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1125
Regional Perfusion with Hemofiltration
(Chemofiltration) for the Treatment of Patients with
Regionally Advanced Cancer
Mordechai Gutman, M.D.'
Subhi Abu-Abid, M.D.'
Patrick Sorkine, M.D?
Moshe Inbar, M . o . ~
Dina Lev, M.D.'
Zipora Chen, M . D . ~
Dan Oron, M.D."
Samario Chaitchik, M . D . ~
Joseph M. Klausner, M.D.'
'
Department of Surgery B&C, Sourasky Tel
Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv, University, Tel Aviv, Israel.
Department of Intensive Care, Sourasky Tel
Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv, University, Tel Aviv, Israel.
Department of Oncology, Sourasky Tel Aviv
Medical Center, Center, Sackler Faculty of Medicine, Tel Aviv, University, Tel Aviv, Israel.
Department of lnvasive Radiology, Sourasky
Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv, University, Tel Aviv, Israel.
Supported by the Nicholas & Elizabeth Slezak
Fund for Experimental Surgery, Tel Aviv University, Israel.
Address for reprints: Joseph M. Klausner, M.D.,
Professor and Head of Surgery, Sourasky Tel
Aviv Medical Center, 6 Weizmann Street, Tel
Aviv 64239, Israel.
Received July 21, 1995; revision received November 24, 1995; accepted February 20, 1996
0 1996 American Cancer Society
BACKGROUND. Regionally advanced cancer is a common, often unresolved problem. Effective local control with chemotherapy is limited by the toxicity following
systemic administration. Chemofiltration (CF) is a form of regional perfusion that
enables the administration of cytotoxic drugs into one body area while limiting
systemic toxicity. The drug is infused into the artery supplying the involved area.
The venous effluent of the same organ is pumped out into a hemofiltration unit
at a high flow rate. The drug is then filtered away and the blood returned to
systemic circulation.
METHODS. Forty-one patients underwent 45 CF. Twenty-four patients had CF of the
pelvis for advanced rectal carcinoma (101, malignant melanoma (6),and cancers of
the uterine cervix (3),ovary (2), vulva (11, endometrium ( l ) ,and anus (1).Seventeen
patients underwent CF of the liver for metastatic colon (101, breast (41, pancreas
(I), ovary (l),and unknown primary (1) cancer. 5-fluorouracil (1 g/m2) and mitomycin-C (30 mglm2); cisplatinum (200 mglm2) alone or combined with bleomycin
(50 mg/m2) and mitomycin-C (20 mg/m2); or melphalan (1 mg/kg) were the combinations used.
RESULTS. Generally the procedure was well tolerated. Complications included
transient leukopenia (18), paralytic ileus (2), hair loss (21, renal failure (1). Two
patients died within 40 days following CF. Of 36 evaluable patients, 16 (44%) had
partial response, 14 (38%)had stable disease, and 6 (18%) had disease progression.
A decrease of at least 30% in carcinoembryonic antigen levels occurred in 12 of
24 patients (50%). Median time to progression was 7 months. Ten of 13 patients
(77%) achieved good symptomatic palliation.
CONCLUSIONS. The results of CF in our study are not superior to alternative methods of drug delivery to the liver and pelvis. However, considering that previous
systemic chemotherapy had failed two-thirds of the patients, some benefit may
be attributed to this regional delivery modality. Furthermore, pelvic CF afforded
very significant symptomatic relief which was definitely superior to other methods.
Cancer 1996; 7 8 1125-30. 0 1996 American Cancer Society.
KEYWORDS: regional perfusion, chemofiltration, regionally advanced cancer, liver
metastasis, pelvic cancer.
R
egionally advanced cancer (RAC) represents a common yet often
unresolved problem: patients with large, nonresectable recurrent
or metastatic tumor confined to one region causing disabling symptoms and eventually death. With colorectal cancer, 65% of the patients
develop liver metastases, this being the only metastatic site in half of
them.' The liver can also be the sole site of metastasis in patients with
cancers of the stomach, pancreas, breast, etc. The pelvis is another
common site of RAC. More than 30% of patients with rectal cancer,
1126
CANCER September 1, 1996 / Volume 78 / Number 5
YlOTOXlC DRUG
ULTRAFILTRATE
FIGURE 1. Liver chemofiltration. The drugs are injected into an hepatic
arterial catheter, which is placed at laparotomy or angiographically. A
16F catheter is inserted into the inferior vena cava, and connected to a
hemofiltration unit. The detoxified blood and substitution fluid are infused
back to the patient via a catheter in the superior vena cava.
-5V85TITUTION
FLUID
I
section, attempts at local control mainly include irradiation or chemotherapy. Radiotherapy is of some
benefit especially with rectal cancer. Currently, systemic chemotherapy has a low therapeutic index since
dosage is limited by toxicity to normal tissue^.^ To
increase the therapeutic index of chemotherapy, regional perfusion techniques were developed. Intra-arterial administration of cytotoxic drugs (CD) has
slightly increased the response rate. However, since
the drug is still distributed systemically from the venous effluent of the infused organ and the dosage cannot be significantly increased, systemic toxicity is not
Attempts to limit systemic toxicity by means of
vascular isolation led to the development of isolated
limb perfusion (ILP) which enables delivery of very
high doses of CD with total vascular isolation of the
perfused organ using tissue oxygenation by a heartlung machine. This method is especially suitable for
cancer confined to the limbs, mainly malignant melanoma or sarcoma, since the main blood vessels can
be easily isolated. As expected, the response rate is
superior to systemic treatment and systemic toxicity
is virtually eliminated.8 Obviously it is difficult to implement this technique in the trunk or abdominal viscera due to the complexity of their blood h up ply.^ Recently a method has been developed which enables
the delivery of high dose CD to organs such as the
liver or pelvis, while reducing systemic toxicity by concomitant detoxification of the venous effluent of the
infused organ by hemofiltration.'0-'2 Presented is our
initial experience with 41 cancer patients with RAC in
the liver or pelvis who were treated by chemofiltration
(CF1.
MATERIALS AND METHODS
FIGURE 2. Pelvic chemofiltration. The drugs are injected into a catheter
placed angiographically in the aorta just belowthe renal arteries. Pneumatic
tourniquets are used to occlude the blood flow to the limbs. The venous
pelvic blood is pumped out to the hemofiltration unit. The detoxified blood
and substitution fluid are infused back to the patient via a central venous
catheter.
as well as those with cancers of the urinary bladder or
female genitalia, develop pelvic RAC.2,3These patients
are usually highly symptomatic, with pain, tenesmus,
and discharge being the most common complaints.
Since most RAC are not amenable to surgical re-
During the past 2 years, 41 patients underwent 45 CF.
There were 26 females and 15 males. The average age
was 56 years (range: 21-81 yrs). Seventeen patients
had metastatic cancer confined to the liver, originating
in the colorectum (lo), breast (41, pancreas (11, ovary
(l),and unknown (1). Twenty-four patients had RAC
confined to the pelvis, the origin being the rectum
( lo), lymph node metastases of malignant melanoma
( 6 ) )ovary (2) endometrium ( l ) ,uterine cervix (31, vulva
( I ) , and anus (1). Twenty-seven of the 41 patients
(67%) had received previous systemic chemotherapy
and were referred to CF due to treatment failure and
tumor progression.
Treatment Protocol
Liver chemofiltration
An hepatic arterial catheter was placed angiographically (10 patients) or during laparotomy (7 patients).
Chernofiltration/Gutrnan et al.
1127
TABLE 1
Drugs Used in Chemofiltration
Primary tumor
Cytotoxic drugs
No. of patients
Colon-rectum
Uterine, cenix and endometrium
Malignant melanoma
Mitomycin-C 30 mglm’ & 5-FU 1000 mglm’
Cisplatinum 200 mg/m2 & mitomycin-C 20 rnglm’
Melphalan 0.8-1.2 mglkg
or cisplatinum 200 mg/mZ
Melphalan 1.2 rnglkg, mitomycin-C 25 mglm’ & 5-FU 750 mglm’
Mitomycin-C 20 mglm’, bleomycin 50 mglm’ & cisplatinum 200 mglm2
Mitomycin-C 30 mglm2 & 5-FU 750 mglm‘
Mitomycin-C 30 mglm’, cisplatinum 100 mglm’ & 5-FU 1500 mglm’
Mitomycin-C 30 rnglm’ & 5-FU 750 mglm’
Mtomycin-C 30 mglm’ & 5-FU 1000 mglm*
20
Ovary
Vulva
Breast
Anus
Pancreas
Unknown
The tip of the arterial catheter was situated distal to
the bifurcation of the gastroduodenal artery to avoid
infusion of the duodenum and jejunum. A large bore
(16F) catheter was inserted into the inferior vena cava
via a cutdown in the saphenous vein (13 patients),
femoral vein (31, or directly during laparotomy (1).
Using fluoroscopic guidance, the tip of the catheter
was positioned at the level of the diaphragm distal to
the entrance of the hepatic veins. The venous catheter
was then connected to a Gambro hemofiltration unit
(Gambro Instruments, Lund, Sweden) using a 1.2 m2
hollow tube filter (Fig. 1). A balanced hemofiltration
was established at a rate of 500 to 750 mL per minute.
The detoxified (filtered) blood was infused to the superior vena cava via a large bore (Vygon 8F) central venous catheter. It was supplemented by Ringer’slactate
solution (preheated to 38 “C) infused at the same rate
as the efflux of the ultrafiltrate, thus assuring an essentially zero balance. The anesthetized, fully heparinized
patients were carefully monitored, and further fluid
replacement was given to maintain normal hemodynamics. Once stable extracorporeal hemofiltration was
established, the CD was infused into the arterial catheter using an automatic infusion pump over 10 to 30
minutes, depending on the drug. After CD administration, CF was continued for an additional 30 minutes
to ascertain further CD clearance.
Pelvic chemofiltration
An arterial catheter was angiographically placed in the
aorta just distal to the renal arteries. The venous large
bore catheter was inserted into the inferior vena cava
via a saphenous cutdown (22 patients) or femoral venotomy (2 patients), its tip reaching the same level as
the arterial catheter. Blood flow to both lower limbs
was occluded using a pneumatic tourniquet. In melanoma patients, when metastases were confined to one
leg and the pelvis, the pneumatic tourniquet was ap-
4
5
1
3
1
4
1
1
1
plied only to the contralateral leg. The remaining details are identical to liver CF (Fig. 2).
Drugs
Cytotoxic drug combinations were mostly based on
high dose mitomycin-C. They included mitomycin-C
and 5-fluorouracil (5-FU) for cancer of the colon, rectum, breast, pancreas, and ovary, and a combination
of bleomycin, cisplatinum, and mitomycin-C for vulvar cancer. Phenylalanin-mustard (melphalan),at the
same dose used for isolated limb perfusion (0.8-1.2
mg/kg), or high dose cisplatinum were used for malignant melanoma. The doses are detailed in Table 1.
Response Criteria
All patients had measurable lesions. The lesions were
measured prior to, and 4, and 8 weeks following CF.
Complete response (CR) was defined as the disappearance of all known disease determined by 2 observations not less than 4 weeks apart. Partial response (PR)
was defined as a 250% decrease in total tumor load
of the lesions lasting > 4 weeks.I3
RESULTS
Forty-one patients successfully completed CF of the
liver (17) or pelvis (24). Two patients underwent an
additional CF of the liver (1)and pelvis (11, and a third
patient had two additional liver CF. A filtration flow
rate of at least 500 mL per minute was achieved, with
an average ultrafiltration of 11,500 mL (9400- 16000
mL). The extensive fluid exchange was well tolerated
in all but two patients; one developed hypotension
and hypoxemia at the beginning of the procedure
which was terminated before injection of CD. The patient was offered a second attempt to be performed
after extensive hydration, but he refused and therefore
is not included in this series. A second patient developed extreme bradycardia (20/min) and hypotension.
1128
CANCER September 1, 1996 / Volume 78 / Number 5
The procedure was suspended and reperformed successfully 48 hours later, after assuring intact cardiac
and neurologic function.
Two patients died within 40 days following CF.
The first, a male age 68 years, who had multiple liver
metastases of rectal cancer with marked weight loss
and severely impaired liver function, developed pneumonia with respiratory insufficiency which led to his
death 28 days after the procedure. The second was a
female, age 55 years, with a large, nonresectable pancreatic cancer and multiple liver metastases. During
CF, CD were infused to the common hepatic artery to
deliver CD to the pancreatic head via the gastroduodenal artery. Afterwards, the patient had severe gastrointestinal (GI) toxicity and developed respiratory failure
necessitating prolonged ventilation, leading to her
death after 40 days.
Complications attributed to the surgical procedure were observed in 9 of 45 CF (20%)and included
wound hematoma (41, infection (21, deep vein thrombosis (11, pulmonary embolism (11, and pneumothorax (1).
Complications attributed to CD were observed in
22 of 45 CF (48%) and included mild leukopenia
(>lo00 mmi) in 9 patients, severe (<lo00 mm3) in
another 7, and thrombocytopenia in 1. Of the 16 patients who developed leukopenia, 15 (94%) had received previous systemic chemotherapy. Two patients
developed a prolonged paralytic ileus after liver CF.
Partial hair loss was observed in another two patients,
and one, who received cisplatinum in two sequential
pelvic CF, developed moderate renal failure.
Measurable disease could be evaluated in the follow-up of 36 of the 41 patients. Of the remaining five
nonevaluable patients, two died, another had his entire tumor mass (pelvic malignant melanoma) resected, and in two, insufficient time elapsed. There
was no CR. A PR was observed in 16 of 36 patients
(44%).Time to progression in this group was 7 months
(3-22 mos). Fourteen patients (39%)showed stabilization of their disease (SD). Six (16%) experienced disease progression (PD).
Of 14 evaluable patients who underwent liver CF,
7 (50%)had PR and another 5 (37%)SD. Of 22 patients
who underwent pelvic CF and had a measurable tumor, 9 (41%) had PR and 9 (41%) SD (total 82%). PR
was notable in one patient with an inoperable rectal
cancer who underwent CF as a first line treatment.
The tumor’s size was markedly reduced and she underwent an abdominoperineal resection 4 weeks after
CF. The patient is disease-free 20 months afterwards.
PR was demonstrated also in two of four melanoma
patients, and in each of the patients with ovarian, cervical, or vulvar cancer.
Marked symptomatic relief occurred in 10 of 13
(77%) highly symptomatic patients, 2 of whom underwent pelvic CF despite pulmonary metastases due to
huge pelvic masses, causing agonizing pain, discharge,
and tenesmus. In both cases, only SD was achieved
but quality of life was significantly improved.
DISCUSSION
The main theoretical advantage of CF is the ability to
deliver higher doses of CD directly to the tumor, while
the concomitant hemofiltration limits side effects to
an acceptable range. The close relationship between
dosage and response rate has long been established,
and even a small increment in dose may result in a
significant improvement in the response rate.14-”
When relatively low doses are administered, drug resistance and DNA repair commonly occur. This phenomenon has been demonstrated in a variety of CD,
especially alkylating agents and antibiotics, using in
vitro assays and in human studies.’8-20
Indeed, CF achieved high local concentrations of
CD and although pharmacodynamic measurements in
the infused organ, systemic blood, and ultrafiltration
were not performed in the current study, it has been
well demonstrated that CD levels in the perfused tissues during CF were 4 to lox greater compared with
other nonperfused
This would explain the
feasibility of administering mitomycin-C at a dose of
30 mg/m2 which is about 3-fold the usual dose” or
melphalan which is rarely administered systemically
due to its toxicity. The high doses of CD delivered in
CF led to a response rate of 44% (PR), and if SD are
included, 83%,in patients with advanced regional cancer, many of whom (67%) experienced disease progression after previous systemic chemotherapy. Although inferior to ILP, where a 6 to 20-fold increase
in the administered CD dosage leads to a 10 to 20fold increment in tissue CD levels, and hence a much
greater response
CF still demonstrates some
advantages over conventional systemic therapy.
The usual systemic dosage of mitomycin-C is 10
mg/m2.Even at this dosage it is considered to be toxic
and therefore its use is limited. It is considered one of
the drugs of choice in the regional setting and indeed
was the base for the treatment combination in 35 of
the 41 patients in our series. Only those patients with
melanoma did not receive mitomycin-C. The precise
influence of 5-FU remains speculative but given the
fact that most of the patients in this series had previously failed with 5-FU based therapy, it can be assumed that the addition of another drug, i.e., mitomycin-C, was of major impact. Furthermore, the dosage
of mitomycin-C was two to three times greater than
the usual systemic one.
ChemofiItration/Gutman et al.
The most impressive effect of CF was the palliative
one observed among the pelvic CF patients. Seventyseven percent of patients suffering from disabling
symptoms, such as pain, secretions, and tenesmus reported a significant improvement in their quality of
life. This effect was not related to the magnitude of
the objective response, leading us to conclude that it
was not necessarily due to a cytotoxic response of CF,
but rather to a plausible form of neurotoxicity.
However, CF does have several disadvantages: it
is an invasive procedure, associated with general anesthesia, angiography, operation, heparinization, and
massive fluid exchange. Despite filtration of the CD,
related complications are still encountered. Since CF is
a semiclosed technique, unlike isolated limb perfusion
which enables total vascular isolation, one cannot expect to pump out all the venous effluent from the liver
or the pelvis into the hemofiltration unit, and therefore
a significant portion of the infused CD “leaks” into
the systemic circulation. Furthermore, serum proteins
may bind to the CD and due to their large molecular
weight are not filtered thus contributing to systemic
toxicity. Previous studies estimated the “leakage” to
the systemic circulation at 30 to 70%.” Considering
the fact that the infused dose of CD is sometimes 3fold the conventional one, even a 30% leak can be
significant.
Hemofiltration is most effective in recapturing CD
which are of small molecular weight and low ability
to bind to serum proteins. Fortunately, many CD are
in this category, and as shown by Aigner et al.,’”commonly used CDs, such as mitomycin-C, 5-FU, cisplatir u m , and adriamycin are suitable for the procedure.
Antimetabolites such as methotraxate and actinomycin-D are considered to be less suitable for CF.
The 44% response rate which consisted of PR is
not better than that obtained by other locoregional
methods. Coupled with the relatively short time to
progression (7 m), it seems that CF is not effective
enough. There are several factors which could explain
the lack of significant improvement in response rate
to be expected with a 2 to 3-fold increase in dose.
Infusion of high dose CD into an organ does not
guarantee high tumor concentrations. There are two
major obstacles to the distribution of drugs in a tumor.
One is the nonuniform blood supply resulting in areas
of hypoperfusion within the tumor.24The other is the
abnormally high interstitial pressure within tumors,
measuring up to lox more than the adjacent normal
l i s ~ u e sThe
. ~ ~efficacy of CD which to penetrate tumor
cells may also be hindered by the development of drug
resistance in patients previously treated with systematically administered CD.
The results of CF in our study were not superior
1129
to alternative methods of drug delivery. On the surface,
CF might not be justified. However, it should be emphasized that these results were obtained in a selected
group of patients, two-thirds of whom failed systemic
delivery of chemotherapy. In addition, CF is a single
procedure compared with prolonged systemic treatments.
Based on our results, we cannot state that CF is
superior to other methods. However, its palliative effect, especially in pelvic cancer patients, merits its use
in selected cancer patients.
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