Rothbarth et al., 2002b).
Based on the advantage of HAI in terms of tumor exposure to cytostatics,
melphalan is expected to be more effective if infused arterially during IHP.
In a preclinical study in rats (Marinelli
et al., 1991) and a phase I study in patients
(Vahrmeijer et al., 2000), the
maximum tolerated total doses of melphalan during IHP for both rats and
patients have been determined. A study in rats confirmed the importance of
arterial administration of melphalan
(Rothbarth et al., 2002a).
Nevertheless, the optimum conditions (duration and concentration) of the
intra-arterial melphalan infusion in relation to its antitumor effect and the
safety are not known. For instance, should the melphalan dose be infused over
a short or long period of time during the vascular isolation of the liver?
Obviously, a short infusion time of the cytostatic compound in a clinical
setting leads to a shorter duration of the whole procedure and therefore is
preferable, but only when the antitumor effect is equal or better and the
(hepato) toxicity is not increased. When a fixed dose of melphalan is infused
over a short period of time, the melphalan concentration of the infused volume
is higher, and the tumor is exposed to a higher melphalan concentration.
Conversely, when the same melphalan dose is infused over a longer period of
time, the tumor is exposed to a lower melphalan concentration but for a longer
period of time. We wanted to determine whether there is a difference in tumor
and liver uptake of melphalan, in antitumor effect and in hepatotoxicity,
between a short- and long-term infusion because this could have consequences
for the treatment strategy of our current clinical IHP program.
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Materials and Methods
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Chemicals. Melphalan was purchased from GlaxoSmithKline (Zeist, The
Netherlands). A melphalan solution (16.4 mM) was prepared by dissolving 1 mg
of melphalan in 200 µl of 0.09% (w/v) hydrochloric acid, which was
subsequently diluted with Gelofusine, a colloid solution of 4% gelatin in 0.9%
NaCl (Vifor Medical, Sempach, Switzerland) to a concentration of 480 µM;
the pH was adjusted to 7.4 with 1 N NaOH.
Rat Model for Colorectal Liver Metastases. The CC531 tumor cell line
used is a carcinoma of the colon, syngeneic for WAG/Rij rats
(Marquet et al., 1984). The
cells were cultured in medium that consisted of RPMI 1640 medium supplemented
with 10% (v/v) fetal calf serum, 2 mM L-glutamine, 50 µg/ml
streptomycin, and 50 IU/ml penicillin (Invitrogen, Breda, The Netherlands).
Cells were maintained by serial passage.
For tumor inoculation, exponentially growing cells were harvested by
trypsinization, washed twice in phosphate-buffered saline, and suspended at
1.0 x 107 tumor cells/ml. Male WAG/Rij rats (Harlan/CPB,
Zeist, The Netherlands), anesthetized using halothane, underwent laparotomy,
and tumor cells were inoculated at three or four sites by injecting 5 x
105 cells subcapsularly into the left and right main lobes and into
the right accessory lobes of the liver.
Surgical Procedures. The animals were anesthetized by an
intraperitoneal injection with a mixture of Hypnorm (fentanyl citrate, 0.315
mg/ml; fluanisone, 10 mg/ml) (Janssen Pharmaceutics, Beerse, Belgium) and
Dormicum (midazolam) (Roche Nederland B.V., Mijdrecht, The Netherlands).
Melphalan Concentration Study: Single Pass Liver Perfusion. Rats
bearing four liver tumors were used 12 days after tumor inoculation. At the
time of IHP, mean body weight was 289 ± 8 g (range 282–302). A
single-pass isolated hepatic perfusion with melphalan infusion in the hepatic
artery was performed in the normal flow direction, as previously described
(Pang and Terrell, 1981;
Rothbarth et al., 2002a). In
brief, after a V-line abdominal incision was made, the gastroduodenal artery
and the pyloric vein were tied off. The common hepatic artery was cannulated
with polyethylene tubing (PE-50, Ø 0.61 mm). Perfusion of the liver was
initiated upon cannulation of the portal vein with a 16-gauge double-needle
cannula. The inferior caval vein above the kidneys was tied to ensure
unidirectional flow, whereas the lower abdominal inferior caval vein close to
the extremities was severed to allow immediate drainage. The diaphragm was
then opened, and a 16-gauge cannula was placed in the suprahepatic inferior
caval vein through the right atrium to collect the outflow from the hepatic
veins. The liver was perfused through the hepatic artery and portal vein using
the caval vein for the outflow. The perfusion circuit consisted of a low-flow
roller pump (Watson-Marlow BV, Rotterdam, The Netherlands), an infusion pump
(perfusor; B. Braun, Melsungen, Germany), a collection reservoir/oxygenator
and a heat exchanger. The perfusate, consisting of Gelofusine with 20% (v/v)
outdated washed human erythrocytes (courtesy of the Blood Bank Leiden, The
Netherlands), was oxygenated (95% oxygen/5% carbon dioxide) and kept at
37°C. The pH was adjusted to 7.4 with sodium hydrogen carbonate 8.4%. The
liver was perfused through the portal vein at a flow rate of 10 ml/min and
through the hepatic artery at a flow rate of 1.0 ml/min; the melphalan
solution was added to the hepatic artery perfusate by an infusion pump at a
flow rate of 0.5 ml/min. At the end of the perfusion, a washout was performed
through the portal vein with 30 ml of ice-cold saline during 3 min. A total
amount of 0.9 mg (2.9 µmol) of melphalan was infused in the hepatic artery
in either 5 or 20 min. When the arterial infusion of melphalan was started,
samples of the effluent of the caval vein were taken at 0, 1, 2, 3, 4, 5, 10,
15, and 20 min. After the liver was excised, the tumors were removed from the
liver. All samples were stored at -70°C until analysis.
Melphalan Antitumor Effect and Toxicity Study in the Rat in Vivo.
Rats bearing three liver tumors were treated with HAI at 10 days after tumor
cell inoculation. At time of HAI treatment, mean body weight was 234 ±
10 g (range 215–255), and the mean cross-sectional tumor area was 26.3
mm2. For hepatic artery infusion, a cannula (PE-50, Ø 0.61
mm) was inserted into the gastroduodenal artery with the tip in the common
hepatic artery leaving normal arterial blood flow intact. After infusion, the
gastroduodenal artery was tied off. For systemic infusion a cannula (PE-50,
Ø 0.61 mm) was inserted in a lumbar vein, which was tied off after
infusion. The rats were randomly assigned to the following treatment groups:
1) 25 min of saline via HAI (control group), 2) 10 min of systemically infused
melphalan and 25 min of saline via HAI (systemic melphalan group), 3) 5 min of
melphalan followed by 20 min of saline via HAI (5-min HAI melphalan group),
and 4) 20 min of melphalan followed by 5 min of saline via HAI (20-min HAI
group). All melphalan-treated rats received a total dose of 1.35 mg (4.4
µmol) of melphalan infused over a period of 5, 10, or 20 min. HAI was
performed with an infusion pump (perfusor; B. Braun) at a flow rate of 25
µl/min. Before treatment, the cross-sectional tumor area was determined
(estimated by caliper measurements and calculated as: 
x 0.25
x largest diameter x perpendicular diameter). Toxicity was
assessed by effects on survival, body weight (4 days, 1 week, and 2 weeks
after treatment), serum levels of sodium (Na), potassium (K), creatinine,
bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline
phosphatase (blood samples at day of tumor cell inoculation and 1 week and 2
weeks after treatment). To determine the antitumor effect of the different
treatments, rats were sacrificed 2 weeks after treatment, the tumors were
weighed, and the tumor growth index was calculated. The tumor growth index was
defined as cross-sectional tumor area 2 weeks after treatment divided by the
cross-sectional tumor area at day of treatment. After the rats were
sacrificed, the livers were examined macroscopically and microscopically. For
histological examination, 5-µm thick cryosections were cut from snap frozen
liver tissue. Sections were dried overnight at 60°C and fixed in acetone.
Sections were stained with H&E.
Melphalan Concentration Assay. The concentration of melphalan in the
effluent samples, as well as in tumor and liver tissue samples, was measured
using high-performance liquid chromatography assay, as previously described
(Rothbarth et al., 2002a).
Statistical Analysis. All data were analyzed with SPSS statistical
software (version 9.0 for Windows; SPSS, Inc., Chicago, IL). Correlation
coefficients were calculated using the paired Student's t test. A
p value <0.05 was considered statistically significant.
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Results
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Melphalan Concentration Study: Single-Pass Liver Perfusion. We
investigated tumor and liver uptake of melphalan in a single-pass IHP after 5-
and 20-min arterial infusion of a fixed dose of melphalan; tumor-bearing rat
livers were perfused for either 5- or 20-min with a total dose of 0.9 mg (2.9
µmol) of melphalan in the hepatic artery in each case. The melphalan dose
was based on the dose currently used in the clinical IHP (3.0 mg
kg-1) (Vahrmeijer et
al., 2000). High-performance liquid chromatography analysis of
tumor and liver tissue revealed that uptake in both tumor and liver of
arterially infused melphalan was indeed very similar in the two groups
(Fig. 1). There was no
statistical difference in the tumor and liver content of melphalan after
either 5- or 20-min single-pass IHP. As expected
(Rothbarth et al., 2002a),
melphalan concentration in tumor tissue was much higher than in liver tissue
in both groups (p < 0.05). A rapid extraction of melphalan by the
liver and tumor occurred during the first 5 min in both groups
(Fig. 2); in the 20-min HAI
group, steady state was reached after 10 min. In concordance with the arterial
inflow concentrations in the 5- and 20-min HAI groups (0.12 and 0.03 mg
ml-1, respectively), the concentration of melphalan in
the effluent of the 5-min HAI was approximately 4 times higher than that of
the 20-min HAI group (Fig.
2).
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Fig. 1. Mean concentration of melphalan in tumor and liver tissue (±S.D.)
after single-pass isolated hepatic perfusion with arterial administration of a
fixed dose melphalan in 5 or 20 min (n = 5).
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Melphalan Antitumor Effect and Toxicity Study in the Rat in Vivo.
For the study on the antitumor effect and toxicity after different modes of
melphalan administration, nine rats were treated with 5-min HAI with
melphalan; in the control, systemic melphalan and 20-min HAI melphalan groups
eight rats were treated. Four of the nine rats in the 5-min HAI melphalan
group died or were sacrificed because of bad physical condition before the end
of the experiment (two at day 6, one at day 8, and one at day 10 after
treatment). The antitumor effect could not be evaluated in one surviving rat
because necrotic cavities filled with pus were present at the tumor sites;
therefore, the volume of tumor tissue could not be assessed. As a result, the
antitumor effect after treatment could only be evaluated in four of nine rats
in the 5-min HAI melphalan group. In the other three groups, none of the rats
died prematurely, and antitumor effect after treatment was evaluable in all
rats. There was no statistically significant difference between the antitumor
effect of a 5- and 20-min HAI with melphalan, as determined by both the tumor
growth index and the average tumor weight at the end of the experiment
(Table 1). The 5- and 20-min
HAI melphalan groups showed a strongly decreased tumor weight and tumor growth
index compared with the control group (p < 0.05). The antitumor
effect was 2 times higher when compared with the group that received
systemically administered melphalan (p < 0.05 for 20-min HAI
melphalan group; p = 0.18 for the 5-min HAI melphalan group), as
determined by the tumor growth index. The average tumor weights of the 5- and
20-min HAI melphalan groups were 6 to 10 times lower than of the control group
(p < 0.05) and 2 to 3 times lower than of systemically
administered melphalan group (p < 0.05 for 20-min HAI melphalan
group; p = 0.11 for the 5-min HAI melphalan group).
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TABLE 1 Antitumor effect on rat liver tumors after different modes of melphalan
administration
Tumor growth index and tumor weight 2 weeks after treatment. The tumor
growth index was defined as cross-sectional tumor area 2 weeks after treatment
divided by the cross-sectional tumor area at day of melphalan treatment.
Values are the mean ± S.D.
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Rat body weight was strongly affected by the type of treatment
(Fig. 3). Rats treated with
5-min HAI with melphalan weighed significantly less than rats of all other
groups at 4 days, 1 week, and 2 weeks after treatment (p < 0.05).
As mentioned before, four rats of this group (5-min HAI) died before the end
of the experiment; at the time of death, mean body weight was 171 ± 7 g
(range 161–176). Rats treated with 20-min HAI or with systemically
administered melphalan initially weighed less than those of the control group
at 4 days (p < 0.05 both groups) and 1 week (p < 0.05
systemic melphalan group only) after treatment
(Fig. 3). Two weeks after
treatment, however, there was no statistical difference between the body
weights of the rats treated with systemic and 20-min HAI melphalan on one hand
and the control group on the other. In the control, systemic melphalan, and
20-min HAI melphalan groups, no changes in serum levels of sodium, potassium,
creatinine, and liver toxicity parameters (aspartate aminotransferase, alanine
aminotransferase, alkaline phosphatase, and bilirubin) were found 1 and 2
weeks after treatment. Liver toxicity parameters of the 5-min HAI melphalan
group were significantly higher compared with those of all other groups both 1
and 2 weeks after treatment (p < 0.05)
(Table 2).
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TABLE 2 Effect of the different treatments on blood serum levels
Levels of sodium (Na), potassium (K), creatinine, aspartate
aminotransferase (ASAT), alanine aminotransferase (ALAT), and alkaline
phosphatase (AP) levels 1 and 2 weeks after melphalan treatment. Values are
median (S.D.).
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Macroscopic examination of the rat livers showed clear signs of cholestasis
in eight of the nine rats treated with 5-min HAI and one of the rats treated
with 20-min HAI with melphalan: massive bile accumulation in the liver,
yellow-spotted livers, yellow-brown skin and sclera, and swelling and
obstruction of the bile duct were observed. In addition, sera of these rats
were yellow-colored. All rats showing macroscopic signs of cholestasis had
elevated bilirubin levels 1 week (mean 42 µM, range 6–76) and 2 weeks
(mean 97 µM, range 32–168) after treatment. Microscopic examination
of these rat livers showed atypical glandular structures lined by basophilic,
occasionally dysplastic epithelium ranging from flattened to cuboidal cells.
The presence of connective tissue in all of these rat livers indicated
cholangiofibrosis (Goodman et al.,
1994) (Fig. 4).
None of the other rats showed macroscopic signs of cholestasis or histological
signs of cholangiofibrosis.
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Fig. 4. Histological section of a control rat liver (a) and a rat liver treated
with 5-min HAI with melphalan (b) (H&E; 200x). The control rat liver
(a) shows a normal bile duct (thin arrow). The rat liver treated with 5-min
HAI with melphalan shows severe cholangiofibrosis (b). This lesion is
characterized by atypical glandular structure lines by basophilic,
occasionally dysplastic, epithelium ranging from flattened to cuboidal cells
(thin arrow). Connective tissue is clearly present. Multifocal areas of
cholangiofibrosis often are continuous with one another as is also the case in
this figure (thick arrow).
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Discussion
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Local administration of cytostatics in the hepatic artery leads to more
selective liver tumor exposure (Sigurdson
et al., 1987; Rothbarth et
al., 2002a) and consequently to safer tumor treatment when
compared with systemic administration of cytostatics, including higher tumor
response rates. This has been confirmed by many clinical studies
(Chang et al., 1987;
Kemeny et al., 1987;
Hohn et al., 1989;
Kemeny, 1995;
Vahrmeijer et al., 1995;
Meta-Analysis Group in Cancer,
1996; Lorenz et al.,
2001). No information is available on the optimum infusion
duration, however. A short infusion time of the cytostatic compound in a
clinical setting obviously leads to a shorter duration of the whole procedure
and therefore is preferable. This study was performed to find out how infusion
duration of melphalan affects tumor melphalan uptake and antitumor efficacy on
one the one hand and liver toxicity on the other.
Our results show that there is no difference in tumor and liver uptake of
melphalan after short-term (5 min) or long-term (20 min) arterial infusion of
a fixed dose of melphalan. Evidently, when the total administered amount of
melphalan (based on a clinically relevant dose) is equal, neither duration of
melphalan exposure nor melphalan concentration affect the tumor and liver
uptake of melphalan within the conditions of our experiment. Based on these
results, no differences in antitumor effect would be expected after 5- or
20-min arterial infusion either; melphalan exerts its cytotoxic effect by
formation of DNA-adducts (Kohn,
1981), and a clear correlation has been observed between melphalan
concentration, level of melphalan-derived DNA-adducts, and
(Tilby et al., 1993)
cytotoxicity (Hansson et al.,
1987; Tilby et al.,
1993; Frank et al.,
1996).
Indeed, there was no significant difference in antitumor effect between 5-
and 20-min arterial infusion of the fixed dose of melphalan (p <
0.05). To exclude the possibility that this equal antitumor effect was simply
due to the fact that all rats in these two groups received an equal amount of
melphalan and, therefore, had an equal total body exposure of melphalan,
another group of rats was treated systemically with the same amount of
melphalan. In this group, the antitumor effect was 2 to 3 times less when
compared with the HAI groups. Therefore, the additional antitumor effect of
melphalan in both the 5- and 20-min HAI group must be due to the arterial
administration of melphalan; this confirmed the route-dependent effect of
melphalan administration. Thus, the antitumor effect of 5- and 20-min HAI is
equal, and because a shorter infusion time is desirable, 5-min HAI would be
preferred.
Unfortunately, the group of rats treated with 5-min HAI with melphalan
experienced major hepatobiliary toxicity. Histochemical examination showed
cholangiofibrosis in the liver of our rats, which histopathologically is
similar to biliary sclerosis in humans, a well known complication of
arterially infused fluorodeoxyuridine
(Hohn et al., 1985;
Kemeny et al., 1992;
Rougier et al., 1992;
Lorenz and Muller, 2000).
The fact that mainly biliary toxicity is seen in hepatic arterial infusion
therapy might be explained by the difference in arterial and portal blood
supply between bile ducts and liver parenchyma. The liver parenchyma is
perfused by the hepatic artery and portal vein at physiologic ratio of
arterial to portal flow of about 1:3
(Rappaport, 1980;
Watanabe et al., 1994). Bile
ducts, however, are, mainly vascularized by the hepatic artery and not the
portal vein (Mitra, 1966;
Northover and Terblanche,
1979; Cho and Lunderquist,
1983), just like liver tumors
(Breedis and Young, 1954;
Sigurdson et al., 1987;
Wang et al., 1994).
Consequently, the bile duct is exposed to a much higher drug concentration
compared with the liver parenchyma when infused in the hepatic artery. Liver
parenchyma is not exposed to the high arterial concentration because
arterially infused drugs are substantially diluted by portal venous blood.
This may be the explanation for the fact that mainly hepatobiliary toxic
effects occur after hepatic arterial drug infusion, as is the case in our
experiments.
In the current experiments, the tumor response was not affected by
melphalan concentration as long as the tumors were exposed to the same amount
of melphalan. Unfortunately, the concentration-toxicity curve appeared to be
very steep, indicating that once the toxicity threshold concentration is
reached, a small increase in melphalan concentration leads to a large increase
in toxicity.
How would these results "translate" to the clinical situation?
Assuming that hepatic arterial flow in the our rats was between 1 and 3 ml
min-1 (
4.3 to 12.8 ml min-1
kg-1) (Daemen et al.,
1989; Tanaka et al.,
1999), the calculated arterial melphalan concentration was 0.02 to
0.05 mg ml-1 for the 20-min HAI and 0.07 to 0.20 mg
ml-1 for the 5-min HAI group. In our current clinical
IHP, a total of 200 mg of melphalan is infused over 20 min in the hepatic
artery at a flow rate of 100 ml min-1, resulting in a
concentration of 0.1 mg ml-1. As this is already within
the concentration range of the 5-min HAI group and as most patients already
experience a transient elevation of liver toxicity parameters (unpublished
data), a further increase in hepatic arterial infusion concentration is not
favored. Consequently, caution should be taken when the infusion concentration
of melphalan of such a treatment regimen is increased.
In conclusion, the current results reveal that the duration of HAI with a
fixed dose melphalan does not affect the tumor uptake of melphalan and the
antitumor effect but that relatively small changes in melphalan concentration
in the hepatic artery can have major impact on hepatobiliary toxicity.
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Acknowledgements
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We thank Drs. R. I. J. M. Aalbers, F. H. van Duijnhoven, and G. M. van
Brakel for the technical assistance.
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Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
DOI: 10.1124/jpet.103.049379.
This study was supported by Grant 2000-2198 from the Dutch Cancer Society
(K.W.F.).
ABBREVIATIONS: HAI, hepatic artery infusion; IHP, isolated hepatic
perfusion.
Address correspondence to: Dr. G. J. Mulder, Division of Toxicology,
LACDR, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
E-mail:
g.mulder{at}lacdr.leidenuniv.nl
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Abstract
Materials and Methods
) or 20 min (
) (n = 5).
, systemic melphalan (n = 8);